Sarfaraz K. Niazi-Handbook of Pharmaceutical Manufacturing Formulations Series, Second Edition, Volume 5_ Over-The-Counter Products (2009)

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V O L U M E

F I V E

Second Edition

Handbook of

Pharmaceutical Manufacturing Formulations

Over-the-Counter Products

S a r f a r a z K. N i a z i Pharmaceutical Scientist, Inc. Deerfield, Illinois, USA

Handbook of Pharmaceutical Manufacturing Formulations Second Edition Volume Series Sarfaraz K. Niazi Volume 1 Handbook of Pharmaceutical Manufacturing Formulations: Compressed Solid Products Volume 2 Handbook of Pharmaceutical Manufacturing Formulations: Uncompressed Solid Products Volume 3 Handbook of Pharmaceutical Manufacturing Formulations: Liquid Products Volume 4 Handbook of Pharmaceutical Manufacturing Formulations: Semisolid Products Volume 5 Handbook of Pharmaceutical Manufacturing Formulations: Over-the-Counter Products Volume 6 Handbook of Pharmaceutical Manufacturing Formulations: Sterile Products

Informa Healthcare USA, Inc. 52 Vanderbilt Avenue New York, NY 10017  C

2009 by Informa Healthcare USA, Inc. Informa Healthcare is an Informa business No claim to original U.S. Government works Printed in the United States of America on acid-free paper 10 9 8 7 6 5 4 3 2 1 International Standard Book Number-10: 1-4200-8116-0 (Volume 1; Hardcover) International Standard Book Number-13: 978-1-4200-8116-9 (Volume 1: Hardcover) International Standard Book Number-10: 1-4200-8118-7 (Volume 2; Hardcover) International Standard Book Number-13: 978-1-4200-8118-3 (Volume 2; Hardcover) International Standard Book Number-10: 1-4200-8123-3 (Volume 3; Hardcover) International Standard Book Number-13: 978-1-4200-8123-7 (Volume 3; Hardcover) International Standard Book Number-10: 1-4200-8126-8 (Volume 4; Hardcover) International Standard Book Number-13: 978-1-4200-8126-8 (Volume 4; Hardcover) International Standard Book Number-10: 1-4200-8128-4 (Volume 5; Hardcover) International Standard Book Number-13: 978-1-4200-8128-2 (Volume 5; Hardcover) International Standard Book Number-10: 1-4200-8130-6 (Volume 6; Hardcover) International Standard Book Number-13: 978-1-4200-8130-5 (Volume 6; Hardcover) This book contains information obtained from authentic and highly regarded sources. Reprinted material is quoted with permission, and sources are indicated. A wide variety of references are listed. Reasonable efforts have been made to publish reliable data and information, but the author and the publisher cannot assume responsibility for the validity of all materials or for the consequence of their use. No part of this book may be reprinted, reproduced, transmitted, or utilized in any form by any electronic, mechanical, or other means, now known or hereafter invented, including photocopying, microfilming, and recording, or in any information storage or retrieval system, without written permission from the publishers. For permission to photocopy or use material electronically from this work, please access www.copyright.com (http://www.copyright.com/) or contact the Copyright Clearance Center, Inc. (CCC) 222 Rosewood Drive, Danvers, MA 01923, 978-750-8400. CCC is a not-for-profit organization that provides licenses and registration for a variety of users. For organizations that have been granted a photocopy license by the CCC, a separate system of payment has been arranged. Trademark Notice: Product or corporate names may be trademarks or registered trademarks, and are used only for identification and explanation without intent to infringe. Library of Congress Cataloging-in-Publication Data Niazi, Sarfaraz, 1949– Handbook of pharmaceutical manufacturing formulations / Sarfaraz K. Niazi. – 2nd ed. p. ; cm. Includes bibliographical references and index. ISBN-13: 978-1-4200-8106-0 (set) (hardcover : alk. paper) ISBN-10: 1-4200-8106-3 (set) (hardcover : alk. paper) ISBN-13: 978-1-4200-8116-9 (v. 1) (hardcover : alk. paper) ISBN-10: 1-4200-8116-0 (v. 1) (hardcover : alk. paper) [etc.] 1. Drugs–Dosage forms–Handbooks, manuals, etc. I. Title. [DNLM: 1. Drug Compounding–Handbooks. 2. Dosage Forms–Handbooks. 3. Formularies as Topic–Handbooks. 4. Technology, Pharmaceutical–Handbooks. QV 735 N577h 2009] RS200.N53 2009 615 .19–dc22 2009009979

For Corporate Sales and Reprint Permission call 212-520-2700 or write to: Sales Department, 52 Vanderbilt Avenue, 16th floor, New York, NY 10017. Visit the Informa Web site at www.informa.com and the Informa Healthcare Web site at www.informahealthcare.com

to the memory of Dean Allen I. White

Preface to the Series—Second Edition

The science and the art of pharmaceutical formulation keeps evolving as new materials, methods, and machines become readily available to produce more reliable, stable, and releasecontrolled formulations. At the same time, globalization of sourcing of raw and finished pharmaceuticals brings challenges to regulatory authorities and results in more frequent revisions to the current good manufacturing practices, regulatory approval dossier requirements, and the growing need for cost optimization. Since the publication of the first edition of this book, a lot has changed in all of these areas of importance to pharmaceutical manufacturers. The second edition builds on the dynamic nature of the science and art of formulations and provides an evermore useful handbook that should be highly welcomed by the industry, the regulatory authorities, as well as the teaching institutions. The first edition of this book was a great success as it brought under one umbrella the myriad of choices available to formulators. The readers were very responsive and communicated with me frequently pointing out to the weaknesses as well as the strengths of the book. The second edition totally revised attempts to achieve these by making major changes to the text, some of which include:

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1. Complete, revised errors corrected and subject matter reorganized for easy reference. Whereas this series has six volumes differentiated on the basis of the type of dosage form and a separate inclusion of the U.S. OTC products, ideally the entire collection is needed to benefit from the myriad of topics relating to formulations, regulatory compliance, and dossier preparation. 2. Total number of pages is increased from 1684 to 2726. 3. Total number of formulations is expanded by about 30% with many newly approved formulations. 4. Novel formulations are now provided for a variety of drugs; these data are collected from the massive intellectual property data and suggest toward the future trend of formulations. While some of these formulations may not have been approved in the United States or Europe, these do provide additional choices, particularly for the NDA preparation. As always, it is the responsibility of the manufacturer to assure that the intellectual property rights are not violated. 5. A significant change in this edition is the inclusion of commercial products; while most of this information is culled out from the open source such as the FOIA (http://www.fda.gov/foi/default.htm), I have made attempts to reconstruct the critical portions of it based on what I call the generally acceptable standards. The drug companies are advised to assure that any intellectual property rights are not violated and this applies to all information contained in this book. The freedom of information act (FOIA) is an extremely useful conduit for reliable information and manufacturers are strongly

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urged to make use of this information. Whereas this information is provided free of charge, the process of obtaining the information may be cumbersome, in which case, commercial sources of these databases can prove useful, particularly for the non-U.S. companies. Also included are the new Good Manufacturing Guidelines (2007) with amendments (2008) for the United States and similar updates for European Union and WHO; it is strongly urged that the companies discontinue using all old documents as there are significant changes in the revised form, and many of them are likely to reduce the cost of GMP compliance. Details on design of clean rooms is a new entry that will be of great use to sterile product manufacturers; whereas the design and flow of personnel and material flow is of critical nature, regulatory agencies view these differently and the manufacturer is advised always to comply with most stringent requirements. Addition of a self-auditing template in each volume of the series. While the cGMP compliance is a complex issue and the requirements diversified across the globe, the basic compliance remains universal. I have chosen the European Union guidelines (as these are more in tune with the ICH) to prepare a self-audit module that I recommend that every manufacturer adopt as a routine to assure GMP compliance. In most instances reading the template by those responsible for compliance with keep them sensitive to the needs of GMP. OTC products cross-referenced in other volumes where appropriate. This was necessary since the regulatory authorities worldwide define this class of drug differently. It is important to iterate that regardless of the prescription or the OTC status of a product, the requirements for compliance with the cGMP apply equally. OTC monograph status is a new section added to the OTC volume and this should allow manufacturers to chose appropriate formulations that may not require a filing with the regulatory agencies; it is important to iterate that an approved OTC monograph includes details of formulation including the types and quantities of active drug and excipients, labeling, and presentation. To qualify the exemption, the manufacturer must comply with the monograph in its entirety. However, subtle modifications that are merely cosmetic in nature and where there is an evidence that the modification will not affect the safety and efficacy of the products can be made but require prior approval of the regulatory agencies and generally these approvals are granted. Expanded discussion on critical factors in the manufacturing of formulations provided; from basic shortcuts to smart modifications now extend to all dosage forms. Pharmaceutical compounding is one of the oldest professions and whereas the art of formulations has been

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Preface to the Series—Second Edition

relegated to more objective parameters, the art nevertheless remains. An experienced formulator, like an artist, would know what goes with what and why; he avoids the pitfalls and stays with conservative choices. These sections of the book present advice that is time tested, although it may appear random at times; this is intended for experienced formulators. 12. Expanded details on critical steps in the manufacturing processes provided but to keep the size of the book manageable, and these are included for prototype formulations. The reader is advised to browse through similar formulations to gain more insight. Where multiple formulations are provided for the same drug, it intended to show the variety of possibilities in formulating a drug and whereas it pertains to a single drug, the basic formulation practices can be extended to many drugs of same class or even of diversified classes. Readers have often requested that more details be provided in the Manufacturing Direction sections. Whereas sufficient details are provided, this is restricted to prototype formulations to keep the size of the book manageable and to reduce redundancy. 13. Addition of a listing of approved excipients and the level allowed by regulatory authorities. This new section allows formulators a clear choice on which excipients to choose; the excipients are reported in each volume pertaining to the formulation type covered. The listing is drawn from the FDA-approved entities. For the developers of an ANDA, it is critical that the level of excipients be kept within the range generally approved to avoid large expense in justifying any unapproved level. The only category for which the listing is not provided separately is the OTC volume since it contains many dosage forms and the reader is referred to dosage form–specific title of the series. The choice of excipients forms keeps increasing with many new choices that can provide many special release characteristics to the dosage forms. Choosing correct excipients is thus a tedious exercise and requires sophisticated multivariate statistical analysis. Whereas the formulator may choose any number of novel or classical components, it is important to know the levels of excipients that are generally allowed in various formulations to reduce the cost of redundant exercises; I have therefore included, as an appendix to each volume, a list of all excipients that are currently approved by the U.S. FDA along their appropriate levels. I suggest that a formulator consult this table before deciding on which level of excipient to use; it does not mean that the excipient cannot be used outside this range but it obviates the need for a validation and lengthy justification studies in the submission of NDAs. 14. Expanded section on bioequivalence submission was required to highlight the recent changes in these requirements. New entries include a comprehensive listing of bioequivalence protocols in abbreviated form as approved by the U.S. FDA; these descriptions are provided in each volume where pertinent. To receive approval for an ANDA, an applicant must generally demonstrate, among other things, equivalence of the active ingredient, dosage form, strength, route of administration and conditions of use as the listed drug, and that the proposed drug product is bioequivalent to the reference listed drug [21 USC 355(j)(2)(A); 21 CFR 314.94(a)]. Bioequivalent drug products show no significant difference in

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the rate and extent of absorption of the therapeutic ingredient [21 U.S.C. 355(j)(8); 21 CFR 320.1(e)]. BE studies are undertaken in support of ANDA submissions with the goal of demonstrating BE between a proposed generic drug product and its reference listed drug. The regulations governing BE are provided at 21 CFR in part 320. The U.S. FDA has recently begun to promulgate individual bioequivalence requirements. To streamline the process for making guidance available to the public on how to design product-specific BE studies, the U.S. FDA will be issuing product-specific BE recommendations (www.fda.gov/cder/ogd/index.htm). To make this vital information available, an appendix to each volume includes a summary of all currently approved products by the U.S. FDA where a recommendation on conducting bioequivalence studies is made available by the U.S. FDA. When filing an NDA or an ANDA, the filer is faced with the choice of defending the methods used to justify the bioavailability or bioequivalence data. The U.S. FDA now allows application for waiver of bioequivalence requirement; a new chapter on this topic has been added along with details of the dissolution tests, where applicable, approved for various dosage forms. Dissolution testing requirements are included for all dosage forms where this testing is required by the FDA. Surrogate testing to prove efficacy and compliance is getting more acceptance at regulatory agencies; in my experience, a well-designed dissolution test is the best measure of continuous compliance. Coupled with chapters on waivers of bioequivalence testing, this information on dissolution testing should be great value to all manufacturers; it is recommended that manufacturers develop their own in-house specifications, more stringent than those allowed in these listings and the USP. Best-selling products (top 200 prescription products) are identified with an asterisk and a brand name where applicable; in all instances, composition of these products is provided and formulation of generic equivalents. Despite the vast expansion of pharmaceutical sales and shifting of categories of blockbuster drugs, basic drugs affecting gastrointestinal tract, vascular system, and brain remain most widely prescribed. Updated list of approved coloring agents in the United States, Canada, European Union, and Japan is included to allow manufactures to design products for worldwide distribution. Tablet-coating formulations that meet worldwide requirements of color selection are included in the Volume 1 (compressed solids) and Volume 5 (OTC) because these represent the products often coated. Guidelines on preparing regulatory filings are now dispersed throughout the series depending on where these guidelines are more crucial. However, the reader would, as before, need access to all volumes to benefit from the advice and guidelines provided.

As always, comments and criticism from the readers are welcomed and these can be sent to me at [email protected] .com or [email protected] I would try to respond to any inquiries requiring clarification of the information enclosed in these volumes. I would like to express deep gratitude to Sherri R. Niziolek and Michelle Schmitt-DeBonis at Informa, the publisher of

Preface to the Series—Second Edition

this work, for seeing an immediate value to the readers in publishing the second edition of this book and allowing me enough time to prepare this work. The diligent editing and composing staff at Informa, particularly Joseph Stubenrauch, Baljinder Kaur and others are highly appreciated. Regardless, all errors and omissions remain altogether mine.

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In the first edition, I had dedicated each volume to one of my mentors; the second edition continues the dedication to these great teachers. Sarfaraz K. Niazi, Ph.D. Deerfield, Illinois, U.S.A.

Preface to the Series—First Edition

erations have led to the classification of products into these six categories. Each volume includes a description of regulatory filing techniques for the formulations described. Also included are the current regulatory guidelines on cGMP compliance specific to the dosage form. Advice is offered on how to scale up the production batches. It is expected that formulation scientists will use this information to benchmark their internal development protocols and cut the race to file short by adopting formulae that have survived the test of time. Many of us who have worked in the pharmaceutical industry suffer from a close paradigm when it comes to selecting formulations—”not invented here” perhaps reigns in the mind of many seasoned formulations scientists subconsciously when they prefer to choose only a certain platform for development. It is expected that with the quick review of possibilities available to formulate made available in this book, scientists will benefit from the experience of others. For the teachers of formulation sciences, this series offers a wealth of information. Whether it is a selection of a preservative system or the choice of a disintegrant, the series offers a wide choice to study and rationalize. Many have assisted me in the development of this work that has taken years to compile, and I thank scores of my graduate students and colleagues for their help. A work of this size cannot be produced without errors, although I hope that these errors do not distract the reader from the utility of the book. I would sincerely appreciate if readers point out these mistakes for corrections in future editions.

No industry in the world is more highly regulated than the pharmaceutical industry because of potential threat to a patient’s life from the use of pharmaceutical products. The cost of taking a new chemical entity (amortized over the cost of all molecules racing) to final regulatory approval is a staggering $800 million, making the pharmaceutical industry one of the most research-intensive industries in the world. In the year 2004, it is anticipated that the industry will spend about $20 billion on research and development. The generic market of drugs as the new entities come off patent is one of the fastest growing segments of the pharmaceutical industry, with every major multinational company having a significant presence in this field. Whereas many stages of new drug development are inherently constrained with time, the formulation of drugs into desirable dosage forms remains an area where expediency can be practiced with appropriate knowledge by those who have mastered the skills of pharmaceutical formulations. The Handbook of Pharmaceutical Manufacturing Formulations is the first major attempt to consolidate the available knowledge about formulations in a comprehensive, and by nature a rather voluminous, presentation. The book is divided into six volumes, based strictly on the type of formulation science involved in the development of these dosage forms: sterile products, compressed solids, uncompressed solids, liquid products, semisolid products, and OTC products. The separation of OTC products, even though they may easily fall into one of the other five categories, is made to comply with the industry norms of separate research divisions for OTC products. Sterile products require skills related to sterilization of product, and of less importance is the bioavailability issue, which is an inherent problem of compressed dosage forms. These types of consid-

Sarfaraz K. Niazi, Ph.D. Deerfield, Illinois, U.S.A.

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Preface to the Volume—First Edition

The Final Rule requirements have primarily been applied to products on the market and a newcomer is well advised to study competitor products for market leaders as ample opportunities are available to innovate these products. R Examples include the Tylenol Hot Therapy products and loratidine tablets that dissolve in the mouth and do not require water. I foresee more such products entering into the ever-competitive OTC market. It is imperative that any prospective entry into the OTC market should begin with a thorough consultation of the Final Rules; an examination of Proposed Rules and notifications to issue Proposed Rules is also helpful in determining what rules are about to become Final Rules. Reviewing the discussions about Proposed Rules that have affected their finalization can be very helpful in understanding the relevant issues of safety, efficacy, and labeling. Because the marketing of OTC products requires a large investment in marketing efforts, it is prudent to develop a clear understanding of the legality of formulations and claims made in the initial phases of product development. A large number of products on the market today are not covered by the U.S. FDA monographs but does that make them legitimate? This is the often-asked question. The U.S. FDA has limited resources to tackle everything that is out there on the market. When emergencies arise, however, the U.S. FDA reacts immediately as it did in the case of phenylpropanolamine, pseudoephedrine, and recently, kava kava. Here are some broad guidelines adopted by the U.S. FDA for the most commonly abused categories of products:

The Handbook of Pharmaceutical Manufacturing Formulations— OTC Drugs is written for the pharmaceutical scientist and others involved in the regulatory filing and manufacturing of new OTC products. Because of the wide variety of products involved, from those bordering on cosmetics to proton pump inhibitors, the OTC products are manufactured by the most sophisticated global manufacturers as well as small one-room makeshift manufacturing houses. The OTC products comprise a special category of healthcare products in that they can be dispensed without prescription; the rationale being that the use of these products does not expose patients to serious risks associated with side effects even if some misuse or overuse of these products occurs. The OTC category includes three types of products: Products that require full filing with the U.S. Food and Drug Administration (FDA) for marketing approval (the NDA/NADA or ANDA/ANADA process) including products or compositions not included in the monographs (see below) or administered in controlled release formulations. Products that do not require filing with the U.S. FDA because they comply with the monographs issued by the U.S. FDA in its Code of Federal Regulations (CFR). Products that fall under the category of grandfather products which have been in use prior to the 1960s and have not been specifically excluded by the FDA; not all grandfather products fall under the OTC category—only those that are generally regarded as safe (GRAS). The U.S. FDA provides excellent support through its OTC website (http://www.fda.gov/cder/otc/index.htm) and formulators are highly encouraged to make use of the information available, particularly the updates in the monograph label requirements and withdrawal of approvals of formulations. With the safety of consumers in mind, the U.S. FDA is in the process of establishing guidelines for all OTC products. Although the U.S. FDA began this work over three decades ago, much remains to be done. The U.S. FDA process begins with the issuance of Proposed Rules; this notification is like a warning (or advice) to the industry that this category of products is now under the U.S. FDA watch. Often years go by before Proposed Rules are published in the Code of Federal Regulations. The Proposed Rules include not only identification of approved active ingredients but also inactive ingredients that are deemed compatible with the active ingredients and safe for consumers. The Proposed Rules are subject to criticism by the industry health-care practitioners and consumers. After receiving these comments over what can be a period of several years, the U.S. FDA issues Final Rules on a specific category of products; these become official on the date of publication in the Code of Federal Regulations. In many cases, however, the U.S. FDA issues subsequent rules either to delay application of Final Rules or to modify the Final Rules if new information has become available.

No treatments are approved for hair growth except for minoxidil. No treatments are approved for enhancing sexual performance except for sildenafil citrate (and that only in MED). The few treatments approved for weight loss include olristat phentermine and sibutramine (phenylpropanolamine is no longer a recommended compound). It is noteworthy that the U.S. FDA does not differentiate between botanical products and chemical-based products. If a product bears an efficacy claim, it must be governed by the U.S. FDA rules; however, a product that falls into a drug category that makes nutritional claims falls under a food category with its own set of detailed rules. Vitamins and minerals fall under food labeling guidelines; however, a single-entity vitamin product with specific claims to treat or ameliorate a disease is a drug product. These definitions do not necessarily coincide with the rulings of regulatory authorities worldwide. In many countries nutritional products are controlled as drugs and require prescriptions; these same products would be considered nonprescription items in the United States. On the other hand, a number of highly active drugs are available without prescription in many countries such as the Traditional Chinese Medicine (TCM) in China and Ayurvedic and Unani medicines in South Asia. ix

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Preface to the Volume—First Edition

A reclassification of a drug to OTC status can be requested by drug manufacturers. Recent examples of such a prescription-to-OTC switch include ibuprofen (200 mg), ranitidine hydrochloride (75 mg), and loratidine (10 mg). Note that specific strengths, not necessarily the chemical entity itself, are made OTC. In other words, it is not necessary to have an official monograph to secure OTC status for a drug. The decision to request reclassification of a drug as OTC is always a well-calculated business decision. Generally, drugs with an OTC status will not qualify for medical reimbursement by insurance companies or federal assistance programs in the United States. This can substantially reduce sales of the product; on the other hand, ease of availability to a greater number of patients can easily compensate for this loss. The most lucrative opportunities arise when one strength is made OTC while other strengths remain available by prescription only. It is noteworthy that the decision to allow a switch from prescription to OTC by the U.S. FDA is primarily driven by the side effects or toxicity of the drug. For example, in Australia a Roche request for a prescription-to-OTC switch for R its weight-loss drug orlistat (Xenical ) was recently turned down because of extensive side effects associated with the use of Xenical. The drug itself is very safe as it does not enter the body and acts only locally to partially block absorption of fat. The unabsorbed fat produces many gastrointestinal symptoms which though temporary were sufficient to disallow the status switch. Obviously, Roche would have been best advised to develop an OTC formulation with fewer side effects before requesting this switch. (In the case of orlistat, the solution was simple as described in U.S. Patent No. 6,251,421 by this author wherein combining orlistat with a natural fiber reduced the side effects by 70%.) The OTC category of products represents a wide range of dosage forms. These formulations have much in common with their prescription counterparts but are presented in this volume of the Handbook of Pharmaceutical Manufacturing Formulations because of the development approach taken, labeling considerations, and support available from suppliers of ingredients in designing these products. Because the consumer is inevitably involved in the selection of these products, packaging considerations are much more important than in the prescription category of products. Additional considerations include ease of administration, palatability, and stability in storage as consumers are likely to keep leftovers around for a long time. Additionally, price constraints often make it difficult to enjoy some freedom of choice in formulations, especially if the innovator company faces the competition of house brands. All of these considerations taken together make the OTC category one that should be presented in a single volume of this series of books. Formulating OTC products is generally easier than formulating prescription products if the product is described in U.S. FDA monographs (either as Proposed Rules or Final Rules); such formulations become merely an exercise in mechanics. Whereas a manufacturer is not bound by these rules, complying with them reduces the costs and time involved securing approval from regulatory authorities. The multibillion-dollar market of OTC products has attracted major chemical suppliers to develop support ingredients that are much easier to use; they have also developed typical formulations for hundreds of these products. The most notable industry leaders include Amerchol, American Colloid, Aqualon,

BASF, BF Goodrich, Calgon, Colorcon, Croda, Dow Corning, FMC, Gattefose, General Electric, Henkel, Hormel, Huls America, ICI Americas, Inolex, International Sourcing, International Specialty, Laboratoires Serobioligique, Lonza, NIPA, PPG Industries, R.I.T.A., Reheis, Rheox, Rhone-Poulenc, Rohm and Haas, Southern Clay, Sutton, and Vanderbilt. The formulations recommended by these and other companies have acquired almost a universal appeal; throughout this book you will find formulations recommended by these laboratories, as acknowledged by the listing of a brand name in the formula. The best way to connect to these companies is to search the Internet for contact information; it is no longer necessary to reproduce such information here. Whereas many companies prefer to use generic components in the dosage form, it has been found that the use of proprietary components can indeed reduce costs in the long run. The choice of color is a highly sensitive issue in the formulation of OTC products; only FDC colors are allowed. Whereas there is a great need to make the products attractive and appealing, the choices of safe colors are dwindling quickly, such as for red colors. The formulator is encouraged to review the status of approved colors around the world before committing to a specific color. Many OTC solid dosage forms are available in coated form. Sugar coatings have yielded to film coatings, and this book contains a large number of sugar-coating, sealcoating, subcoating, film-coating, and polish-coating formulations that can be easily adapted to various dosage form sizes. The use of organic solvent-based coatings has become prohibitive because of environment considerations, but in those cases where formulations are extremely sensitive to moisture, organic coatings may still offer a valid choice. A few companies offer ready-made coating formulations, and these are worth considering. The Appendix to this book includes a large number of formulations of coatings of solid dosage forms. A keen formulator will have no difficulty based on these formulations in adopting a coating system that will provide the necessary protection and offer esthetic appeal as well. Solid dosage forms are coated for many reasons, including masking the taste, making them easier to swallow, and providing protection against the environment. Stability considerations remain paramount, and the data in the final packaging must be evaluated carefully before

Preface to the Volume—First Edition

adjusting formulae for excesses; in this book, most formulations are provided without this consideration. A strip or blister dosage form is more popular around the world, but the plastic bottle is the most popular final form in the United States. The development of OTC products is similar to the development of prescription dosage forms; as a result, cGMP and Good Laboratory Practice (GLP) considerations apply equally. The first chapter describes in greater detail the cGMP considerations. An appendix to chapter 1 provides a comprehensive checklist of items to review to ensure that a manufacturing facility is in compliance with cGMP standards. Appropriate identification is made in this checklist of those items that comply with EC guidelines. The U.S. FDA guidelines are available from the U.S. FDA website: http://www.fda.gov. The World Health Organization (WHO) provides GMP guidelines that are less stringent than those of the U.S. FDA and EC, and formulators should be aware of the fact that all of these are simply guidelines. One should be fully cognizant of the fact that no agencies are bound by these guidelines, particularly the U.S. FDA. Manufacturers cannot take refuge in the defense that they have complied with these guidelines. It is further worthwhile remembering that all of these guidelines are continuously revised, and the “c” in the cGMP does refer to current. The second chapter deals with the most popular category of dosage forms encountered in OTC offerings—solids. Issues specific to manufacturing of these dosage forms are described from a practical viewpoint, indicating the problem areas frequently encountered in manufacturing practice. The third chapter deals with liquids and suspensions and includes, like the chapter above, practical advice on how to bring manufacturing practices into compliance with regulatory requirements. The fourth chapter offers highlights of cleaning validation, a topic often ignored by OTC manufacturers as not being significant because of the safety of ingredients used. It is true that the same stringent standards may not apply, but compliance with cleaning standards and validation of processes go a long way toward ensuring overall compliance. The first four chapters were drawn from the advice which the U.S. FDA gives to its inspectors before they inspect a manufacturer. The CFR includes complete details of what is considered acceptable by the U.S. FDA; this advice is of a practical nature, and I find it to be extremely helpful in enhancing awareness of the guidelines of regulatory authorities. It is noteworthy that EC guidelines, particularly in light of the harmonization of specifications, are somewhat identical to the U.S. FDA guidelines; in chapter 1, specific references

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are made to EC guidelines. The Appendix includes formulations of coating solutions; these should prove useful for the pharmaceutical formulation teams. The formulations in this book generally fall into three categories. Some formulations are presented in greater detail, including indications of where quality assurance (QA)/quality control (QC) sampling is to be done and describing the tooling and in-process and finished product specifications. The other extreme is a mere listing of components with a bare minimum of manufacturing methods. This was necessary for two reasons: first, to contain the size of this book, and second, to keep from presenting superfluous information, as formulators would eventually adopt such a formula to their own delivery forms. Also, at times the various strengths are merely achieved through adjustment of dosage size, so it was considered unnecessary to reproduce manufacturing steps where they are obvious. The primary source of these formulations is publicly available knowledge about formulae that have proven to provide stable products. No representation is made that these formulations meet U.S. FDA monographs or any other regulatory guidelines for safety of inert ingredients. The formulator is advised to determine guideline compliance before adopting any of the formulations given in this book. Those interested in obtaining detailed information about these formulations are encouraged to contact the author at http://www.pharmsci.com. Because of the wide variety of sources from which the information has been gathered in the book, the format of formulations also varies. For example, in some instances scale is provided, whereas in others a percentage by weight is described. In still other instances, quantities for a specific batch size are provided. Obviously, it would be desirable to convert these formulations into a uniform format, but the task would be daunting and inevitably would lead to inclusion of errors. Professional formulators should not encounter any difficulty in adapting these formulations to their own system. As mentioned before, not all formulations contain the required overages for stability considerations and losses during manufacturing; formulators are expected to develop these based on the final packaging chosen for the product. The author would appreciate being notified of any special problems encountered in adopting these formulations or of any errors ([email protected]). Whereas much care has gone into ensuring the accuracy of quantities and proper identification of ingredients, such errors shall remain in a work as large as that presented here. Sarfaraz K. Niazi, Ph.D. Deerfield, Illinois, U.S.A.

About the Author

Sarfaraz K. Niazi has been teaching and conducting research in the pharmaceutical industry for over 35 years. He has authored hundreds of scientific papers, textbooks, and presentations on the topics of pharmaceutical formulation, biopharmaceutics, and pharmacokinetics of drugs. He is also an inventor with scores of patents in the field of drug and dosage form delivery systems; he is also licensed to practice law before the U.S. Patent and Trademark Office. Having formulated hundreds of products from the most popular consumer entries to complex biotechnology-derived products, he has accumulated a wealth of knowledge in the science and art of formulating and regulatory filings of investigational new drugs (INDs) and new drug applications (NDAs). Dr. Niazi advises the pharmaceutical industry internationally on issues related to formulations, cGMP compliance, pharmacokinetics and bioequivalence evaluation, and intellectual property issues (http://www.pharmsci.com). He can be contacted at [email protected]

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Contents

General 11 Prevention of Cross-Contamination in Production 11 Validation 11 Starting Materials 11 Processing Operations: Intermediate and Bulk Products 12 Packaging Materials 12 Packaging Operations 12 Finished Products 13 Rejected, Recovered, and Returned Materials 13 Chapter 6: Quality Control 13 Principle 13 General 13 Good Quality Control Laboratory Practice 13 Documentation 13 Sampling 14 Testing 14 Ongoing Stability Program 14 Chapter 7: Contract Manufacture and Analysis 15 Principle 15 General 15 The Contract Giver 15 The Contract Acceptor 15 The Contract 16 Chapter 8: Complaints and Product Recall 16 Principle 16 Complaints 16 Recalls 16

Preface to the Series—Second Edition . . . . v Preface to the Series—First Edition . . . . viii Preface to the Volume—First Edition . . . . ix About the Author . . . . xii PART I REGULATORY GUIDANCE

1 EU Guidelines to Good Manufacturing Practice: Medicinal Products for Human and Veterinary Use 2 Introduction 2 Part I Chapter 1: Quality Management 3 Principle 3 Quality Assurance 3 Good Manufacturing Practice for Medicinal Products 3 Quality Control 4 Product Quality Review 4 Quality Risk Management 5 Chapter 2: Personnel 5 Principle 5 General 5 Key Personnel 5 Training 6 Personnel Hygiene 6 Chapter 3: Premises and Equipment 6 Principle 6 Premises 6 General 6 Production Area 7 Storage Areas 7 Quality Control Areas 7 Ancillary Areas 8 Equipment 8 Chapter 4: Documentation 8 Principle 8 General 8 Specifications for Starting and Packaging Materials 9 Specifications for Intermediate and Bulk Products 9 Specifications for Finished Products 9 Manufacturing Formula and Processing Instructions 9 Packaging Instructions 9 Batch Processing Records 9 Batch Packaging Records 10 Procedures and Records 10 Receipt 10 Sampling 10 Testing 10 Other 10 Chapter 5: Production 10 Principle 10

2 EDQM Certification 17 I.2.3.S Drug Substance 17 A.2.3.S.1 General Information 17 1.2.3.S.1.1 Nomenclature 17 1.2.3.S.1.2 General Properties 18 2.3.S.2 Manufacture 18 2.3.S.2.1 Manufacturer(s) (Name, Manufacturer) and Sites Involved in the Entire Process 18 2.3.S.2.2 Description of Manufacturing Process and Process Controls 18 2.3.S.2.3 Control of Materials 18 2.3.S.2.4 Controls of Critical Steps and Intermediates 18 2.3.S.2.5 Process Validation and/or Evaluation 18 2.3.S.3 Characterization 18 2.3.S.3.1 Impurities 18 2.3.S.4 Control of the Drug Substance 18 2.3.S.4.1 Specification 18 2.3.S.4.2 Analytical Procedures 18 2.3.S.4.3 Validation of Analytical Procedures 18 2.3.S.4.4 Batch Analyses 18 2.3.S.4.5 Justification of Specification 18 2.3.S.5 Reference Standards or Materials 18 2.3.S.6 Container Closure System 19 xiii

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2.3.S.7 Stability 19 2.3.S.7.1 Stability Summary and Conclusions 19 2.3.S.7.2 Postapproval Stability Protocol and Stability Commitment 19 3 GMP Audit Template, EU Guidelines Glossary 39

20

4 WHO Good Manufacturing Guidelines 42 Quality Management in the Drug Industry: Philosophy and Essential Elements 42 1. Quality Assurance 42 2. GMPs for Pharmaceutical Products 43 3. Sanitation and Hygiene 43 4. Qualification and Validation 43 5. Complaints 44 6. Product Recalls 44 7. Contract Production and Analysis 44 General 44 The Contract Giver 44 The Contract Accepter 44 The Contract 45 8. Self-Inspection and Quality Audits 45 Items for Self-Inspection 45 Self-Inspection Team 45 Frequency of Self-Inspection 45 Self-Inspection Report 45 Follow-Up Action 45 Quality Audit 45 Suppliers’ Audits and Approval 45 9. Personnel 46 General 46 Key Personnel 46 10. Training 47 11. Personal Hygiene 47 12. Premises 48 General 48 Ancillary Areas 48 Storage Areas 48 Weighing Areas 48 Production Areas 48 Quality Control Areas 49 13. Equipment 49 14. Materials 49 General 50 Starting Materials 50 Packaging Materials 50 Intermediate and Bulk Products 50 Finished Products 50 Rejected, Recovered, Reprocessed, and Reworked Materials 50 Recalled Products 51 Returned Goods 51 Reagents and Culture Media 51 Reference Standards 51 Waste Materials 51 Miscellaneous 51 15. Documentation 51 General 51 Documents Required 52 Labels 52 Specifications and Testing Procedures 52

Specifications for Starting and Packaging Materials 52 Specifications for Intermediate and Bulk Products 52 Specifications for Finished Products 53 Master Formulae 53 Packaging Instructions 53 Batch Processing Records 53 Batch Packaging Records 53 Standard Operating Procedures and Records 54 16. Good Practices in Production 55 General 55 Prevention of Cross-Contamination and Bacterial Contamination During Production 55 Processing Operations 56 Packaging Operations 56 17. Good Practices in Quality Control 56 Control of Starting Materials and Intermediate, Bulk, and Finished Products 57 Test Requirements 57 Starting and Packaging Materials 57 In-Process Control 58 Finished Products 58 Batch Record Review 58 Stability Studies 58 Bibliography 58 WHO Inspections Summary 58 5 Solid Oral Dosage Forms Validation 60 I. Introduction 60 II. Background 60 III. Product Development 60 A. Product Development Reports 60 1. Drug Substance Characterization 61 2. Manufacturing Procedures 61 3. In-Process Testing 62 4. Finished Product Testing 62 5. Dissolution Profile 62 6. Stability 62 B. Preapproval Inspections 62 1. Master Formula 62 2. History Section of the Application 62 3. Development Data (Product Development Report) 62 4. Inspection of the Facilities 62 5. Raw Materials 62 6. Laboratory 62 7. Equipment 63 IV. Validation Protocols 63 V. Demonstration Runs (Validation of the Process) 63 A. Test Batch Relationships 63 B. Postapproval Prospective Validation Inspections 63 1. Raw Materials 63 2. Manufacturing Procedures and Equipment 63 3. Granulation/Mix Analysis 65 4. In-Process Testing 66 5. Test Results 66 6. Investigations and Product Failures 66 7. Site Review 67

Contents

6 Current Regulatory Status of Over-the-Counter Products 68 Background 68 Regulatory Definitions 68 Appendix I OTC Ingredient List 69 Appendix II Unproven Safety of OTC Ingredients 137 PART II MANUFACTURING FORMULATIONS

Pharmaceutical Manufacturing Formulations 146 Acetaminophen and Caffeine Tablets 146 Acetaminophen and Caffeine Tablets 147 Acetaminophen and Diphenhydramine Hydrochloride Hot Therapy Sachets 147 Acetaminophen and Pseudoephedrine Hydrochloride Hot Therapy Sachets 148 Acetaminophen and Diphenhydramine Hydrochloride Tablets 148 Acetaminophen Sustained-Release Tablets 149 Acetaminophen and Pseudoephedrine Hydrochloride Tablets 150 Acetaminophen Chewable Tablets 150 Acetaminophen, Chlorpheniramine, and Pseudoephedrine Syrup 151 Acetaminophen, Chlorpheniramine Maleate, and Pseudoephedrine Caplets 152 Acetaminophen, Dextromethorphan, and Pseudoephedrine Caplets 153 Acetaminophen, Doxylamine, and Caffeine Effervescent Granules 153 Acetaminophen Drops 154 Acetaminophen Effervescent Tablets 154 Acetaminophen Fast-Dissolving Tablets 155 Acetaminophen, Ibuprofen, and Orphenadrine Hydrochloride Tablets 155 Acetaminophen Instant Granules 155 Acetaminophen Instant Granules 156 Acetaminophen Instant Granules 156 Acetaminophen Microsphere Tablets 156 Acetaminophen, Norephedrine, and Phenyltoloxamine Tablets 157 Acetaminophen Oral Suspension 157 Acetaminophen, Phenylpropanolamine, Dextromethorphan, and Chlorpheniramine Tablets 158 Acetaminophen, Propoxyphenazone, and Caffeine Tablets 159 Acetaminophen, Pseudoephedrine Hydrochloride, and Chlorpheniramine Hot Therapy Sachet 160 Acetaminophen Suppositories 160 Acetaminophen Suppositories 160 Acetaminophen Suppositories 161 Acetaminophen Suppositories 161 Acetaminophen Suppositories 161 Acetaminophen Suspension 161 Acetaminophen Syrup 162 Acetaminophen Syrup 162 Acetaminophen Syrup for Children 163 Acetaminophen Tablets 163 Acetaminophen Tablets 164 Acetaminophen Tablets 164 Acetaminophen Tablets 165

Acetaminophen Tablets for Children 165 Acetylcysteine Sachets 166 Acetylsalicylic Acid, Acetaminophen and Caffeine Tablets (250 mg + 250 mg + 50 mg) 166 Acetylsalicylic Acid + Paracetamol (=Acetaminophen) Tablets (250 mg + 250 mg) 167 Acetylsalicylic Acid + Vitamin C Tablets (400 mg + 250 mg) 167 Acetylsalicylic Acid Tablets (500 mg) 167 Acetylsalicylic Acid, Acetaminophen, and Caffeine Tablets 168 Acetylsalicylic Acid, Acetaminophen, and Caffeine Tablets (Direct Compression) 168 Acetylsalicylic Acid and Acetaminophen Tablets 168 Acetylsalicylic Acid and Acetaminophen Tablets 169 Acetylsalicylic Acid and Ascorbic Acid Tablets 169 Acetylsalicylic Acid and Ascorbic Acid Tablets 169 Acetylsalicylic Acid Suppositories 170 Acetylsalicylic Acid Tablets (Buffered) 170 Acetylsalicylic Acid Tablets (Direct Compression) 170 Acetylsalicylic Acid Tablets (Direct Compression) 171 Acetylsalicylic Acid Tablets (Direct Compression) 171 Acne Cover Cream 171 Acne Scrub 172 Acne Treatment Cream 172 Alginic Acid + Aluminium Hydroxide + Magnesium Silicate Tablets (500 mg+100 mg+25 mg) 173 Aloe Vera Gel 173 Alpha-Bisabolol Aqueous Mouthwash Solution 173 Alpha-Bisabolol Buccal or Topical Solution 174 Alpha-Bisabolol Ethanolic Mouthwash Solution 174 Alpha-Bisabolol Mouthwash Solution 174 Aluminum Acetylsalicylate Tablets 175 Aluminium Hydroxide + Magnesium Silicate Chewable Tablets (120 mg+250 mg) 175 Aluminum Hydroxide and Magnesium Carbonate Dry Syrup 175 Aluminum Hydroxide and Magnesium Hydroxide Chewable Tablets 176 Aluminum Hydroxide and Magnesium Hydroxide Chewable Tablets 176 Aluminum Hydroxide and Magnesium Hydroxide Antacid Suspension 177 Aluminum Hydroxide and Magnesium Hydroxide Antacid Suspension 177 Aluminum Hydroxide and Magnesium Hydroxide Suspension 178 Aluminum Hydroxide and Magnesium Hydroxide Suspension 179 Aluminum Hydroxide and Magnesium Hydroxide Suspension 179 Aluminum Hydroxide and Magnesium Hydroxide Tablets 180 Aluminum Hydroxide and Magnesium Silicate Chewable Tablets 180 Aluminum Hydroxide, Magnesium Carbonate (or Oxide), and Simethicone Tablets 181

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Aluminum Hydroxide, Magnesium Hydroxide, and Simethicone Suspension 181 Aluminum Hydroxide, Magnesium Hydroxide, and Simethicone Suspension 182 Aluminum Hydroxide, Magnesium Hydroxide, and Simethicone Tablets 182 Analgesic Clear Gel 183 Analgesic Cream 183 Analgesic Lotion 184 Anise Oil Solution 184 Antazoline and Xylometazoline Eye Drops 185 Antiacne Gel 185 Antifungal Foot Powder 186 Antiseptic Cream 186 Antiseptic Lotion 186 Antiseptic Lotion 187 Antiseptic Wet Wipes 187 Asparagus Extract + Parsley Extract Tablets (200 mg+200 mg) 187 Aspartame Effervescent Tablets (20 mg) 188 Aspartame Granules in Sachets 188 Aspartame Powder in Sachets 188 Aspartame Tablets (25 mg), DC 189 Aspartame Tablets 189 Aspartame Tablets 190 Aspartame Tablets 190 Aspartame Tablets, Effervescent 190 Aspirin, Acetaminophen, and Caffeine Tablets 191 Aspirin, Acetaminophen, Caffeine, and Salicylamide Tablets 191 Aspirin Tablets 191 Aspirin-Coated Crystals 192 Attapulgite Tablets 192 Azulene Solution (1%) 193 Baby Cream, Benzalkonium Chloride, and Zinc Oxide 193 Baby Lotion 194 Baby Shampoo 194 Barium Sulfate Oral Suspension (23%) 195 Basic Cream for Various Active Ingredients 195 Benzalkonium Chloride Contraceptive Gel 195 Benzoyl Peroxide and Alpha-Bisabolol Gel 196 Benzoyl Peroxide Antiacne Cream 196 Benzoyl Peroxide Antiacne Gel 197 Benzoyl Peroxide Antiacne Lotion 197 Benzoyl Peroxide Antiacne Microemulsion 198 Benzyl Benzoate Solution 198 Berberine Tablets 198 Beta-Carotene + Vitamin C + Vitamin E Chewable Tablets (10 mg+500 mg+250 mg) 198 Beta-Carotene + Vitamin C + Vitamin E Effervescent Tablets (12 mg+150 mg+25 mg) 198 Beta-Carotene + Vitamin C + Vitamin E Tablets (7 mg+60 mg+25 mg) 199 Beta-Carotene + Vitamin C + Vitamin E Tablets (12 mg+250 mg+125 mg) 199 Beta-Carotene Effervescent Tablets (7 mg) 199 Beta-Carotene Effervescent Tablets 199 Beta-Carotene Tablets 200 Beta-Carotene Tablets 200 Beta-Carotene Tablets 200 Beta-Carotene, Vitamin C, and Vitamin E Chewable Tablets 201

Beta-Carotene, Vitamin C, and Vitamin E Tablets 201 Beta-Carotene, Vitamin C, and Vitamin E Tablets 201 Beta-Carotene, Vitamin C, and Vitamin E Tablets 202 Beta-Carotene, Vitamin C, and Vitamin E Tablets 202 Betamethasone and Neomycin Gel Cream 202 Betamethasone Cream 203 Betamethasone Gel 203 Betamethasone Valerate Cream 203 Betamethasone Valerate Ointment 204 Bisacodyl Delayed-Release Tablets 205 Bisacodyl Suppositories 205 Bismuth Carbonate Suspension 206 Bismuth Subsalicylate and Calcium Carbonate Tablet 206 Bismuth Subsalicylate Suspension 206 Bismuth Subsalicylate Swallow Tablets 207 Bleaching and Antimicrobial Dentifrice 207 Bran–Sucrose–Gelatin–Calcium Carbonate Tablet 207 Bran Tablets 208 Breast Care Cream 208 Bromhexine Hydrochloride Syrup 209 Bromhexine Hydrochloride Syrup (Alcohol Free) 210 Bromhexine Hydrochloride Tablets 210 Burn Cream 211 Burn Cream 211 Caffeine Tablets 212 Calamine Cream 212 Calamine Cream 213 Calamine Lotion 213 Calcium and Vitamin D Tablets 214 Calcium Chewable Tablets (200 mg Ca) 214 Calcium Glycerophosphate Tablets (200 mg) 214 Calcium Carbonate Chewable Tablet 215 Calcium Carbonate and Glycine Tablets 215 Calcium Carbonate and Vitamin D Tablets 215 Calcium Carbonate Tablets 216 Calcium D-Pantothenate Chewable Tablets 216 Calcium D-Pantothenate Tablets 216 Calcium D-Pantothenate Tablets 217 Calcium Effervescent Tablets 217 Calcium Gluconate Tablets 217 Calcium Glycerophosphate Tablets 218 Calcium Glycerophosphate Tablets 218 Calcium Iodide and Ascorbic Acid Syrup 218 Calcium Phosphate Tablets for Cats and Dogs (Direct Compression) 219 Calcium Phosphate Tablets for Cats and Dogs 219 Carbamide Peroxide Chewing Gum 220 Carbamide Peroxide and Hydrogen Peroxide Bleaching Oral Dentifrice 220 Carbinoxamine Maleate, Phenylpropanolamine, and Acetaminophen Sustained-Release Tablets 220 Carbonyl Iron, Copper Sulfate, and Manganese Sulfate Tablets 221 Carnitine and Coenzyme Q Solution 221 Cetrimide Antiseptic Cream 221 Cetirizine Hydrochloride Tablet 222 Cetylpyridinium Lozenges (2.5 mg) 222 Charcoal Tablets 222

Contents

Chlophedianol, Ipecac, Ephedrine, Ammonium Chloride, Carbinoxamine, and Balsam Tolu Syrup 223 Chlorhexidine Gel 224 Chlorhexidine Lozenges 224 Chlorpheniramine Tablets 224 Chlorpheniramine Maleate Syrup 225 Chlorpheniramine and Pseudoephedrine Chewable Tablets 225 Chlorpheniramine, Pseudoephedrine, and Dextromethorphan Chewable Tablets 226 Chymotrypsin Tablets 226 Cimetidine Tablets (200 mg) 226 Cimetidine Chewable Tablets 226 Citrate Effervescent Powder 227 Crospovidone Effervescent Tablets 227 Crospovidone Oral Suspension (2000 mg/ 10 mL) 228 Crospovidone Water-Dispersible Tablets 228 Cyanocobalamin Tablets 228 Dexpanthenol Gel Cream 228 Dextromethorphan, Pseudoephedrine, and Chlorpheniramine Maleate Syrup 229 Dihydroxyaluminum Sodium Carbonate Tablets 229 Dimenhydrinate Tablets 230 Dimenhydrinate Tablets 230 Dimenhydrinate Tablets 230 Dimenhydrinate Tablets (50 mg), DC 231 Diphenhydramine and Pseudoephedrine Chewable Tablets 231 Diphenhydramine Hydrochloride Tablets 231 Econazole Nitrate and Benzoyl Peroxide Antiacne Cream 232 Econazole Nitrate and Benzoyl Peroxide Antiacne Lotion 232 Eucalyptol Solution 232 Eucalyptol Solution (8%) 233 Eucalyptus and Mint Emulsion 233 Eucalyptus and Mint Ointment 233 Ferrous Fumarate Tablets 233 Ferrous Sulfate, Manganese Sulfate, and Copper Sulfate Tablets 234 Ferrous Sulfate Oral Solution 234 Ferrous Sulfate Oral Syrup 235 Ferrous Sulfate Tablets 235 Fir Needle Oil Solution 236 Folic Acid Tablets 236 Folic Acid Tablets 237 Foot Bath 237 Foot Freshener Cream 237 Foot Mousse 238 Garlic Tablets 238 Garlic Extract + Thyme Extract + Vitamin C (300 mg+25 mg+100 mg) 238 Ginkgo Extract Tablets (40 mg) 238 Glycerin Suppositories 239 Glycerin Suppositories for Children 239 Glycol Foam (Nonaqueous) 239 Guaifenesin Pseudoephedrine, Carbinoxamine, and Chlophedianol Drops 240 Guaifenesin Tablets 241 Guaifenesin Tablets 241 Hemorrhoid Cream 242

Herbal Hemorrhoid Tablet 242 Horsetail Extract Tablets 242 Hydrocortisone Aqueous Gel 243 Hydrocortisone Aqueous Gel 243 Hydrocortisone Cream 244 Hydrocortisone Cream 244 Hydrocortisone Ethanolic Gel 245 Hydrocortisone Ointment 245 Hydrogen Peroxide Bleaching Dentifrice Paste 245 Ibuprofen Fast Dissolve Tablet 246 Ibuprofen-Coated Fast-Crumbling Granule Tablet 246 Ibuprofen Pediatric Suspension 247 Ibuprofen Chewable Tablets 247 Ibuprofen Sustained-Release Bilayer Tablets 247 Ibuprofen Tablets 249 Inosin Tablets 250 Insect Bite Cream 251 Iron (Polymer-Coated Particle) Tablets 251 Iron Infant Drops 252 Iron Polystyrene and Vitamin C Syrup 253 Kaolin–Pectin Suspension 254 Kaolin–Pectin Tablets 255 Keratolytic Cream 256 Khellin Tablets 256 Lidocaine Gel 256 Lidocaine Gel Cream 257 Lidocaine Ointment 257 Lidocaine, Eugenol, and Menthol Dental Ointment 258 Loperamide Hydrochloride Fast-Melt Tablet 258 Loratadine and Pseudoephedrine Sulfate Tablets 259 Loratadine Tablets 259 Loratadine Tablets 260 Loratadine Fastab 260 Lycopene Tablet Cores (6 mg) 260 Magaldrate Chewable Tablets 261 Magaldrate Chewable Tablets (500 mg) 261 Magaldrate Chewable Tablets (1000 mg) 261 Magaldrate Dispersible Tablets 261 Magaldrate Instant Powder or Dry Syrup 262 Magaldrate Suspension 262 Magaldrate Tablets 263 Magaldrate with Simethicone Suspension 264 Magaldrate with Simethicone Tablets 265 Magnesium Carbonate Tablets 266 Medicated Foot Cream 266 Menthol Mouthwash 267 Methyl Salicylate Analgesic Cream 267 Methyl Salicylate Analgesic Cream 268 Methyl Salicylate Heat Rub Lotion 268 Methyl Salicylate and Menthol Gel 269 Metoclopramide Tablets 269 Miconazole Nitrate Cream 270 Mineral and Multivitamin Syrup 271 Mint–Menthol Mouthwash 272 Mint Oil Solution 273 Multivitamin and Beta-Carotene Tablets 273 Multivitamin and Calcium Syrup 274 Multivitamin and Carbonyl Iron Tablets 275 Multivitamin and Fluoride Chewable Tablets 276 Multivitamin and Mineral Syrup 277 Multivitamin and Mineral Tablets 278

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Multivitamin and Mineral Tablets with Beta-Carotene 280 Multivitamin, Calcium, and Iron Tablets 280 Multivitamin + Calcium + Iron Tablets (1 RDA of Vitamins) 281 Multivitamin + Carbonyl Iron Tablets (1–2 RDA of Vitamins) 281 Multivitamin Chewable Tablets for Children 281 Multivitamin Chewable Tablets for Children 281 Multivitamin Drops 282 Multivitamin Effervescent Granules 283 Multivitamin Effervescent Tablets 284 Multivitamin Effervescent Tablets 285 Multivitamin Effervescent Tablets I, DC (1–2 RDA of Vitamins) 286 Multivitamin Effervescent Tablets II, DC (3–4 RDA of Vitamins) 286 Multivitamin Effervescent Tablets with Beta-Carotene 286 Multivitamin Infant Drops 287 Multivitamin Infant Drops 288 Multivitamin Instant Granules 289 Multivitamin Mineral Syrup 290 Multivitamin + Minerals Tablets with Beta-Carotene (1 RDA of Vitamins) 291 Multivitamin Oral Gel 291 Multivitamin Oral Gel Veterinary 292 Multivitamin Oral Gel with Linoleic and Linolenic Acid 293 Multivitamin Syrup 294 Multivitamin Syrup 295 Multivitamin Tablet Cores with Beta-Carotene (1–2 RDA of Vitamins) 295 Multivitamin Tablets 296 Multivitamin Tablets 297 Multivitamin Tablets 298 Multivitamin Tablets 299 Multivitamin Tablets, DC (1–2 RDA of Vitamins) 300 Multivitamin Tablets for Dogs 300 Multivitamin Tablets for Dogs 300 Multivitamin Tablets with Beta-Carotene 301 Multivitamin Tablets with Copper and Zinc 301 Multivitamin with Beta-Carotene Tablets 302 Multivitamin with Fluoride Infant Drops 303 Multivitamin with Zinc Tablets 304 Naphazoline Eye Drops 305 Neomycin Gel 305 Nicotinamide Tablets 306 Nicotinic Acid Tablets 306 Nicotinic Acid (Niacin) Tablets 306 Nicotinic Acid (Niacin) Tablets (200 mg) 307 Niacin Tablets 307 Nondetergent Neutral Dry Skin Cream 307 Norephedrine Syrup 308 Nystatin Cream 308 Nystatin Ointment 309 Nystatin, Neomycin Sulfate, Gramicidin, and Triamcinolone Acetonide Cream 309 Nystatin, Neomycin Sulfate, Gramicidin, and Triamcinolone Acetonide Ointment 310 Omega Fatty Acids Tablets 310 Orlistat Chewable Tablets 311

Orlistat Chewable Tablets 311 Orlistat Chewable Tablets 311 Oral Rehydration Salt (45 mEq) 311 Pancreatin Tablets 311 Pancreatin Tablets 312 Pancreatin and Cholic Acid Tablets 312 Panthenol Lotion 312 Panthenol Ointment 313 Papain Chewable Tablets 314 Papain Chewing Gum 314 Peppermint Rub Cream 314 Peptide Sublingual Tablet 315 Peptide Topical Liquid 315 Phenindione Tablets 315 Phenolphthalein Tablets 315 Phenolphthalein Tablets 316 Phenylpropanolamine Hydrochloride Tablets 316 Phenylpropanolamine and Brompheniramine Fast-Dissolving Tablets 317 Phenylpropanolamine, Chlorpheniramine, Dextromethorphan, Vitamin C Syrup 317 Placebo Tablets 318 Polidocanol Wound Spray 318 Potassium Bicarbonate-Coated Tablet 319 Povidone–Iodine and Lidocaine Gel 319 Povidone–Iodine Bar Soap 320 Povidone–Iodine Bar Soap 320 Povidone–Iodine Bar Soap 320 Povidone–Iodine Concentrates for Broilers and Cattle 321 Povidone–Iodine Cream 321 Povidone–Iodine Effervescent Vaginal Tablets 321 Povidone–Iodine Foam Spray 322 Povidone–Iodine Gargle 322 Povidone–Iodine Gargle Solution Concentrate 322 Povidone–Iodine Gel Cream 323 Povidone–Iodine Gels 323 Povidone–Iodine Glucose Ointment 323 Povidone–Iodine Liquid Spray 324 Povidone–Iodine Lozenges 324 Povidone–Iodine Mastitis Cream for Cattle 324 Povidone–Iodine Mouthwash and Gargle Solution Concentrate 325 Povidone–Iodine Powder Spray 325 Povidone–Iodine Pump Spray 325 Povidone–Iodine Shampoo 326 Povidone–Iodine Soft Gel 326 Povidone–Iodine Solution 326 Povidone–Iodine Solution 327 Povidone–Iodine Solution 327 Povidone–Iodine Solution 327 Povidone–Iodine Solution 328 Povidone–Iodine Scrub 328 Povidone–Iodine Surgical Scrub 328 Povidone–Iodine Surgical Scrub 329 Povidone–Iodine Transparent Ointment 329 Povidone–Iodine Vaginal Douche Concentrate 329 Povidone–Iodine Vaginal Ovule 330 Povidone–Iodine Vaginal Ovule 330 Povidone–Iodine Viscous Solution 330 Promethazine Hydrochloride Syrup 331 Promethazine Hydrochloride Tablets 332 Promethazine Hydrochloride Tablets 333

Contents

Pseudoephedrine Hydrochloride Fast-Disintegrating Tablets 333 Pseudoephedrine Hydrochloride Capsules 334 Pseudoephedrine Hydrochloride Syrup 334 Pseudoephedrine Hydrochloride Tablets 335 Pseudoephedrine Tablets 335 Pseudoephedrine Hydrochloride, Carbinoxamine Maleate Oral Drops 336 Psoriasis Cream 336 Psoriasis Cream 337 Psyllium and Dioctyl Sodium Sulfosuccinate Powder 337 Psyllium and Docusate Sodium Tablets 337 Psyllium and Docusate Sodium Wafer 337 Psyllium Husk Granules 337 Psyllium Husk Tablets 338 PVP–Iodine Mouthwash 339 Pyridoxine Tablets 339 Pyridoxine Tablets 339 Pyridoxine Tablets 340 Pyridoxine Tablets 340 Pyridoxine Tablets 340 Pyridoxine Tablets 341 Ranitidine Tablets 341 Ranitidine Tablets 341 Ranitidine Hydrochloride Tablets 342 Riboflavin Tablets 342 Riboflavin Tablets 342 Riboflavin Tablets 343 Riboflavin Tablets 343 Riboflavin Tablets 343 Rubefacient Analgesic Ointment 344 Saccharin Effervescent Tablets 344 Saccharin Tablets 344 Saccharin Tablets 345 Salicylic Acid Cream 345 Scopolamine Tablets 345 Selegiline Tablets 346 Selenium Sulfide Shampoo with Conditioner 346 Sertraline L-Lactate Osmotic Tablets 347 Serratio Peptidase Tablets 347 Silicone Protective Cream 347 Silymarin Tablets 347 Simethicone and Magnesium Carbonate Tablets 348 Simethicone Chewable Tablets 348 Simethicone Chewable Tablets 349 Simethicone Instant Granules (60 mg and 120 mg) 349 Simethicone Tablets 349 Sodium Fluoride Tablets 350 Sodium Fluoride Tablets 350 Spirulina Extract Chewable Tablets 350 Sucralfate and Sodium Alginate Tablets 351 Sulfur Antiseptic Ointment 351 Tannin–Crospovidone Complex Tablets 352 Tetrahydrozoline Eye Drops 352 Thiamine and Caffeine Tablets 353 Thiamine Hydrochloride Tablets 353 Thiamine Hydrochloride Tablets (Sugar-Coated) 354 Thiamine, Pyridoxine, and Cyanocobalamin Tablets 355 Thiamine, Pyridoxine, and Cyanocobalamin Tablets 356

Thiamine, Pyridoxine, and Cyanocobalamin Tablets 356 Thiamine, Pyridoxine, and Cyanocobalamin Tablets 357 Thiamine, Pyridoxine, and Cyanocobalamin Tablets 357 Thiamine Tablets 357 Thiamine Tablets 358 Thiamine Tablets 358 Thiamine Tablets 358 Thiamine Tablets 359 Tolnaftate and Undecylenate Foot Care Cream 359 Tolnaftate Foot Care Microemulsion 359 Tolu Balsam Cough Syrup 360 Triclosan and Zinc Foot Deodorant Powder 361 Triclosan Foot Care Cream 361 Triprolidine and Pseudoephedrine Hydrochloride Syrup 362 Triprolidine and Pseudoephedrine Hydrochloride Tablets 362 Trolamine Salicylate Cream 363 Ultrasonic Adhesive Gel 363 Urea Peroxide Ear Drops 364 Valeriana and Passiflora Extract Tablets 364 Vitamin A and Vitamin D Infant Drops 365 Vitamin A and Vitamin D3 Drops 366 Vitamin A and Vitamin D3 Oral Solution 366 Vitamin A and Vitamin D3 Syrup 366 Vitamin A and Vitamin E Drops 367 Vitamin A and Vitamin E Drops 367 Vitamin A and Vitamin E Tablets 367 Vitamin A Chewable Tablets 367 Vitamin A Concentrate (Water-Miscible) 368 Vitamin A Drops 368 Vitamin A Suppositories 368 Vitamin A Tablets 368 Vitamin A Tablets 369 Vitamin A Tablets 369 Vitamin A Tablets 369 Vitamin A Tablets 369 Vitamin A, Vitamin B6 , and Vitamin E Tablets 370 Vitamin A, Vitamin C, and Vitamin D3 Chewable Tablets 370 Vitamin A, Vitamin C, and Vitamin E Tablets (1200 IU, 60 mg, 30 mg) 370 Vitamin B Complex, Amino Acids, and Magnesium Effervescent Granules (Sugar-Free) 371 Vitamin B Complex + Amino Acid + Magnesium Effervescent Granules (Sugar-free, 1 RDA of vitamins + 500 mg carnitine + 20 mg glutamine) 371 Vitamin B Complex and Carnitine Tablets 372 Vitamin B Complex and Folic Acid Drag´ees 373 Vitamin B Complex and Iron Syrup 374 Vitamin B Complex and Vitamin C Effervescent Tablets 375 Vitamin B Complex and Vitamin C Instant Granules 376 Vitamin B Complex and Vitamin C Syrup 376 Vitamin B Complex and Vitamin C Syrup 377 Vitamin B Complex and Vitamin C Tablets 377 Vitamin B Complex and Vitamin C Tablets 378 Vitamin B Complex, Choline, and Bile Tablets 378

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Vitamin B Complex Syrup 379 Vitamin B Complex Syrup 380 Vitamin B Complex Syrup (without B12 ) 381 Vitamin B Complex Tablets 382 Vitamin B Complex Tablets 382 Vitamin B Complex Tablets 383 Vitamin B Complex, Vitamin A, Vitamin C, and Vitamin D Syrup 384 Vitamin B Complex, Vitamin A, Vitamin C, and Vitamin D Tablets 385 Vitamin B Complex, Vitamin A, Vitamin C, Vitamin D, and Calcium Drops 386 Vitamin B Complex, Vitamin A, Vitamin C, Vitamin D, and Mineral Tablets 387 Vitamin B Complex, Vitamin A, Vitamin C, Vitamin D, and Vitamin E Pediatric Drops 388 Vitamin B Complex, Vitamin C, and Calcium Effervescent Tablets 389 Vitamin B Complex, Vitamin C, and Ferrous Sulfate Tablets 389 Vitamin B Complex, Vitamin C, and Iron Syrup 390 Vitamin B Complex, Vitamin C, and Iron Syrup 391 Vitamin B Complex, Vitamin C, and Vitamin E Tablets 392 Vitamin C and Calcium Carbonate Effervescent Tablets 393 Vitamin C and Vitamin E Lozenges 393 Vitamin C Chewable Tablets 393 Vitamin C Chewable Tablets 394 Vitamin C Chewable Tablets 394 Vitamin C Chewable Tablets 395 Vitamin C Chewable Tablets 395 Vitamin C Chewable Tablets with Dextrose 396 Vitamin C Chewable Tablets with Fructose 396 Vitamin C Chewable Tablets with Sucrose 396 Vitamin C Drops 397 Vitamin C Effervescent Tablets 397 Vitamin C Effervescent Tablets 398 Vitamin C Effervescent Tablets 398 Vitamin C Effervescent Tablets 398 Vitamin C Tablets 399 Vitamin C Tablets 399 Vitamin C Tablets 399 Vitamin E and Benzocaine Solution 400 Vitamin E Chewable Tablets 400 Vitamin E Chewable Tablets 400 Vitamin E Chewable Tablets 401 Vitamin E Concentrate (Water-Miscible) 401 Vitamin E Drops 401 Vitamin E Gel Cream 401 Vitamin E Softgel Capsules 402 Vitamin E Solution with Ethanol 402 Vitamin E Tablets 402 Vitamin E Tablets 402 Zinc Oxide Lotion 403 Zinc Oxide Ointment 403 Zinc Pyrithione Shampoo 404 Zinc Undecylenate Cream 404 Zirconium Oxide Lotion 405

PART III TABLET COATING FORMULATIONS

Pharmaceutical Manufacturing Formulations 407 Introduction 407 I. Cellulose-Based 419 II. Hydroxypropyl Methyl Cellulose (Methocel, HPMC) Aqueous Coatings 419 A. Brite Rose 419 B. Cherry Red 420 C. Geranium Rose 420 D. Gloss 420 E. Red 420 F. Moderate Red 421 G. Clear 421 H. Green 422 I. Holberry Red 422 J. Sun Orange 422 K. Opadry Yellow 423 L. Opadry Yellow 423 M. Opadry Red 423 N. Opadry Green 424 O. White Coating 425 III. HPMC Opaque Organic Coating 425 A. Brite Green 425 B. Red Mahogany 426 C. Sun Orange 426 D. Dark Red 426 E. Deep Yellow 427 F. Pale Yellow 427 G. Scarlet Red 427 R IV. HPMC/HPC (Klucel ) Coating 428 A. White 428 V. HPMC/EC Coating 429 A. Reddish Orange Opaque 429 B. Subcoating Solution 429 VI. Hydroxymethyl Cellulose/Hydroxy Cellulose Coating 430 A. Blue 430 B. Clear (50:50) 430 VII. Hydroxymethyl Cellulose/EC Coating 431 A. Clear 431 VIII. Polyvinylpyrrolidone Coatings 431 A. Subcoating 431 B. Kollidon VA 64 (PVP/Vinyl Acetate Copolymer, BASF) 432 Sugar-Coating Pan 432 Accela Cota (Continuous Spraying) 432 C. Kollidon VA 64 and Polyvinyl Alcohol 433 D. Kollidon 30 and Shellac 434 E. Kollidon VA 64 and HPMC 434 F. Povidone, EC, and Talc 435 IX. Cellulose Acetate Phthalate and Carbowax Coatings 435 A. Brite Green 435 B. Cherry Red 435 C. Clear 435 D. Orange 435 X. Sugarcoatings 436 A. Basic 436 B. Automatic 436 C. Manual, White 437

Contents

XI. Enteric Coatings 438 R A. Kollicoat and Kollidon Enteric Film Coating 438 XII. Eudragit Enteric Aqueous 439 A. Brick Red 439 B. Yellow 439 C. Brown 440 D. Dark Orange 440

E. Orange 440 F. Dispersed Orange 441 XIII. HPMCP Enteric Coating 441 A. Clear Enteric 441 B. Orchid Pink Opaque 442 C. Light Apricot Orange 442 Index . . . . 443

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Part I Regulatory Guidance

1 EU Guidelines to Good Manufacturing Practice: Medicinal Products for Human and Veterinary Use

INTRODUCTION Document History The first edition of the guide was published, including an Annex on the manufacture of sterile medicinal products. The second edition was published; implementing Commission Directives 91/356 of June 13, 1991 and 91/412 of July 23, 1991 laying down the principles and guidelines on good manufacturing practice for medicinal products for human use as well as for veterinary medicinal products. The second edition also included 12 additional annexes. An update of legal references was made. In the meantime, the guide is updated as needed on the Web site of the European Commission, several additional Annexes added. Restructuring of GMP guide, consisting of part I for medicinal products for human and veterinary use and part II for active substances used as starting materials, implementing Directives 2004/27/EC and 2004/28/EC. The current guide includes 17 Annexes, the former Annex 18 being replaced. Implementation of ICH Q9 guideline as GMP Annex 20

1989 January 1992

August 2004 October 2005

March 2008

in two annexes specific to veterinary medicinal products and to immunologic veterinary medicinal products. The guide is presented in two parts of basic requirements and specific annexes. Part I covers GMP principles for the manufacture of medicinal products. Part II covers GMP for active substances used as starting materials. Chapters of part I on “basic requirements” are headed by principles as defined in Directives 2003/94/EC and 91/412/EEC. Chapter 1 on Quality Management outlines the fundamental concept of quality assurance as applied to the manufacture of medicinal products. Thereafter, each chapter has a principle outlining the quality assurance objectives of that chapter and a text which provides sufficient detail for manufacturers to be made aware of the essential matters to be considered when implementing the principle. Part II was newly established on the basis of a guideline developed on the level of ICH and published as ICH Q7 a on “active pharmaceutical ingredients,” which was implemented as GMP Annex 18 for voluntary application in 2001. According to the revised Article 47 and Article 51, respectively, of the Directive 2001/83/EC and Directive 2001/82/EC, as amended, detailed guidelines on the principles of GMP for active substances used as starting materials shall be adopted and published by the Commission. The former Annex 18 has been replaced by the new part II of the GMP guide, which has an extended application both for the human and the veterinary sector. In addition to the general matters of Good Manufacturing Practice outlined in part I and II, a series of annexes providing detail about specific areas of activity is included. For some manufacturing processes, different annexes will apply simultaneously (e.g., Annex on Sterile Preparations and on Radiopharmaceuticals and/or on Biological Medicinal Products). GMP part I, Chapter 1 on Quality Management, has been revised to include aspects of quality risk management within the quality system framework. In future revisions of

The pharmaceutical industry of the European Union maintains high standards of quality assurance in the development, manufacture, and control of medicinal products. A system of marketing authorizations ensures that all medicinal products are assessed by a competent authority to ensure compliance with contemporary requirements of safety, quality, and efficacy. A system of manufacturing authorizations ensures that all products authorized on the European market are manufactured only by authorized manufacturers, whose activities are regularly inspected by the competent authorities. Manufacturing authorizations are required by all pharmaceutical manufacturers in the European Community whether the products are sold within or outside the community. Two directives laying down principles and guidelines of good manufacturing practice (GMP) for medicinal products were adopted by the Commission. Directive 2003/94/EC applies to medicinal products for human use and Directive 91/412/EEC for veterinary use. Detailed guidelines in accordance with those principles are published in the Guide to Good Manufacturing Practice, which will be used in assessing applications for manufacturing authorizations and as a basis for inspection of manufacturers of medicinal products. The principles of GMP and the detailed guidelines are applicable to all operations which require the authorization referred to in Article 40 of Directive 2001/83/EC and in Article 44 of Directive 2001/82/EC, as amended by Directives 2004/27/EC and 2004/28/EC, respectively. They are also relevant for all other large scale pharmaceutical manufacturing processes, such as that undertaken in hospitals, and for the preparation of products for use in clinical trials. All member states and the industry agreed that the GMP requirements applicable to the manufacture of veterinary medicinal products are the same as those applicable to the manufacture of medicinal products for human use. Certain detailed adjustments to the GMP guidelines are set out 2

EU Guidelines to Good Manufacturing Practice: Medicinal Products for Human and Veterinary Use

the guide, the opportunity will be taken to introduce quality risk management elements when appropriate. The new GMP Annex 20, which corresponds to the ICH Q9 guideline, provides guidance on a systematic approach to quality risk management leading to compliance with GMP and other quality requirements. It includes principles to be used and options for processes, methods, and tools, which may be used when applying a formal quality risk management approach. While the GMP guide is primarily addressed to manufacturers, the ICH Q9 guideline, has relevance for other quality guidelines and includes specific sections for regulatory agencies. However, for reasons of coherence and completeness the ICH Q9 guideline has been transferred completely into GMP Annex 20. A glossary of some terms used in the guide has been incorporated after the annexes. The guide is not intended to cover security aspects for the personnel engaged in manufacture. This may be particularly important in the manufacture of certain medicinal products such as highly active, biological, and radioactive medicinal products. However, those aspects are governed by other provisions of Community or National Law. Throughout the guide, it is assumed that the requirements of the Marketing Authorization relating to the safety, quality, and efficacy of the products are systematically incorporated into all the manufacturing, control and release for sale arrangements of the holder of the Manufacturing Authorization. The manufacture of medicinal products has for many years taken place in accordance with guidelines for Good Manufacturing Practice and the manufacture of medicinal products is not governed by CEN/ISO standards. Harmonized standards as adopted by the European Standardization Organizations CEN/ISO may be used at industry’s discretion as a tool for implementing a quality system in the pharmaceutical sector. The CEN/ISO standards have been considered but the terminology of these standards has not been implemented in this edition. It is recognized that there are acceptable methods, other than those described in the guide, which are capable of achieving the principles of Quality Assurance. The guide is not intended to place any restraint upon the development of any new concepts or new technologies which have been validated and which provide a level of Quality Assurance at least equivalent to those set out in this guide. With its principles, methods, and tools, Annex 20 provides a systematic approach, which may be used to demonstrate such equivalence. The GMP guide will be regularly revised. Revisions will be made publicly available on the Web site of the European Commission (http://ec.europa.eu/enterprise/ pharmaceuticals/eudralex/homev4.htm).

PART I CHAPTER 1: QUALITY MANAGEMENT Principle The holder of a Manufacturing Authorization must manufacture medicinal products so as to ensure that they are fit for their intended use, comply with the requirements of the Marketing Authorization, and do not place patients at risk due to inadequate safety, quality, or efficacy. The attainment of this quality objective is the responsibility of senior management and requires the participation and commitment by staff in many different departments and at all levels within the company, by the company’s suppliers, and by the distrib-

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utors. To achieve the quality objective reliably, there must be a comprehensively designed and correctly implemented system of Quality Assurance incorporating Good Manufacturing Practice, Quality Control, and Quality Risk Management. It should be fully documented and its effectiveness monitored. All parts of the Quality Assurance System should be adequately resourced with competent personnel, and suitable and sufficient premises, equipment, and facilities. There are additional legal responsibilities for the holder of the Manufacturing Authorization and for the Qualified Person(s). The basic concepts of Quality Assurance, Good Manufacturing Practice, Quality Control, and Quality Risk Management are interrelated. They are described here in order to emphasize their relationships and their fundamental importance to the production and control of medicinal products.

Quality Assurance 1.1 Quality Assurance is a wide-ranging concept, which covers all matters, which individually or collectively influence the quality of a product. It is the sum total of the organized arrangements made with the objective of ensuring that medicinal products are of the quality required for their intended use. Quality Assurance therefore incorporates Good Manufacturing Practice plus other factors outside the scope of this guide. The system of Quality Assurance appropriate for the manufacture of medicinal products should ensure that (i) medicinal products are designed and developed in a way that takes account of the requirements of GMP; (ii) production and control operations are clearly specified and GMP adopted; (iii) managerial responsibilities are clearly specified; (iv) arrangements are made for the manufacture, supply, and use of the correct starting and packaging materials; (v) all necessary controls on intermediate products, and any other in-process controls and validations are carried out; (vi) the finished product is correctly processed and checked, according to the defined procedures; (vii) medicinal products are not sold or supplied before a Qualified Person has certified that each production batch has been produced and controlled in accordance with the requirements of the Marketing Authorization and any other regulations relevant to the production, control, and release of medicinal products; (viii) satisfactory arrangements exist to ensure, as far as possible, that the medicinal products are stored, distributed, and subsequently handled so that quality is maintained throughout their shelf life; and (ix) there is a procedure for Self-Inspection and/or quality audit, which regularly appraises the effectiveness and applicability of the Quality Assurance system.

Good Manufacturing Practice for Medicinal Products 1.2 GMP is that part of Quality Assurance which ensures that products are consistently produced and controlled to the quality standards appropriate to their intended use and as required by the Marketing Authorization or product specification.

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Handbook of Pharmaceutical Manufacturing Formulations: Over-the-Counter Products

Good Manufacturing Practice is concerned with both production and quality control. The basic requirements of GMP are that (i) all manufacturing processes are clearly defined, systematically reviewed in the light of experience, and shown to be capable of consistently manufacturing medicinal products of the required quality and complying with their specifications; (ii) critical steps of manufacturing processes and significant changes to the process are validated; (iii) all necessary facilities for GMP are provided including appropriately qualified and trained personnel, adequate premises and space, suitable equipment and services, correct materials, containers and labels, approved procedures and instructions, and suitable storage and transport (iv) instructions and procedures are written in an instructional form in clear and unambiguous language, specifically applicable to the facilities provided; (v) operators are trained to carry out procedures correctly; (vi) records are made, manually and/or by recording instruments, during manufacture which demonstrate that all the steps required by the defined procedures and instructions were in fact taken and that the quantity and quality of the product was as expected. Any significant deviations are fully recorded and investigated; (vii) records of manufacture including distribution which enable the complete history of a batch to be traced, are retained in a comprehensible and accessible form; (viii) the distribution (wholesaling) of the products minimizes any risk to their quality; (ix) a system is available to recall any batch of product, from sale or supply; and (x) complaints about marketed products are examined, the causes of quality defects investigated, and appropriate measures taken in respect of the defective products and to prevent reoccurrence.

Quality Control 1.3 Quality Control is that part of Good Manufacturing Practice which is concerned with sampling, specifications, and testing, and with the organization, documentation, and release procedures which ensure that the necessary and relevant tests are actually carried out and that materials are not released for use, nor products released for sale or supply, until their quality has been judged to be satisfactory. The basic requirements of Quality Control are that (i) adequate facilities, trained personnel, and approved procedures are available for sampling, inspecting and testing starting materials, packaging materials, intermediate, bulk, and finished products, and where appropriate for monitoring environmental conditions for GMP purposes; (ii) samples of starting materials, packaging materials, intermediate products, bulk products, and finished products are taken by personnel and by methods approved by Quality Control; (iii) test methods are validated;

(iv) records are made, manually and/or by recording instruments, which demonstrate that all the required sampling, inspecting, and testing procedures were actually carried out. Any deviations are fully recorded and investigated; (v) the finished products contain active ingredients complying with the qualitative and quantitative composition of the Marketing Authorization, are of the purity required, and are enclosed within their proper containers and correctly labeled; (vi) records are made of the results of inspection and that testing of materials, intermediate, bulk, and finished products is formally assessed against specification. Product assessment includes a review and evaluation of relevant production documentation and an assessment of deviations from specified procedures; (vii) no batch of product is released for sale or supply prior to certification by a Qualified Person that it is in accordance with the requirements of the relevant authorizations; and (viii) sufficient reference samples of starting materials and products are retained to permit future examination of the product if necessary and that the product is retained in its final pack unless exceptionally large packs are produced.

Product Quality Review 1.4 Regular periodic or rolling quality reviews of all licensed medicinal products, including export only products, should be conducted with the objective of verifying the consistency of the existing process, the appropriateness of current specifications for both starting materials and finished product to highlight any trends, and to identify product and process improvements. Such reviews should normally be conducted and documented annually, taking into account previous reviews, and should include at least (i) a review of starting materials including packaging materials used in the product, especially those from new sources; (ii) a review of critical in-process controls and finished product results; (iii) a review of all batches that failed to meet established specification(s) and their investigation; (iv) a review of all significant deviations or nonconformances, their related investigations, and the effectiveness of resultant corrective and preventative actions taken; (v) a review of all changes carried out to the processes or analytical methods; (vi) a review of Marketing Authorization variations submitted/granted/refused, including those for third country (export only) dossiers; (vii) a review of the results of the stability monitoring program and any adverse trends; (viii) a review of all quality-related returns, complaints, and recalls and the investigations performed at the time; (ix) a review of adequacy of any other previous product process or equipment corrective actions; (x) for new marketing authorizations and variations to marketing authorizations, a review of postmarketing commitments;

EU Guidelines to Good Manufacturing Practice: Medicinal Products for Human and Veterinary Use

(xi) the qualification status of relevant equipment and utilities, for example, HVAC, water, compressed gases,; and (xii) a review of any contractual arrangements as defined in Chapter 7 to ensure that they are up to date. The manufacturer and marketing authorization holder should evaluate the results of this review, where different, and an assessment made of whether corrective and preventative action or any revalidation should be undertaken. Reasons for such corrective actions should be documented. Agreed corrective and preventative actions should be completed in a timely and effective manner. There should be management procedures for the ongoing management and review of these actions and the effectiveness of these procedures verified during selfinspection. Quality reviews may be grouped by product type, for example, solid dosage forms, liquid dosage forms, sterile products, and so on, where scientifically justified. Where the marketing authorization holder is not the manufacturer, there should be a technical agreement in place between the various parties that defines their respective responsibilities in producing the quality review. The Qualified Person responsible for final batch certification together with the marketing authorization holder should ensure that the quality review is performed in a timely manner and is accurate.

Quality Risk Management 1.5 Quality Risk Management is a systematic process for the assessment, control, communication, and review of risks to the quality of the medicinal product. It can be applied both proactively and retrospectively. 1.6 The Quality Risk Management system should ensure that: the evaluation of the risk to quality is based on scientific knowledge, experience with the process, and ultimately links to the protection of the patient; and the level of effort, formality, and documentation of the quality risk management process is commensurate with the level of risk.

CHAPTER 2: PERSONNEL Principle The establishment and maintenance of a satisfactory system of quality assurance and the correct manufacture of medicinal products relies upon people. For this reason, there must be sufficient qualified personnel to carry out all the tasks which are the responsibility of the manufacturer. Individual responsibilities should be clearly understood by the individuals and recorded. All personnel should be aware of the principles of Good Manufacturing Practice that affect them and receive initial and continuing training, including hygiene instructions, relevant to their needs.

General 2.1 The manufacturer should have an adequate number of personnel with the necessary qualifications and practical experience. The responsibilities placed on any one individual should not be so extensive as to present any risk to quality. 2.2 The manufacturer must have an organization chart. People in responsible positions should have specific duties recorded in written job descriptions and adequate au-

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thority to carry out their responsibilities. Their duties may be delegated to designated deputies of a satisfactory qualification level. There should be no gaps or unexplained overlaps in the responsibilities of those personnel concerned with the application of Good Manufacturing Practice.

Key Personnel 2.3 Key Personnel include the head of Production, the head of Quality Control, and if at least one of these persons is not responsible for the duties described in Article 51 of Directive 2001/83/EC1, the Qualified Person(s) designated for the purpose. Normally, key posts should be occupied by full-time personnel. The heads of Production and Quality Control must be independent from each other. In large organizations, it may be necessary to delegate some of the functions listed in 2.5, 2.6, and 2.7. 2.4 The duties of the Qualified Person(s) are fully described in Article 51 of Directive 2001/83/EC, and can be summarized as follows: (a) For medicinal products manufactured within the European Community, a Qualified Person must ensure that each batch has been produced and tested/ checked in accordance with the directives and the marketing authorization (2). (b) For medicinal products manufactured outside the European Community, a Qualified Person must ensure that each imported batch has undergone, in the importing country, the testing specified in paragraph 1(b) of Article 51; Article 55 of Directive 2001/82/EC (2) According to Directive 75/319/EEC (now codified Directive 2001/83/EC) and the Ruling (Case 247/81) of the Court of Justice of the European Communities, medicinal products which have been properly controlled in the EU by a Qualified Person do not have to be recontrolled or rechecked in any other member state of the community. (c) a Qualified Person must certify in a register or equivalent document, as operations are carried out and before any release, that each production batch satisfies the provisions of Article 51. The persons responsible for these duties must meet the qualification requirements laid down in Article 49(3) of the same Directive, they shall be permanently and continuously at the disposal of the holder of the Manufacturing Authorization to carry out their responsibilities. Their responsibilities may be delegated, but only to other Qualified Person(s). 2.5 The head of the Production Department generally has the following responsibilities: i. to ensure that products are produced and stored according to the appropriate documentation in order to obtain the required quality; ii. to approve the instructions relating to production operations and to ensure their strict implementation; iii. to ensure that the production records are evaluated and signed by an authorized person before they are sent to the Quality Control Department; iv. to check the maintenance of his department, premises, and equipment; v. to ensure that the appropriate validations are done; and vi. to ensure that the required initial and continuing training of his department personnel is carried out and adapted according to need.

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Handbook of Pharmaceutical Manufacturing Formulations: Over-the-Counter Products

2.6 The head of the Quality Control Department generally has the following responsibilities: i. to approve or reject, as he sees fit, starting materials, packaging materials, and intermediate, bulk, and finished products; ii. to evaluate batch records; iii. to ensure that all necessary testing is carried out; iv. to approve specifications, sampling instructions, test methods, and other Quality Control procedures; v. to approve and monitor any contract analysts; vi. to check the maintenance of his department, premises, and equipment; vii. to ensure that the appropriate validations are done; and viii. to ensure that the required initial and continuing training of his department personnel is carried out and adapted according to need. Other duties of the Quality Control Department are summarized in Chapter 6. 2.7 The heads of Production and Quality Control generally have some shared, or jointly exercised, responsibilities relating to quality. These may include, subject to any national regulations: - the authorization of written procedures and other documents, including amendments; - the monitoring and control of the manufacturing environment; - plant hygiene; - process validation; - training; - the approval and monitoring of suppliers of materials; - the approval and monitoring of contract manufacturers; - the designation and monitoring of storage conditions for materials and products; - the retention of records; - the monitoring of compliance with the requirements of Good Manufacturing Practice; and - the inspection, investigation, and taking of samples, in order to monitor factors which may affect product quality.

Training 2.8 The manufacturer should provide training for all the personnel whose duties take them into production areas or into control laboratories (including the technical, maintenance, and cleaning personnel), and for other personnel whose activities could affect the quality of the product. 2.9 Besides the basic training on the theory and practice of Good Manufacturing Practice, newly recruited personnel should receive training appropriate to the duties assigned to them. Continuing training should also be given, and its practical effectiveness should be periodically assessed. Training programs should be available, approved by either the head of Production or the head of Quality Control, as appropriate. Training records should be kept. 2.10 Personnel working in areas where contamination is a hazard, for example, clean areas or areas where highly active, toxic, infectious, or sensitizing materials are handled, should be given specific training. 2.11 Visitors or untrained personnel should, preferably, not be taken into the production and quality control areas. If this is unavoidable, they should be given information in advance, particularly about personal hygiene and the

prescribed protective clothing. They should be closely supervised. 2.12 The concept of Quality Assurance and all the measures capable of improving its understanding and implementation should be fully discussed during the training sessions.

Personnel Hygiene 2.13 Detailed hygiene programs should be established and adapted to the different needs within the factory. They should include procedures relating to the health, hygiene practices, and clothing of personnel. These procedures should be understood and followed in a very strict way by every person whose duties take him into the production and control areas. Hygiene programs should be promoted by management and widely discussed during training sessions. 2.14 All personnel should receive medical examination upon recruitment. It must be the manufacturer’s responsibility that there are instructions ensuring that health conditions that can be of relevance to the quality of products come to the manufacturer’s knowledge. After the first medical examination, examinations should be carried out when necessary for the work and personal health. 2.15 Steps should be taken to ensure as far as is practicable that no person affected by an infectious disease or having open lesions on the exposed surface of the body is engaged in the manufacture of medicinal products. 2.16 Every person entering the manufacturing areas should wear protective garments appropriate to the operations to be carried out. 2.17 Eating, drinking, chewing or smoking, or the storage of food, drink, smoking materials, or personal medication in the production and storage areas should be prohibited. In general, any unhygienic practice within the manufacturing areas or in any other area where the product might be adversely affected, should be forbidden. 2.18 Direct contact should be avoided between the operator’s hands and the exposed product as well as with any part of the equipment that comes into contact with the products. 2.19 Personnel should be instructed to use the hand-washing facilities. 2.20 Any specific requirements for the manufacture of special groups of products, for example sterile preparations, are covered in the Annexes.

CHAPTER 3: PREMISES AND EQUIPMENT Principle Premises and equipment must be located, designed, constructed, adapted, and maintained to suit the operations to be carried out. Their layout and design must aim to minimize the risk of errors and permit effective cleaning and maintenance in order to avoid cross-contamination, build up of dust or dirt and, in general, any adverse effect on the quality of products.

Premises General 3.1 Premises should be situated in an environment which, when considered together with measures to protect the

EU Guidelines to Good Manufacturing Practice: Medicinal Products for Human and Veterinary Use

3.2

3.3

3.4 3.5

manufacture, presents minimal risk of causing contamination of materials or products. Premises should be carefully maintained, ensuring that repair and maintenance operations do not present any hazard to the quality of products. They should be cleaned and, where applicable, disinfected according to detailed written procedures. Lighting, temperature, humidity, and ventilation should be appropriate and such that they do not adversely affect, directly or indirectly, either the medicinal products during their manufacture and storage, or the accurate functioning of equipment. Premises should be designed and equipped so as to afford maximum protection against the entry of insects or other animals. Steps should be taken in order to prevent the entry of unauthorized people. Production, storage, and quality control areas should not be used as a right of way by personnel who do not work in them.

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3.12 Production areas should be effectively ventilated, with air control facilities (including temperature and, where necessary, humidity, and filtration) appropriate both to the products handled, to the operations undertaken within them and to the external environment. 3.13 Weighing of starting materials usually should be carried out in a separate weighing room designed for that use. 3.14 In cases where dust is generated (e.g., during sampling, weighing, mixing and processing operations, packaging of dry products), specific provisions should be taken to avoid cross- contamination and facilitate cleaning. 3.15 Premises for the packaging of medicinal products should be specifically designed and laid out so as to avoid mix-ups or cross-contamination. 3.16 Production areas should be well lit, particularly where visual controls are carried out. 3.17 In-process controls may be carried out within the production area provided they do not carry any risk for the production.

Storage Areas Production Area 3.6 In order to minimize the risk of a serious medical hazard due to cross-contamination, dedicated and selfcontained facilities must be available for the production of particular medicinal products, such as highly sensitizing materials (e.g., penicillins) or biological preparations (e.g., from live microorganisms). The production of certain additional products, such as certain antibiotics, certain hormones, certain cytotoxics, certain highly active drugs, and nonmedicinal products should not be conducted in the same facilities. For those products, in exceptional cases, the principle of campaign working in the same facilities can be accepted provided that specific precautions are taken and the necessary validations are made. The manufacture of technical poisons, such as pesticides and herbicides, should not be allowed in premises used for the manufacture of medicinal products. 3.7 Premises should preferably be laid out in such a way as to allow the production to take place in areas connected in a logical order corresponding to the sequence of the operations and to the requisite cleanliness levels. 3.8 The adequacy of the working and in-process storage space should permit the orderly and logical positioning of equipment and materials so as to minimize the risk of confusion between different medicinal products or their components, to avoid cross-contamination and to minimize the risk of omission or wrong application of any of the manufacturing or control steps. 3.9 Where starting and primary packaging materials, intermediate or bulk products are exposed to the environment, interior surfaces (walls, floors, and ceilings) should be smooth, free from cracks and open joints, and should not shed particulate matter and should permit easy and effective cleaning and, if necessary, disinfection. 3.10 Pipework, light fittings, ventilation points, and other services should be designed and sited to avoid the creation of recesses which are difficult to clean. As far as possible, for maintenance purposes, they should be accessible from outside the manufacturing areas. 3.11 Drains should be of adequate size, and have trapped gullies. Open channels should be avoided where possible, but if necessary, they should be shallow to facilitate cleaning and disinfection.

3.18 Storage areas should be of sufficient capacity to allow orderly storage of the various categories of materials and products: starting and packaging materials, intermediate, bulk, and finished products, products in quarantine, released, rejected, returned, or recalled. 3.19 Storage areas should be designed or adapted to ensure good storage conditions. In particular, they should be clean and dry and maintained within acceptable temperature limits. Where special storage conditions are required (e.g., temperature, humidity) these should be provided, checked, and monitored. 3.20 Receiving and dispatch bays should protect materials and products from the weather. Reception areas should be designed and equipped to allow containers of incoming materials to be cleaned where necessary before storage. 3.21 Where quarantine status is ensured by storage in separate areas, these areas must be clearly marked and their access restricted to authorized personnel. Any system replacing the physical quarantine should give equivalent security. 3.22 There should normally be a separate sampling area for starting materials. lf sampling is performed in the storage area, it should be conducted in such a way as to prevent contamination or cross-contamination. 3.23 Segregated areas should be provided for the storage of rejected, recalled, or returned materials or products. 3.24 Highly active materials or products should be stored in safe and secure areas. 3.25 Printed packaging materials are considered critical to the conformity of the medicinal product and special attention should be paid to the safe and secure storage of these materials.

Quality Control Areas 3.26 Normally, Quality Control laboratories should be separated from production areas. This is particularly important for laboratories for the control of biologicals, microbiologicals, and radioisotopes, which should also be separated from each other. 3.27 Control laboratories should be designed to suit the operations to be carried out in them. Sufficient space should be given to avoid mix-ups and cross-contamination. There should be adequate suitable storage space for samples and records.

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Handbook of Pharmaceutical Manufacturing Formulations: Over-the-Counter Products

3.28 Separate rooms may be necessary to protect sensitive instruments from vibration, electrical interference, humidity, and so on. 3.29 Special requirements are needed in laboratories handling particular substances, such as biological or radioactive samples.

Ancillary Areas 3.30 Rest and refreshment rooms should be separate from other areas. 3.31 Facilities for changing clothes, washing, and toilet purposes should be easily accessible and appropriate for the number of users. Toilets should not directly communicate with production or storage areas. 3.32 Maintenance workshops should as far as possible be separated from production areas. Whenever parts and tools are stored in the production area, they should be kept in rooms or lockers reserved for that use. 3.33 Animal houses should be well isolated from other areas, with separate entrance (animal access) and air handling facilities.

Equipment 3.34 Manufacturing equipment should be designed, located, and maintained to suit its intended purpose. 3.35 Repair and maintenance operations should not present any hazard to the quality of the products. 3.36 Manufacturing equipment should be designed so that it can be easily and thoroughly cleaned. It should be cleaned according to detailed and written procedures and stored only in a clean and dry condition. 3.37 Washing and cleaning equipment should be chosen and used in order not to be a source of contamination. 3.38 Equipment should be installed in such a way as to prevent any risk of error or of contamination. 3.39 Production equipment should not present any hazard to the products. The parts of the production equipment that come into contact with the product must not be reactive, additive, or absorptive to such an extent that it will affect the quality of the product and thus present any hazard. 3.40 Balances and measuring equipment of an appropriate range and precision should be available for production and control operations. 3.41 Measuring, weighing, recording, and control equipment should be calibrated and checked at defined intervals by appropriate methods. Adequate records of such tests should be maintained. 3.42 Fixed pipework should be clearly labeled to indicate the contents and, where applicable, the direction of flow. 3.43 Distilled, deionized, and, where appropriate, other water pipes should be sanitized according to written procedures that detail the action limits for microbiological contamination and the measures to be taken. 3.44 Defective equipment should, if possible, be removed from production and quality control areas, or at least be clearly labeled as defective.

CHAPTER 4: DOCUMENTATION Principle Good documentation constitutes an essential part of the quality assurance system. Clearly written documentation prevents errors from spoken communication and permits tracing of batch history. Specifications, Manufacturing Formulae and

instructions, procedures, and records must be free from errors and available in writing. The legibility of documents is of paramount importance.

General 4.1 Specifications describe in detail the requirements with which the products or materials used or obtained during manufacture have to conform. They serve as a basis for quality evaluation. Manufacturing Formulae, Processing, and Packaging Instructions state all the starting materials used and lay down all processing and packaging operations. Procedures give directions for performing certain operations for example, cleaning, clothing, environmental control, sampling, testing, equipment operation. Records provide a history of each batch of product, including its distribution, and also of all other relevant circumstances pertinent to the quality of the final product. 4.2 Documents should be designed, prepared, reviewed, and distributed with care. They should comply with the relevant parts of the manufacturing and marketing authorization dossiers. 4.3 Documents should be approved, signed, and dated by appropriate and authorized persons. 4.4 Documents should have unambiguous contents; title, nature, and purpose should be clearly stated. They should be laid out in an orderly fashion and be easy to check. Reproduced documents should be clear and legible. The reproduction of working documents from master documents must not allow any error to be introduced through the reproduction process. 4.5 Documents should be regularly reviewed and kept upto-date. When a document has been revised, systems should be operated to prevent inadvertent use of superseded documents. 4.6 Documents should not be handwritten; although, where documents require the entry of data, these entries may be made in clear, legible, and indelible handwriting. Sufficient space should be provided for such entries. 4.7 Any alteration made to the entry on a document should be signed and dated; the alteration should permit the reading of the original information. Where appropriate, the reason for the alteration should be recorded. 4.8 The records should be made or completed at the time each action is taken and in such a way that all significant activities concerning the manufacture of medicinal products are traceable. They should be retained for at least 1 year after the expiry date of the finished product. 4.9 Data may be recorded by electronic data processing systems, photographic or other reliable means, but detailed procedures relating to the system in use should be available and the accuracy of the records should be checked. If documentation is handled by electronic data processing methods, only authorized persons should be able to enter or modify data in the computer and there should be a record of changes and deletions; access should be restricted by passwords or other means and the result of entry of critical data should be independently checked. Batch records electronically stored should be protected by back-up transfer on magnetic tape, microfilm, paper, or other means. It is particularly important that the data are readily available throughout the period of retention.

EU Guidelines to Good Manufacturing Practice: Medicinal Products for Human and Veterinary Use

4.10 There should be appropriately authorized and dated specifications for starting and packaging materials, and finished products; where appropriate, they should be also available for intermediate or bulk products.

Specifications for Starting and Packaging Materials 4.11 Specifications for starting and primary or printed packaging materials should include, if applicable: r a description of the materials, including ◦ the designated name and the internal code reference; ◦ the reference, if any, to a pharmacopoeia monograph; ◦ the approved suppliers and, if possible, the original producer of the products; r (a) specimen of printed materials; (b) directions for sampling and testing or reference to procedures; (c) qualitative and quantitative requirements with acceptance limits; and (d) storage conditions and precautions; r the maximum period of storage before reexamination.

Specifications for Intermediate and Bulk Products 4.12 Specifications for intermediate and bulk products should be available if these are purchased or dispatched, or if data obtained from intermediate products are used for the evaluation of the finished product. The specifications should be similar to specifications for starting materials or for finished products, as appropriate.

Specifications for Finished Products 4.13 Specifications for finished products should include (a) the designated name of the product and the code reference where applicable; (b) the formula or a reference; (c) a description of the pharmaceutical form and package details; (d) directions for sampling and testing or a reference to procedures; (e) the qualitative and quantitative requirements, with the acceptance limits; (f) the storage conditions and any special handling precautions, where applicable; and (g) the shelf life.

Manufacturing Formula and Processing Instructions Formally authorized Manufacturing Formula and Processing Instructions should exist for each product and batch size to be manufactured. They are often combined in one document. 4.14 The Manufacturing Formula should include (a) the name of the product, with a product reference code relating to its specification; (b) a description of the pharmaceutical form, strength of the product, and batch size; (c) a list of all starting materials to be used, with the amount of each, described using the designated name and a reference which is unique to that material; mention should be made of any substance that may disappear in the course of processing; and (d) a statement of the expected final yield with the acceptable limits, and of relevant intermediate yields, where applicable. 4.15 The Processing Instructions should include a) a statement of the processing location and the principal equipment to be used; b) the methods, or reference to the methods, to be used for preparing the critical equipment (e.g., cleaning, assembling, calibrating, sterilizing); c) detailed stepwise processing instructions (e.g., checks on materials, pretreatments, sequence for adding materials, mixing times, temperatures);

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d) the instructions for any in-process controls with their limits; e) where necessary, the requirements for bulk storage of the products; including the container, labeling, and special storage conditions where applicable; and f) any special precautions to be observed.

Packaging Instructions 4.16 There should be formally authorized Packaging Instructions for each product, pack size, and type. These should normally include, or have a reference to, the following: a) name of the product; b) description of its pharmaceutical form, and strength where applicable; c) the pack size expressed in terms of the number, weight, or volume of the product in the final container; d) a complete list of all the packaging materials required for a standard batch size, including quantities, sizes, and types, with the code or reference number relating to the specifications of each packaging material; e) where appropriate, an example or reproduction of the relevant printed packaging materials, and specimens indicating where to apply batch number references, and shelf life of the product; f) special precautions to be observed, including a careful examination of the area and equipment in order to ascertain the line clearance before operations begin; g) a description of the packaging operation, including any significant subsidiary operations, and equipment to be used; and h) details of in-process controls with instructions for sampling and acceptance limits.

Batch Processing Records 4.17 A Batch Processing Record should be kept for each batch processed. It should be based on the relevant parts of the currently approved Manufacturing Formula and Processing Instructions. The method of preparation of such records should be designed to avoid transcription errors. The record should carry the number of the batch being manufactured. Before any processing begins, there should be recorded checks that the equipment and work station are clear of previous products, documents, or materials not required for the planned process, and that equipment is clean and suitable for use. During processing, the following information should be recorded at the time each action is taken and, after completion, the record should be dated and signed in agreement by the person responsible for the processing operations: a) the name of the product; b) dates and times of commencement, of significant intermediate stages and of completion of production; c) name of the person responsible for each stage of production; d) initials of the operator of different significant steps of production and, where appropriate, of the person who checked each of these operations (e.g., weighing); e) the batch number and/or analytical control number as well as the quantities of each starting material actually weighed (including the batch number and amount of any recovered or reprocessed material added);

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Handbook of Pharmaceutical Manufacturing Formulations: Over-the-Counter Products

f) any relevant processing operation or event and major equipment used; g) a record of the in-process controls and the initials of the person(s) carrying them out, and the results obtained; h) the product yield obtained at different and pertinent stages of manufacture; and i) notes on special problems including details, with signed authorization for any deviation from the Manufacturing Formula and Processing Instructions.

Batch Packaging Records 4.18 A Batch Packaging Record should be kept for each batch or part batch processed. It should be based on the relevant parts of the Packaging Instructions and the method of preparation of such records should be designed to avoid transcription errors. The record should carry the batch number and the quantity of bulk product to be packed, as well as the batch number and the planned quantity of finished product that will be obtained. Before any packaging operation begins, there should be recorded checks that the equipment and work station are clear of previous products, documents, or materials not required for the planned packaging operations, and that equipment is clean and suitable for use. The following information should be entered at the time each action is taken and, after completion, the record should be dated and signed in agreement by the person(s) responsible for the packaging operations: a) the name of the product; b) the date(s) and times of the packaging operations; c) the name of the responsible person carrying out the packaging operation; d) the initials of the operators of the different significant steps; e) records of checks for identity and conformity with the packaging instructions, including the results of in-process controls; f) details of the packaging operations carried out, including references to equipment and the packaging lines used; g) whenever possible, samples of printed packaging materials used, including specimens of the batch coding, expiry dating, and any additional overprinting; h) notes on any special problems or unusual events including details, with signed authorization for any deviation from the Manufacturing Formula and Processing Instructions; and i) the quantities and reference number or identification of all printed packaging materials and bulk product issued, used, destroyed, or returned to stock and the quantities of obtained product, in order to provide for an adequate reconciliation.

Procedures and Records Receipt 4.19 There should be written procedures and records for the receipt of each delivery of each starting and primary and printed packaging material. 4.20 The records of the receipts should include (a) the name of the material on the delivery note and the containers; (b) the “in-house” name and/or code of material (if different from a); (c) date of receipt; (d) supplier’s name and, if possible, manufacturer’s name; (e) manufacturer’s batch or reference number; (f) total quantity,

and number of containers received; (g) the batch number assigned after receipt; and (h) any relevant comment (e.g., state of the containers). 4.21 There should be written procedures for the internal labeling, quarantine and storage of starting materials, packaging materials, and other materials, as appropriate.

Sampling 4.22 There should be written procedures for sampling, which include the person(s) authorized to take samples, the methods and equipment to be used, the amounts to be taken, and any precautions to be observed to avoid contamination of the material or any deterioration in its quality (see Chapter 6, item 13).

Testing 4.23 There should be written procedures for testing materials and products at different stages of manufacture, describing the methods and equipment to be used. The tests performed should be recorded (see Chapter 6, item 17).

Other 4.24 Written release and rejection procedures should be available for materials and products, and in particular for the release for sale of the finished product by the Qualified Person(s) in accordance with the requirements of Article 51 of Directive 2001/83/EC.1 4.25 Records should be maintained of the distribution of each batch of a product in order to facilitate the recall of the batch if necessary. 4.26 There should be written procedures and the associated records of actions taken or conclusions reached, where appropriate, for - validation; - equipment assembly and calibration; - maintenance, cleaning, and sanitation; - personnel matters including training, clothing, and hygiene; - environmental monitoring; - pest control; - complaints; - recalls; and - returns. 4.27 Clear operating procedures should be available for major items of manufacturing and test equipment. 4.28 Log books should be kept for major or critical equipment recording, as appropriate, any validations, calibrations, maintenance, cleaning, or repair operations, including the dates and identity of people who carried these operations out. 4.29 Log books should also record in chronological order the use of major or critical equipment and the areas where the products have been processed.

CHAPTER 5: PRODUCTION Principle Production operations must follow clearly defined procedures; they must comply with the principles of Good Manufacturing Practice in order to obtain products of the requisite quality and be in accordance with the relevant manufacturing and marketing authorizations.

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General

Prevention of Cross-Contamination in Production

5.1 Production should be performed and supervised by competent people. 5.2 All handling of materials and products, such as receipt and quarantine, sampling, storage, labeling, dispensing, processing, packaging, and distribution should be done in accordance with written procedures or instructions and, where necessary, recorded. 5.3 All incoming materials should be checked to ensure that the consignment corresponds to the order. Containers should be cleaned where necessary and labeled with the prescribed data. 5.4 Damage to containers and any other problem, which might adversely affect the quality of a material should be investigated, recorded, and reported to the Quality Control Department. 5.5 Incoming materials and finished products should be physically or administratively quarantined immediately after receipt or processing, until they have been released for use or distribution. 5.6 Intermediate and bulk products purchased as such should be handled on receipt as though they were starting materials. 5.7 All materials and products should be stored under the appropriate conditions established by the manufacturer and in an orderly fashion to permit batch segregation and stock rotation. 5.8 Checks on yields, and reconciliation of quantities, should be carried out as necessary to ensure that there are no discrepancies outside acceptable limits. 5.9 Operations on different products should not be carried out simultaneously or consecutively in the same room unless there is no risk of mix-up or cross-contamination. 5.10 At every stage of processing, products and materials should be protected from microbial and other contamination. 5.11 When working with dry materials and products, special precautions should be taken to prevent the generation and dissemination of dust. This applies particularly to the handling of highly active or sensitizing materials. 5.12 At all times during processing, all materials, bulk containers, major items of equipment, and where appropriate rooms used should be labeled or otherwise identified with an indication of the product or material being processed, its strength (where applicable) and batch number. Where applicable, this indication should also mention the stage of production and batch number. 5.13 Labels applied to containers, equipment, or premises should be clear, unambiguous, and in the company’s agreed format. It is often helpful in addition to the wording on the labels to use colors to indicate status (e.g., quarantined, accepted, rejected, clean). 5.14 Checks should be carried out to ensure that pipelines and other pieces of equipment used for the transportation of products from one area to another are connected in a correct manner. 5.15 Any deviation from instructions or procedures should be avoided as far as possible. lf a deviation occurs, it should be approved in writing by a competent person, with the involvement of the Quality Control Department when appropriate. 5.16 Access to production premises should be restricted to authorized personnel. 5.17 Normally, the production of nonmedicinal products should be avoided in areas and with the equipment destined for the production of medicinal products.

5.18 Contamination of a starting material or of a product by another material or product must be avoided. This risk of accidental cross-contamination arises from the uncontrolled release of dust, gases, vapors, sprays, or organisms from materials and products in process, from residues on equipment, and from operators clothing. The significance of this risk varies with the type of contaminant and of product being contaminated. Among the most hazardous contaminants are highly sensitizing materials, biological preparations containing living organisms, certain hormones, cytotoxics, and other highly active materials. Products in which contamination is likely to be most significant are those administered by injection, those given in large doses and/or over a long time. 5.19 Cross-contamination should be avoided by appropriate technical or organizational measures, for example a) production in segregated areas (required for products such as penicillins, live vaccines, live bacterial preparations, and some other biologicals), or by campaign (separation in time) followed by appropriate cleaning; b) providing appropriate air locks and air extraction; c) minimizing the risk of contamination caused by recirculation or reentry of untreated or insufficiently treated air; d) keeping protective clothing inside areas where products with special risk of cross- contamination are processed; e) using cleaning and decontamination procedures of known effectiveness, as ineffective cleaning of equipment is a common source of cross-contamination; f) using “closed systems” of production; and g) testing for residues and use of cleaning status labels on equipment. 5.20 Measures to prevent cross-contamination and their effectiveness should be checked periodically according to set procedures.

Validation 5.21 Validation studies should reinforce Good Manufacturing Practice and be conducted in accordance with defined procedures. Results and conclusions should be recorded. 5.22 When any new manufacturing formula or method of preparation is adopted, steps should be taken to demonstrate its suitability for routine processing. The defined process, using the materials and equipment specified, should be shown to yield a product consistently of the required quality. 5.23 Significant amendments to the manufacturing process, including any change in equipment or materials, which may affect product quality and/or the reproducibility of the process should be validated. 5.24 Processes and procedures should undergo periodic critical revalidation to ensure that they remain capable of achieving the intended results.

Starting Materials 5.25 The purchase of starting materials is an important operation, which should involve staff who have a particular and thorough knowledge of the suppliers. 5.26 Starting materials should only be purchased from approved suppliers named in the relevant specification

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5.27

5.28 5.29

5.30

5.31 5.32

5.33 5.34

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and, where possible, directly from the producer. It is recommended that the specifications established by the manufacturer for the starting materials be discussed with the suppliers. It is of benefit that all aspects of the production and control of the starting material in question, including handling, labeling and packaging requirements, as well as complaints and rejection procedures are discussed with the manufacturer and the supplier. For each delivery, the containers should be checked for integrity of package and seal and for correspondence between the delivery note and the supplier’s labels. lf one material delivery is made up of different batches, each batch must be considered as separate for sampling, testing, and release. Starting materials in the storage area should be appropriately labeled (see Chapter 5, item 13). Labels should bear at least the following information: - the designated name of the product and the internal code reference where applicable; - a batch number given at receipt; - where appropriate, the status of the contents (e.g., in quarantine, on test, released, rejected); and - where appropriate, an expiry date or a date beyond which retesting is necessary. When fully computerized storage systems are used, all the above information need not necessarily be in a legible form on the label. There should be appropriate procedures or measures to assure the identity of the contents of each container of starting material. Bulk containers from which samples have been drawn should be identified (see Chapter 6, item 13). Only starting materials which have been released by the Quality Control Department and which are within their shelf life should be used. Starting materials should only be dispensed by designated persons, following a written procedure, to ensure that the correct materials are accurately weighed or measured into clean and properly labeled containers. Each dispensed material and its weight or volume should be independently checked and the check recorded. Materials dispensed for each batch should be kept together and conspicuously labeled as such.

Processing Operations: Intermediate and Bulk Products 5.35 Before any processing operation is started, steps should be taken to ensure that the work area and equipment are clean and free from any starting materials, products, product residues, or documents not required for the current operation. 5.36 Intermediate and bulk products should be kept under appropriate conditions. 5.37 Critical processes should be validated (see “Validation” in this Chapter). 5.38 Any necessary in-process controls and environmental controls should be carried out and recorded. 5.39 Any significant deviation from the expected yield should be recorded and investigated.

Packaging Materials 5.40 The purchase, handling, and control of primary and printed packaging materials shall be accorded attention similar to that given to starting materials.

5.41 Particular attention should be paid to printed materials. They should be stored in adequately secure conditions such as to exclude unauthorized access. Cut labels and other loose printed materials should be stored and transported in separate closed containers so as to avoid mix-ups. Packaging materials should be issued for use only by authorized personnel following an approved and documented procedure. 5.42 Each delivery or batch of printed or primary packaging material should be given a specific reference number or identification mark. 5.43 Outdated or obsolete primary packaging material or printed packaging material should be destroyed and this disposal recorded.

Packaging Operations 5.44 When setting up a program for the packaging operations, particular attention should be given to minimizing the risk of cross-contamination, mix-ups, or substitutions. Different products should not be packaged in close proximity unless there is physical segregation. 5.45 Before packaging operations are begun, steps should be taken to ensure that the work area, packaging lines, printing machines, and other equipment are clean and free from any products, materials, or documents previously used, if these are not required for the current operation. The line clearance should be performed according to an appropriate checklist. 5.46 The name and batch number of the product being handled should be displayed at each packaging station or line. 5.47 All products and packaging materials to be used should be checked on delivery to the packaging department for quantity, identity, and conformity with the Packaging Instructions. 5.48 Containers for filling should be clean before filling. Attention should be given to avoiding and removing any contaminants such as glass fragments and metal particles. 5.49 Normally, filling and sealing should be followed as quickly as possible by labeling. lf it is not the case, appropriate procedures should be applied to ensure that no mix-ups or mislabeling can occur. 5.50 The correct performance of any printing operation (e.g., code numbers, expiry dates) to be done separately or in the course of the packaging should be checked and recorded. Attention should be paid to printing by hand which should be rechecked at regular intervals. 5.51 Special care should be taken when using cut labels and when overprinting is carried out off-line. Roll feed labels are normally preferable to cut labels, in helping to avoid mix-ups. 5.52 Checks should be made to ensure that any electronic code readers, label counters, or similar devices are operating correctly. 5.53 Printed and embossed information on packaging materials should be distinct and resistant to fading or erasing. 5.54 Online control of the product during packaging should include at least checking the following: a) general appearance of the packages; b) whether the packages are complete; c) whether the correct products and packaging materials are used; d) whether any overprinting is correct; and e) correct functioning of line monitors. Samples taken away from the packaging line should not be returned.

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5.55 Products which have been involved in an unusual event should only be reintroduced into the process after special inspection, investigation, and approval by authorized personnel. Detailed record should be kept of this operation. 5.56 Any significant or unusual discrepancy observed during reconciliation of the amount of bulk product and printed packaging materials and the number of units produced should be investigated and satisfactorily accounted for before release. 5.57 Upon completion of a packaging operation, any unused batch-coded packaging materials should be destroyed and the destruction recorded. A documented procedure should be followed if uncoded printed materials are returned to stock.

CHAPTER 6: QUALITY CONTROL Principle

Finished Products

6.1 Each holder of a manufacturing authorization should have a Quality Control Department. This department should be independent from other departments, and under the authority of a person with appropriate qualifications and experience, who has one or several control laboratories at his disposal. Adequate resources must be available to ensure that all the Quality Control arrangements are effectively and reliably carried out. 6.2 The principal duties of the head of Quality Control are summarized in Chapter 2. The Quality Control Department as a whole will also have other duties, such as to establish, validate, and implement all quality control procedures, keep the reference samples of materials and products, ensure the correct labeling of containers of materials and products, ensure the monitoring of the stability of the products, participate in the investigation of complaints related to the quality of the product, and so on. All these operations should be carried out in accordance with written procedures and, where necessary, recorded. 6.3 Finished product assessment should embrace all relevant factors, including production conditions, results of inprocess testing, a review of manufacturing (including packaging) documentation, compliance with Finished Product Specification, and examination of the final finished pack. 6.4 Quality Control personnel should have access to production areas for sampling and investigation as appropriate.

5.58 Finished products should be held in quarantine until their final release under conditions established by the manufacturer. 5.59 The evaluation of finished products and documentation, which is necessary before release of product for sale are described in Chapter 6, “Quality Control”. 5.60 After release, finished products should be stored as usable stock under conditions established by the manufacturer.

Rejected, Recovered, and Returned Materials 5.61 Rejected materials and products should be clearly marked as such and stored separately in restricted areas. They should either be returned to the suppliers or, where appropriate, reprocessed or destroyed. Whatever action is taken should be approved and recorded by authorized personnel. 5.62 The reprocessing of rejected products should be exceptional. It is only permitted if the quality of the final product is not affected, if the specifications are met and if it is done in accordance with a defined and authorized procedure after evaluation of the risks involved. Record should be kept of the reprocessing. 5.63 The recovery of all or part of earlier batches which conform to the required quality by incorporation into a batch of the same product at a defined stage of manufacture should be authorized beforehand. This recovery should be carried out in accordance with a defined procedure after evaluation of the risks involved, including any possible effect on shelf life. The recovery should be recorded. 5.64 The need for additional testing of any finished product which has been reprocessed, or into which a recovered product has been incorporated, should be considered by the Quality Control Department. 5.65 Products returned from the market and which have left the control of the manufacturer should be destroyed unless without doubt their quality is satisfactory; they may be considered for resale, relabeling, or recovery in a subsequent batch only after they have been critically assessed by the Quality Control Department in accordance with a written procedure. The nature of the product, any special storage conditions it requires, its condition and history, and the time elapsed since it was issued should all be taken into account in this assessment. Where any doubt arises over the quality of the product, it should not be considered suitable for reissue or reuse, although basic chemical reprocessing to recover active ingredient may be possible. Any action taken should be appropriately recorded.

Quality Control is concerned with sampling, specifications and testing as well as the organization, documentation, and release procedures which ensure that the necessary and relevant tests are carried out, and that materials are not released for use, nor products released for sale or supply, until their quality has been judged satisfactory. Quality Control is not confined to laboratory operations, but must be involved in all decisions, which may concern the quality of the product. The independence of Quality Control from Production is considered fundamental to the satisfactory operation of Quality Control. (see also chapter 1).

General

Good Quality Control Laboratory Practice 6.5 Control laboratory premises and equipment should meet the general and specific requirements for Quality Control areas given in Chapter 3. 6.6 The personnel, premises, and equipment in the laboratories should be appropriate to the tasks imposed by the nature and the scale of the manufacturing operations. The use of outside laboratories, in conformity with the principles detailed in Chapter 7, Contract Analysis, can be accepted for particular reasons, but this should be stated in the Quality Control records.

Documentation 6.7 Laboratory documentation should follow the principles given in Chapter 4. An important part of this documentation deals with Quality Control and the following details should be readily available to the Quality Control Department: r specifications; r sampling procedures; r testing procedures and records (including analytical worksheets and/or laboratory notebooks); r analytical reports and/or certificates;

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r data from environmental monitoring, where required; r validation records of test methods, where applicable; and r procedures for and records of the calibration of instruments and maintenance of equipment. 6.8 Any Quality Control documentation relating to a batch record should be retained for 1 year after the expiry date of the batch and at least 5 years after the certification referred to in Article 51(3) of Directive 2001/ 83/EC. 6.9 For some kinds of data (e.g., analytical tests results, yields, environmental controls), it is recommended that records are kept in a manner permitting trend evaluation. 6.10 In addition to the information, which is part of the batch record, other original data such as laboratory notebooks and/or records should be retained and readily available.

6.18

6.19

6.20

Sampling 6.11 The sample taking should be done in accordance with approved written procedures that describe: r the method of sampling; r the equipment to be used; r the amount of the sample to be taken; r instructions for any required subdivision of the sample; r the type and condition of the sample container to be used; r the identification of containers sampled; r any special precautions to be observed, especially with regard to the sampling of sterile or noxious materials; r the storage conditions; and r instructions for the cleaning and storage of sampling equipment. 6.12 Reference samples should be representative of the batch of materials or products from which they are taken. Other samples may also be taken to monitor the most stressed part of a process (e.g., beginning or end of a process). 6.13 Sample containers should bear a label indicating the contents, with the batch number, the date of sampling and the containers from which samples have been drawn. 6.14 Further guidance on reference and retention samples is given in Annex 19.

Testing 6.15 Analytical methods should be validated. All testing operations described in the marketing authorization should be carried out according to the approved methods. 6.16 The results obtained should be recorded and checked to make sure that they are consistent with each other. Any calculations should be critically examined. 6.17 The tests performed should be recorded and the records should include at least the following data: (a) name of the material or product and, where applicable, dosage form; (b) batch number and, where appropriate, the manufacturer and/or supplier; (c) references to the relevant specifications and testing procedures; (d) test results, including observations and calculations, and reference to any certificates of analysis; (e) dates of testing; (f) initials of the persons who performed the testing; (g)

6.21

6.22

initials of the persons who verified the testing and the calculations, where appropriate; and (h) a clear statement of release or rejection (or other status decision) and the dated signature of the designated responsible person. All the in-process controls, including those made in the production area by production personnel, should be performed according to methods approved by Quality Control and the results recorded. Special attention should be given to the quality of laboratory reagents, volumetric glassware and solutions, reference standards, and culture media. They should be prepared in accordance with written procedures. Laboratory reagents intended for prolonged use should be marked with the preparation date and the signature of the person who prepared them. The expiry date of unstable reagents and culture media should be indicated on the label, together with specific storage conditions. In addition, for volumetric solutions, the last date of standardization and the last current factor should be indicated. Where necessary, the date of receipt of any substance used for testing operations (e.g., reagents and reference standards) should be indicated on the container. Instructions for use and storage should be followed. In certain cases, it may be necessary to carry out an identification test and/or other testing of reagent materials upon receipt or before use. Animals used for testing components, materials, or products, should, where appropriate, be quarantined before use. They should be maintained and controlled in a manner that assures their suitability for the intended use. They should be identified, and adequate records should be maintained, showing the history of their use.

Ongoing Stability Program 6.23 After marketing, the stability of the medicinal product should be monitored according to a continuous appropriate program that will permit the detection of any stability issue (e.g., changes in levels of impurities or dissolution profile) associated with the formulation in the marketed package. 6.24 The purpose of the ongoing stability program is to monitor the product over its shelf life and to determine that the product remains, and can be expected to remain, within specifications under the labeled storage conditions. 6.25 This mainly applies to the medicinal product in the package in which it is sold, but consideration should also be given to the inclusion in the program of bulk product. For example, when the bulk product is stored for a long period before being packaged and/or shipped from a manufacturing site to a packaging site, the impact on the stability of the packaged product should be evaluated and studied under ambient conditions. In addition, consideration should be given to intermediates that are stored and used over prolonged periods. Stability studies on reconstituted product are performed during product development and need not be monitored on an ongoing basis. However, when relevant, the stability of reconstituted product can also be monitored. 6.26 The ongoing stability program should be described in a written protocol following the general rules of Chapter 4 and results formalized as a report. The equipment

EU Guidelines to Good Manufacturing Practice: Medicinal Products for Human and Veterinary Use

6.27

6.28

6.29

6.30

6.31

6.32

6.33

used for the ongoing stability program (stability chambers among others) should be qualified and maintained following the general rules of Chapter 3 and Annex 15. The protocol for an ongoing stability program should extend to the end of the shelf life period and should include, but not be limited to, the following parameters: r number of batch(es) per strength and different batch sizes, if applicable; r relevant physical, chemical, microbiological, and biological test methods; r acceptance criteria; r reference to test methods; r description of the container closure system(s); r testing intervals (time points); r description of the conditions of storage (standardized ICH conditions for long-term testing, consistent with the product labeling, should be used); and r other applicable parameters specific to the medicinal product. The protocol for the ongoing stability program can be different from that of the initial long-term stability study as submitted in the marketing authorization dossier provided that this is justified and documented in the protocol (e.g., the frequency of testing, or when updating to ICH recommendations). The number of batches and frequency of testing should provide a sufficient amount of data to allow for trend analysis. Unless otherwise justified, at least one batch per year of product manufactured in every strength and every primary packaging type, if relevant, should be included in the stability program (unless none are produced during that year). For products where ongoing stability monitoring would normally require testing using animals and no appropriate alternative, validated techniques are available, the frequency of testing may take account of a risk–benefit approach. The principle of bracketing and matrixing designs may be applied if scientifically justified in the protocol. In certain situations, additional batches should be included in the ongoing stability program. For example, an ongoing stability study should be conducted after any significant change or significant deviation to the process or package. Any reworking, reprocessing, or recovery operation should also be considered for inclusion. Results of ongoing stability studies should be made available to key personnel and, in particular, to the Qualified Person(s). Where ongoing stability studies are carried out at a site other than the site of manufacture of the bulk or finished product, there should be a written agreement between the parties concerned. Results of ongoing stability studies should be available at the site of manufacture for review by the competent authority. Out of specification or significant atypical trends should be investigated. Any confirmed out of specification result, or significant negative trend, should be reported to the relevant competent authorities. The possible impact on batches on the market should be considered in accordance with Chapter 8 of the GMP guide and in consultation with the relevant competent authorities. A summary of all the data generated, including any interim conclusions on the program, should be written and maintained. This summary should be subjected to periodic review.

15

CHAPTER 7: CONTRACT MANUFACTURE AND ANALYSIS Principle Contract manufacture and analysis must be correctly defined, agreed and controlled in order to avoid misunderstandings which could result in a product or work of unsatisfactory quality. There must be a written contract between the Contract Giver and the Contract Acceptor which clearly establishes the duties of each party. The contract must clearly state the way in which the Qualified Person releasing each batch of product for sale exercises his full responsibility. Note: This chapter deals with the responsibilities of manufacturers toward the Competent Authorities of the Member States with respect to the granting of marketing and manufacturing authorizations. It is not intended in any way to affect the respective liability of contract acceptors and contract givers to consumers; this is governed by other provisions of Community and National Law.

General 7.1 There should be a written contract covering the manufacture and/or analysis arranged under contract and any technical arrangements made in connection with it. 7.2 All arrangements for contract manufacture and analysis including any proposed changes in technical or other arrangements should be in accordance with the marketing authorization for the product concerned.

The Contract Giver 7.3 The Contract Giver is responsible for assessing the competence of the Contract Acceptor to carry out successfully the work required and for ensuring by means of the contract that the principles and guidelines of GMP as interpreted in this guide are followed. 7.4 The Contract Giver should provide the Contract Acceptor with all the information necessary to carry out the contracted operations correctly in accordance with the marketing authorization and any other legal requirements. The Contract Giver should ensure that the Contract Acceptor is fully aware of any problems associated with the product or the work, which might pose a hazard to his premises, equipment, personnel, other materials, or other products. 7.5 The Contract Giver should ensure that all processed products and materials delivered to him by the Contract Acceptor comply with their specifications or that the products have been released by a Qualified Person.

The Contract Acceptor 7.6 The Contract Acceptor must have adequate premises and equipment, knowledge and experience, and competent personnel to carry out satisfactorily the work ordered by the Contract Giver. Contract manufacture may be undertaken only by a manufacturer who is the holder of a manufacturing authorization. 7.7 The Contract Acceptor should ensure that all products or materials delivered to him are suitable for their intended purpose. 7.8 The Contract Acceptor should not pass to a third party any of the work entrusted to him under the contract without the Contract Giver’s prior evaluation and approval of the arrangements. Arrangements made between the Contract Acceptor and any third party should ensure that the manufacturing and analytical information is made available in the same way as between the original Contract Giver and Contract Acceptor.

16

Handbook of Pharmaceutical Manufacturing Formulations: Over-the-Counter Products

7.9 The Contract Acceptor should refrain from any activity, which may adversely affect the quality of the product manufactured and/or analyzed for the Contract Giver.

The Contract 7.10 A contract should be drawn up between the Contract Giver and the Contract Acceptor which specifies their respective responsibilities relating to the manufacture and control of the product. Technical aspects of the contract should be drawn up by competent persons suitably knowledgeable in pharmaceutical technology, analysis, and Good Manufacturing Practice. All arrangements for manufacture and analysis must be in accordance with the marketing authorization and agreed by both parties. 7.11 The contract should specify the way in which the Qualified Person releasing the batch for sale ensures that each batch has been manufactured and checked for compliance with the requirements of Marketing Authorization. 7.12 The contract should describe clearly who is responsible for purchasing materials, testing and releasing materials, undertaking production and quality controls, including in-process controls, and who has responsibility for sampling and analysis. In the case of contract analysis, the contract should state whether or not the Contract Acceptor should take samples at the premises of the manufacturer. 7.13 Manufacturing, analytical and distribution records, and reference samples should be kept by, or be available to, the Contract Giver. Any records relevant to assessing the quality of a product in the event of complaints or a suspected defect must be accessible and specified in the defect/recall procedures of the Contract Giver. 7.14 The contract should permit the Contract Giver to visit the facilities of the Contract Acceptor. 7.15 In the case of contract analysis, the Contract Acceptor should understand that he is subject to Inspection by the competent Authorities.

CHAPTER 8: COMPLAINTS AND PRODUCT RECALL Principle All complaints and other information concerning potentially defective products must be reviewed carefully according to written procedures. In order to provide for all contingencies, and in accordance with Article 117 of Directive 2001/83/EC and Article 84 of Directive 2001/82/EC, a system should be designed to recall, if necessary, promptly and effectively products known or suspected to be defective from the market.

Complaints 8.1 A person should be designated responsible for handling the complaints and deciding the measures to be taken together with sufficient supporting staff to assist him. If this person is not the Qualified Person, the latter should be made aware of any complaint, investigation, or recall. 8.2 There should be written procedures describing the action to be taken, including the need to consider a recall, in the case of a complaint concerning a possible product defect.

8.3 Any complaint concerning a product defect should be recorded with all the original details and thoroughly investigated. The person responsible for Quality Control should normally be involved in the study of such problems. 8.4 If a product defect is discovered or suspected in a batch, consideration should be given to checking other batches in order to determine whether they are also affected. In particular, other batches which may contain reworks of the defective batch should be investigated. 8.5 All the decisions and measures taken as a result of a complaint should be recorded and referenced to the corresponding batch records. 8.6 Complaints records should be reviewed regularly for any indication of specific or recurring problems requiring attention and possibly the recall of marketed products. 8.7 Special attention should be given to establishing whether a complaint was caused because of counterfeiting. 8.8 The competent authorities should be informed if a manufacturer is considering action following possibly faulty manufacture, product deterioration, detection of counterfeiting, or any other serious quality problems with a product

Recalls 8.9 A person should be designated as responsible for execution and coordination of recalls and should be supported by sufficient staff to handle all the aspects of the recalls with the appropriate degree of urgency. This responsible person should normally be independent of the sales and marketing organization. If this person is not the Qualified Person, the latter should be made aware of any recall operation. 8.10 There should be established written procedures, regularly checked and updated when necessary, in order to organize any recall activity. 8.11 Recall operations should be capable of being initiated promptly and at any time. 8.12 All Competent Authorities of all countries to which products may have been distributed should be informed promptly if products are intended to be recalled because they are, or are suspected of being defective. 8.13 The distribution records should be readily available to the person(s) responsible for recalls, and should contain sufficient information on wholesalers and directly supplied customers (with addresses, phone, and/or fax numbers inside and outside working hours, batches, and amounts delivered), including those for exported products and medical samples. 8.14 Recalled products should be identified and stored separately in a secure area while awaiting a decision on their fate. 8.15 The progress of the recall process should be recorded and a final report issued, including a reconciliation between the delivered and recovered quantities of the products. 8.16 The effectiveness of the arrangements for recalls should be evaluated regularly.

2 EDQM Certification

manufacturing site(s). CMPs are mainly used by companies to support applications to export their pharmaceutical products to countries with less developed regulatory systems. CEPs are certificates issued by the European Directorate for the Quality of Medicines (EDQM) to confirm that a certain active substance is produced according to the requirements of the relevant monograph of the European Pharmacopoeia or of the monograph on TSE. CEPs can be used by companies when submitting an application for marketing authorization, and replaces much of the documentation required for the active substance in the marketing authorization dossier. GMP inspections of active substance manufacturers can be requested by EDQM in the context of the CEP certification scheme. EMEA does not perform inspections; they are carried out on its behalf by the national competent authorities of the member states of the EEA, in connection with products under the centralized marketing authorization procedure. The competent authority responsible for carrying out the inspection issues the GMP certificate, or makes an entry of noncompliance into the EudraGMP Database. The EDQM allows raw material manufacturers to submit and secure approval for their active pharmaceutical ingredients besides the approval of the finished products; such approvals are not available in the jurisdictions of the FDA. Given below is submission requirement that can be used by the manufacturers to audit for the quality of the API in those instances where such certificates and/or DMF are not available.

The European legislation does not require mandatory routine GMP inspections for active substance manufacturers. Responsibility for using only active substances that have been manufactured in accordance with good manufacturing practice is placed on the holders of a manufacturing authorization. Art. 111 Directive 2001/83/EC (Art. 80 Directive 2001/82/EC for veterinary medicinal products), however makes provision for GMP inspections of active substance manufacturing sites to be carried out at the request of the manufacturer itself. The request for the inspection should be made to the EEA competent authority where the site is located or, in case of sites located in third countries, to a competent authority where the active substance is used as a starting material in the manufacture of medicinal products. If this is not the case, any EEA authority can be approached. There is no guarantee that such a request will be fulfilled, as the competent authorities need to balance such requests with other priorities. It should also be borne in mind that an inspection does not replace the responsibility of the manufacturing authorization holder using the active substance in question as a starting material and will not be accepted alone as adequate assurance that the manufacturing authorization holder has fulfilled its responsibilities. Manufacturing authorization holders sometimes confuse the role of inspectorates with their own obligations but nevertheless, when inspection reports or GMP certificates issued by EEA, MRA partners, or other recognized authorities are available; these can provide useful information to manufacturing authorization holders. However, these alone cannot fulfill the statutory obligations of the manufacturing authorization holder or the requirements of section 5.25 of the GMP Guide, but the results of inspections, may be used together with other supporting information in a risk-based approach by the manufacturer in establishing priorities for its own audit program of active substance suppliers. A GMP certificate is a certificate issued, following a GMP inspection, by the competent authority responsible for carrying out the inspection, to confirm the GMP compliance status of the inspected site. GMP certificates are site specific, but can be restricted to particular activities depending on the scope of the inspection (e.g., manufacturing activities related to a specific product). Directives 2001/82/EC and 2001/83/EC, as amended state that after every GMP inspection, and within 90 days of the inspection, a GMP certificate shall be issued to a manufacturer, if the outcome of the inspection shows that the manufacturer complies with GMP. CMPs are product specific certificates, issued by the competent authority that granted the marketing authorization (EMEA issues CMPs on behalf of the European Commission for centrally authorized products), in the context of the WHO certification scheme on the quality of pharmaceutical products moving in international commerce, to confirm the marketing authorization status of the products. These certificates also confirm the GMP compliance status of the

I.2.3.S DRUG SUBSTANCE A.2.3.S.1 General Information Use of the substance: Route(s) of administration, maximum daily dose. Commercialization history: Summarize the history based on the table in application form. Declarations: Summarize the declarations appended to the application form: - Manufacture of the substance in accordance with ICH Q7A GMP rules - Commitment by the manufacturer to keep the proposed holder informed of any changes to the documentation - If applicable: manufacturer’s authorization for X to act as representative - Willingness to be inspected (holder, manufacturers) - Nonuse/use of materials of human or animal origin in the process

1.2.3.S.1.1 Nomenclature (a) Recommended International Nonproprietary name (INN) (b) Chemical name(s) (c) Company or laboratory code 17

18

Handbook of Pharmaceutical Manufacturing Formulations: Over-the-Counter Products

(d) Other nonproprietary name(s) (e.g., national name, USAN, BAN) (e) CAS No.: Molecular Formula MW

Applicant’s Ph.Eur. LOD LOQ Chemical Ph.Eur. Specific- SpecificLevels of the of the Name Impurity ations ations Origin Found Method Method

1.2.3.S.1.2 General Properties Give summarized data on (a) Physical description (e.g., appearance, color, physical state. . .) (b) Physical form (e.g., polymorphic form, solvate, hydrate): to be commented especially if requested as grade (c) Solubility and other properties as necessary (d) Particle size: for example, nonmicronized, micronized, or any grade claimed as subtitle

2.3.S.2 Manufacture 2.3.S.2.1 Manufacturer(s) (Name, Manufacturer) and Sites Involved in the Entire Process Give the name, address, and responsibility of each manufacturer, including contractors and manufacturer and each proposed production site or facility involved in manufacture.

2.3.S.2.2 Description of Manufacturing Process and Process Controls (a) Give a brief narrative step-by-step description of the manufacturing process(es) and provide reference to detailed description in the documentation. Confirm the maximum batch size (b) If applicable, summarize alternate processes and give a short explanation of their use (c) Comment shortly on recovery of materials (solvents, reagents, and mother liquor) together with reprocessing steps and give a brief justification

(b) Justify these specifications based on data observed for impurities in relevant batches (c) Discuss briefly about the suitability of the monograph to control the potential impurities present in the substance (residual starting materials, reactants, and reagents etc.) (d) Specific discussion on possible genotoxic impurities: Give a brief discussion on impurities with potential genotoxicity based on the requirements of the guideline (II) Residual solvent(s)/reagent(s)/catalyst(s) (a) Fill in the following table Solvent/ Reagent/ Catalyst

Used in Step X/Y

Applicant’s Limit

ICH Class/ Limit

Levels (PPM)

LOD of the Method

LOQ of the Method

(b) Discuss briefly the basis for setting the specification

2.3.S.2.3 Control of Materials (I) Starting material(s) (a) Give summarized specifications (including impurities profile) including their justification based on studies of carryover. NB: If starting material is obtained by fermentation or is from herbal origin, summarize the information related to the nature of this material. (II) Reagents and solvents Summarize the quality and controls of the materials (e.g., raw materials, solvents pure, and/or recovered, reagents, catalysts) used in the manufacture of the drug substance.

2.3.S.2.4 Controls of Critical Steps and Intermediates Summary of the controls performed at critical steps of the manufacturing process and on intermediates, compare analytical procedures used for intermediates and final substance.

2.3.S.2.5 Process Validation and/or Evaluation For aseptic processing and sterilization, only give the summary of process validation and/or evaluation studies.

2.3.S.3 Characterization 2.3.S.3.1 Impurities (I) Related substances (a) Fill in the following table identifying related substances, their origin, and distinguishing between potential and actual impurities and comparing with impurity section of the monograph

2.3.S.4 Control of the Drug Substance 2.3.S.4.1 Specification Give a table summarizing the proposed specifications.

2.3.S.4.2 Analytical Procedures (a) Summarize of the analytical procedures

2.3.S.4.3 Validation of Analytical Procedures Give the summary of the validation information for any in-house tests and compare shortly with the method(s) described in the monograph (cross-validation).

2.3.S.4.4 Batch Analyses (a) Give a short description of the batches: batch number, batch size date, and site of production (b) Summarize the results for relevant batches (according to specifications and showing equivalence of any alternative supplier, process etc.)

2.3.S.4.5 Justification of Specification Justify the drug substance specification

2.3.S.5 Reference Standards or Materials (a) Give the source of primary reference standards or reference materials (e.g., Ph.Eur.) for final substance and its impurities where relevant (b) Summarize characterization and evaluation of in-house standards

EDQM Certification

19

2.3.S.6 Container Closure System

2.3.S.7.1 Stability Summary and Conclusions

(a) Describe shortly the container closure system(s) for the storage and shipment of the drug substance, as it has to be mentioned on the CEP in case a retest period is requested (i.e.. in a clear and understandable manner) (b) Summarize the specifications (description + identification)

(a) Summarize accelerated and long-term testing (e.g., studies conducted, protocols used, results obtained) (b) Justify of the retest period claimed based on data available

2.3.S.7 Stability State retest period claimed for the substance and storage recommendations, if any.

2.3.S.7.2 Postapproval Stability Protocol and Stability Commitment Give the stability protocol for commitment batches.

3 GMP Audit Template, EU Guidelines (http://ec.europa.eu/enterprise/pharmaceuticals/eudralex/vol4 en.htm)

Compliance 1 2 3a

Remarks

EU-Guide

1

PERSONNEL

1.1

Qualified personnel available?

  

2.1

1.2

Organization charts available?

  

2.2

1.3

Job descriptions available?

  

2.2

1.4

Responsibilities clearly defined?

  

2.2

  

2.5

Key personnel Responsible persons designated for 1.5

• production? • quality control?

  

2.6

1.7

Are they independent from each other?

  

2.3

1.8

Are joint functions clearly defined?

  

2.7

1.9

Are the responsible persons working full time?

  

2.3

1.10

Do the responsible persons have the appropriate formation, knowledge, and experience?

  

2.1/2.2

1.11

Do the relevant departments have enough personnel?

  

2.1

1.6

Training 1.12

Continuous training programs for the production and QC staff?

  

2.8

1.13

Initial job training for all employees?

  

2.9

1.14

Teaching aids (videos, slides, and brochures) available?

  

2.9

1.15

External training courses for the staff?

  

2.9

1.16

Training records?

  

2.9

1.17

Special training in sensitive areas? (sterile prod. and toxic subs.)

  

2.10

1.18

Information for visitors to the manufacturing area?

  

2.11

2

HYGIENE Personnel hygiene Detailed written hygiene programs for

2.1

• clothing?

  

2.13

2.2

• use of washrooms?

  

2.13

2.3

• behavior in production areas?

  

2.13

  

2.14

2.4

Precautions against sick or personnel with open wounds in production? Medical examination:

2.5

• on recruitment?

  

2.15

2.6

• regular reexaminations?

  

2.15

20

21

GMP Audit Template, EU Guidelines

Compliance 1 2 3a

Remarks

EU-Guide

Duty of notification after 2.7

• trips to tropical countries?

  

2.15

2.8

• cases of contagious illness in the family?

  

2.15

2.9

Instructions for appropriate working clothes?

  

2.16

2.10

Absence of food and drinks (chewing gum!) in the working area?

  

2.17

2.11

Measures against contact with open product (gloves etc.)?

  

2.18

2.12

Instructions for hand washing in production?

  

2.19

2.13

Change of clothes when entering and leaving the production area?

  

5.19

2.14

Change rooms and toilets easily within reach?

  

3.31

2.15

Toilets and restrooms sufficiently separated from production areas?

  

3.30/3.31

2.16

Workshops separate from production areas?

  

3.32

2.17

Laboratory animal rooms totally segregated from production rooms?

  

3.33

3

WAREHOUSE Rooms, general   

3

3.2

• adequate size?

  

3

3.3

• clean?

  

3

3.1

Suitable for the intended use?

3.4

Located and designed to exclude external contamination?

  

3.1

3.5

Appropriate level of maintenance?

  

3.2

3.6

Maintenance works possible without contamination risk?

  

3.2

3.7

Appropriate lighting and air-conditioning?

  

3.3

3.8

Recording of temperature and humidity?

  

3.9

Protection against the entry of insects or other animals?

  

3.4

3.10

Controlled access for authorized personnel only?

  

3.5

Rooms, special requirements Type of warehousing: 3.11

Separation of goods sufficient?

  

3.18

3.12

Provision for different storage temperatures?

  

3.19

3.13

Goods receiving zone weather protected?

  

3.20

3.14

Cleaning zone for incoming goods?

  

3.20

3.15

Separate quarantine area with controlled access?

  

3.21

3.16

Separate, protected sampling area?

  

3.22

Separate and safe storage of 3.17

• returned goods?

  

3.23

3.18

• rejected goods?

  

3.23

3.19

Separate and safe storage of highly active, toxic, or dangerous substances?

  

3.24

3.20

Safe storage of narcotics?

  

3.24

3.21

Safe storage of printed packaging materials?

  

3.25

3.22

Security measurements against theft?

  

3.25

3.23

Smoke detectors?

  

3.25

3.24

Fire extinguishing system?

  

3.25

22

Handbook of Pharmaceutical Manufacturing Formulations: Over-the-Counter Products

Compliance 1 2 3a

Remarks

EU-Guide

Operations 3.25

Reception, sampling, and labeling according to written procedures?

  

5.2

3.26

Is a sampling plan available?

  

suppl. 4

3.27

Cleaning of incoming containers?

  

5.3

3.28

Investigation and recording of damaged deliveries?

  

5.4

3.29

FIFO principle?

  

5.7

3.30

Inventory system?

  

5.8

3.31

The location of materials can be detected at all times?

  

3.32

Incoming goods: containers and seals intact?

  

5.27

3.33

Incoming goods: conformity with bill of delivery?

  

5.27

Labeling of incoming containers with 3.34

• internal name and code?

  

5.29

3.35

• allocated batch number?

  

5.29

3.36

• quarantine status?

  

5.29

• expiry date or reanalysis date?

  

5.29

3.38

Identity test for each incoming container?

  

5.29

3.39

Are the sampled containers marked?

  

5.30

3.40

Are reference samples taken?

  

5.30

3.41

Safe storage of printed packaging materials?

  

5.41

3.42

Lot tracing of all packaging materials possible?

  

5.42

3.43

Are excessive packaging materials destroyed?

  

5.43

3.37

Release of starting materials by physical/inventory checks on raw materials, packaging materials, and finished goods: Item:

4

Stocks: Physical:

Stocks: Inventory:

Storage conditions:

DISPENSING/ASSEMBLING Rooms, general

4.1

Suitable for the intended use?

  

3

4.2

• adequate size?

  

3

4.3

• clean?

  

3

4.4

Located and designed to exclude external contamination?

  

3.1

4.5

Appropriate level of maintenance?

  

3.2

4.6

Maintenance works possible without contamination risk?

  

3.2

23

GMP Audit Template, EU Guidelines

Compliance 1 2 3a

Remarks

EU-Guide

4.7

Appropriate lighting and air-conditioning?

  

4.8

Recording of temperature and humidity?

  

4.9

Protection against the entry of insects or other animals?

  

3.4

4.10

Controlled access for authorized personnel only?

  

3.5

3.3

Rooms, special requirements 4.11

Segregated from production and warehouse?

  

3.13

4.12

Separate weighing cabins?

  

3.13

4.13

Separate AHU for each cabin?

  

3.12

Air pressure gradient from weighing cabin → corridor: 4.14

Dust extraction systems available?

3.3   

5.11

Operations 4.15

Balances regularly calibrated?

  

3.41

4.16

Only pharmaceutical raw materials in this area?

  

5.17

4.17

Check on remains from previous materials before entering of new materials into a weighing cabin?

  

5.9/5.35

4.18

Only one material in one cabin?

  

5.9

4.19

Are dispensed materials correct labeled?

  

5.29

4.20

Only released products in the dispensing?

  

5.31

4.21

Cleaning SOPs for the dispensing?

  

4.28

4.22

Previously dispensed material recorded on weighing protocol?

  

4.8

4.23

Safety measures against mix-up’s during assembling (e.g., cage pallets)?

  

5.32/5.34

5

SOLIDS MANUFACTURING Field of activity: • Granulation



• Compression



• Encapsulation



• Film and sugar coating



• Visual inspection (capsules, tablets, etc.)



• Premix (human)



Rooms, general 5.1

Suitable for the intended use?

  

3

5.2

• adequate size?

  

3

5.3

• clean?

  

3

5.4

Located and designed to exclude external contamination?

  

3.1

5.5

Appropriate level of maintenance?

  

3.2

5.6

Maintenance works possible without contamination risk?

  

3.2

5.7

Appropriate lighting and air-conditioning?

  

3.3

5.8

Recording of temperature and humidity?

  

5.9

Protection against the entry of insects or other animals?

  

3.4

5.10

Controlled access for authorized personnel only?

  

3.5

5.11

Separate manufacturing area for penicillins/cephalosporins or highly sensitizing substances?

  

3.6

Rooms, special requirements

24

Handbook of Pharmaceutical Manufacturing Formulations: Over-the-Counter Products

Compliance 1 2 3a

Remarks

EU-Guide

5.12

Only for processing of pharmaceuticals?

  

3.6

5.13

Logical flow of materials?

  

3.7

5.14

Walls, floors, and ceilings: smooth surface and free of cracks?

  

3.8

5.15

Easy cleaning possible?

  

3.10

5.16

Adequate drains with traps and grilles?

  

3.11

5.17

Appropriate air-handling system?

  

3.12

Air pressure gradient from working bay → corridor: Classification according to EC guide? 5.18

Appropriate dust extraction system?

  

3.14

5.19

Appropriate lighting?

  

3.16

5.20

Separate rest rooms?

  

3.30

5.21

Changing rooms designed to avoid contamination?

  

3.31

5.22

Toilets segregated from manufacturing areas?

  

3.31

Equipment 5.23

Suitable for the intended use?

  

3.34

5.24

Well maintained?

  

3.34

5.25

Written & validated cleaning procedures?

  

3.36

5.26

Maintenance without contamination risk (sep. area)?

  

3.35

5.27

Equipment in contact with product: suitable materials quality?

  

3.39

5.28

Machinery equipped with measuring and control devices?

  

3.40

5.29

Calibration in fixed intervals acc. to written procedures?

  

3.41

5.30

Calibration records available?

  

3.41

5.31

Contents and flow direction marked on pipes?

  

3.42

5.32

Pipes for distilled and demineralized water regularly monitored and sanitized?

  

3.43

5.33

Not functioning equipment in the production area (if yes: clearly marked)?

Y

3.44

  

5.34

Status of cleanliness indicated?

  

5.13

5.35

Previous product indicated?

  

5.13

N

Operations 5.36

Are written and validated procedures for all manufacturing steps available?

  

5.2

5.37

Are all manufacturing steps recorded with actual parameters?

  

5.2

5.38

Check of each single container of the starting materials (contents, weight, and identity)?

  

5.3

5.39

Limits for yields?

  

5.8

5.40

Only one batch of one product processed?

  

5.9

5.41

Protection against microbial contamination?

  

5.10

5.42

Appropriate measures against generation of dust (e.g., closed systems)?

  

5.11

Correct labeling of containers, materials, equipment, and rooms with

5.12

GMP Audit Template, EU Guidelines

Compliance 1 2 3a

Remarks

EU-Guide

5.43

• product name and batch no.

  

5.12

5.44

• quarantine status?

  

5.12

5.45

Deviations from standard procedures recorded and signed by the supervisor?

  

5.14

5.46

Special procedures for the production of antibiotics, hormones, etc.?

  

5.19

5.47

• Campaign production?

  

5.19

5.48

• Special monitoring?

  

5.19

5.49

• Validated decontamination procedure?

  

5.19

5.50

Double check on weight?

  

5.34

5.51

Line clearance before start of production?

  

5.35

5.52

Investigation of deviations in yields?

  

5.39

5.53

Validated procedures for reworking of rejected batches?

  

5.62

5.54

Detailed procedures for the addition of previous batches?

  

5.63

5.55

Special release procedure (QA) for those batches?

  

5.64

5.56

Use of protective clothing (hair cover, shoes, masks, and gloves)?

  

2.16

5.57

Clothing regulation for visitors?

  

2.11

IPC

5.38

Who performs IPC? 5.58

Are IPC methods approved by QC?

  

Performance of IPCs:

During Start-up? Yes

No

6.18 Frequency

Automatic data recording? Yes

No

Tablets/Kernels 5.59

Individual weights

 

 

5.60

Disintegration

 

 

5.61

Thickness

 

 

5.62

Hardness

 

 

5.63

Friability/Abrasion

 

 

Sugar-/Film-coated tablets 5.64

Weights

 

 

5.65

Disintegration

 

 

5.66

Residual absolute humidity (IR or)

 

 

Capsules 5.67

Individual weights

 

 

5.68

Disintegration

 

 

Validation 5.69

Validation according to fixed procedures?

  

5.21

5.70

New procedures released only after validation?

  

5.22

Validation of changes of 5.71

• processes?

  

5.23

5.72

• starting materials?

  

5.23

5.73

• equipment?

  

5.23

25

26

Handbook of Pharmaceutical Manufacturing Formulations: Over-the-Counter Products

Compliance 1 2 3a 5.74

Revalidation in fixed intervals?

  

5.75

Procedures for the retrospective validation of old procedures?

  

6

LIQUIDS MANUFACTURING

Remarks

EU-Guide 5.24

Operations carried out: • • • • • • • • •

Dispensing (if different from solid) Syrups and suspensions Drops Ointment manufacture Ointment filling Ampoule solution manufacture Sterile or aseptic ampoule filling Sterile freeze drying Sterile powder filling

                          

Rooms, general 6.1

Suitable for the intended use?

  

3

6.2

• adequate size?

  

3

6.3

• clean?

  

3

6.4

Located and designed to exclude external contamination?

  

3.1

6.5

Appropriate level of maintenance?

  

3.2

6.6

Maintenance works possible without contamination risk?

  

3.2

6.7

Appropriate lighting and air-conditioning?

  

3.3

6.8

Recording of temperature and humidity?

  

6.9

Protection against the entry of insects or other animals?

  

3.4

6.10

Controlled access for authorized personnel only?

  

3.5

6.11

Separate manufacturing area for penicillins/cephalosporins or highly sensitizing substances?

  

3.6

6.12

Only for processing of pharmaceuticals?

  

3.6

6.13

Logical flow of materials?

  

3.7

6.14

Walls, floors, and ceilings: smooth surface and free of cracks?

  

3.8

6.15

Easy cleaning possible?

  

3.10

6.16

Adequate drains with traps and grilles?

  

3.11

6.17

Appropriate air-handling system with filtered air where open products are exposed to the environment?

  

3.12

Rooms, special requirements

Air pressure gradient from working bay → corridor: Classification according to EC guide? 6.18

Appropriate lighting?

  

3.16

6.19

Separate rest rooms?

  

3.30

6.20

Changing rooms designed to avoid contamination?

  

3.31

6.21

Toilets segregated from manufacturing areas?

  

3.31

6.22

Suitable for the intended use?

  

3.34

6.23

Well maintained?

  

3.34

6.24

Tanks, containers, pipework, and pumps designed for easy cleaning and sanitation (dead legs!)?

  

Suppl. 2

Equipment

GMP Audit Template, EU Guidelines

Compliance 1 2 3a

Remarks

EU-Guide

6.25

Written & validated cleaning procedures?

  

3.36

6.26

Maintenance without contamination risk (sep. area)?

  

3.35

6.27

Equipment in contact with product: suitable materials quality?

  

3.39

6.28

Machinery equipped with measuring and control devices?

  

3.40

6.29

Calibration in fixed intervals acc. to written procedures?

  

3.41

6.30

Calibration records available?

  

3.41

6.31

Contents and flow direction marked on pipes?

  

3.42

6.32

Pipes for distilled and demineralized water regularly monitored and sanitized?

  

3.43

6.33

Not functioning equipment in the production area (if yes: clearly marked)?

Y

3.44

  

6.34

Status of cleanliness indicated?

  

5.13

6.35

Previous product indicated?

  

5.13

6.36

Are written and validated procedures for all manufacturing steps available?

  

5.2

6.37

Are all manufacturing steps recorded with actual parameters?

  

5.2

6.38

Check of each single container of the starting materials (contents, weight, and identity)?

  

5.3

6.39

Limits for yields?

  

5.8

6.40

Only one batch of one product processed?

  

5.9

6.41

Protection against microbial contamination?

  

5.10

N

Operations

Correct labeling of containers, materials, equipment, and rooms with:

5.12

6.42

• product name and batch no.

  

5.12

6.43

• quarantine status?

  

5.12

6.44

Deviations from standard procedures recorded and signed by the supervisor?

  

5.14

6.45

Special procedures for the production of antibiotics, hormones, etc.?

  

5.19

6.46

• Campaign production?

  

5.19

6.47

• Special monitoring?

  

5.19

6.48

• Validated decontamination procedure?

  

5.19

6.49

Double check on weight?

  

5.34

6.50

Line clearance before start of production?

  

5.35

6.51

Investigation of deviations in yields?

  

5.39

6.52

Specification of max. storage time and storage conditions if products are not immediately filled or packaged?

  

Suppl. 9

6.53

Validated procedures for reworking of rejected batches?

  

5.62

6.54

Detailed procedures for the addition of previous batches?

  

5.63

6.55

Special release procedure (QA) for those batches?

  

5.64

6.56

Use of protective clothing (hair cover, shoes, masks, and gloves)?

  

2.16

6.57

Clothing regulation for visitors?

  

2.11

27

28

Handbook of Pharmaceutical Manufacturing Formulations: Over-the-Counter Products

Compliance 1 2 3a

Remarks

EU-Guide

Water 6.58

Loop system for purified water?

  

Suppl. 4

6.59

Antimicrobial treatment of purified water?

  

Suppl. 4

6.60

Loop system for water for injection?

  

Suppl. 4

Storage temperature of water for injection:

Suppl. 4

6.61

Loop system constructed to avoid dead legs?

  

Suppl. 4

6.62

Regular microbiological monitoring?

  

Suppl. 4

6.63

Regular endotoxin control?

  

Suppl. 4

Special requirements for sterile and aseptic products

Suppl.

Rooms and equipment 6.64

Access of staff and materials to clean areas only through air locks?

  

1

6.66

Rooms classified according EC Guide?

  

3

• Solution preparation (EC: class C, with special precautions class D):

Class:

5

• Filling (EC: under LF in class C):

Class:

5

Classification for products to be sterilized: 6.67 6.68

Classification for aseptic products: 6.69

• Handling of starting materials that can be sterile filtered (EC: class C):

Class:

6

6.70

• Handling of starting materials that cannot be sterile filtered (EC: class A in class B):

Class:

6

6.71

• Handling and filling of bulk (EC: class A in Class B):

Class:

6

6.72

All rooms easy to clean disinfect?

  

17

6.73

Doors, windows, frames, lighting, etc. without edges?

  

18

6.74

Suspended ceilings (if yes: sealed?)?

  

19

6.75

Traps constructed to avoid microb. contamination?

  

21

6.76

Appropriate constructed changing rooms?

  

22

6.77

Measures against opening of both doors of air locks?

  

23

6.78

Overpressure gradient from cleanest areas to others?

  

24

6.79

AHU validated and regularly revalidated?

  

25

6.80

Control instruments for pressure gradient?

  

26

6.81

Warning system for errors in air supply?

  

26

6.82

Recording of pressure gradients?

  

26

6.83

Do conveyor belts leave sterile areas?

  

28

6.84

Maintenance works outside from clean areas possible?

  

28

6.85

Cleaning and disinfection procedure after maintenance works?

  

29

6.86

Regular revalidation of all equipment and systems?

  

30

6.87

Water prepared, circulated, and stored to exclude microb. contamination?

  

31

6.88

Cleaning and disinfection of rooms according to validated SOPs rooms?

  

32

  

33

• Disinfection methods? 6.89

Microb. monitoring of cleaning and disinfection agents?

29

GMP Audit Template, EU Guidelines

Compliance 1 2 3a

Remarks

EU-Guide

6.90

Microb. monitoring program of production areas?

  

35

6.91

Results recorded and considered for the release?

  

35

Personnel and hygiene 6.92

Minimal no. of personnel in clean areas?

  

7

6.93

Special and regular training?

  

8

6.94

Regular medical examinations?

  

10

6.95

Appropriate clean room clothes (material, and design)?

  

12

6.96

Protective clothes worn correctly?

  

12

6.97

Prohibition of cosmetics, jewelery, and watches?

  

13

6.98

New clean room clothes for each working cycle?

  

15

6.99

Appropriate washing and sterilization of clothes?

  

16

  

38

Operations 6.100

Validation (media filling) in regular intervals? Monitoring of water preparation system, frequency:

6.101

• microbiological:

40

6.102

• chemical:

40

6.103

• particles:

40

6.104

• endotoxins:

40

6.105

Microbiological monitoring of starting materials?

  

42

6.106

Max. storage times defined for sterilized equipment?

  

45

6.107

Max. storage time defined between solution preparation and filtration?

  

46

6.108

Material transfer to clean areas through double door autoclaves?

  

48

Sterilization processes 6.109

All processes validated?

  

50

6.110

Sterilized and nonsterilized materials clearly separated?

  

54

Trays and boxes clearly labeled with 6.111

• product name and code

  

54

6.112

• batch no.

  

54

6.113

• status: sterilized or nonsterilized

  

54

Sterilizers 6.114

• Recording of temp., pressure, and time?

  

55

6.115

• Coldest point determined?

  

55

6.116

• Independent counter check probe?

  

55

6.117

• Heat-up time for each product determined?

  

56

6.118

• Sterile cooling media?

  

57

6.119

• Tightness tests for vacuum autoclaves?

  

58

6.120

• Clean steam for steam autoclaves?

  

58

6.121

• Circulated air with overpressure?

  

61

6.122

• Recirculated air: sterile filtered?

  

61

6.123

• Ethylene oxide autoclaves: humidity, temp., and time recorded?

  

69

6.124

• Ethylene oxide autoclaves: use of bioindicators?

  

70

30

Handbook of Pharmaceutical Manufacturing Formulations: Over-the-Counter Products

Compliance 1 2 3a

Remarks

EU-Guide

Filtration 6.125

Double filtration?

  

75

6.126

Integrity testing of filters immediately after use?

  

77

6.127

Are results a part of the batch protocol?

  

77

6.128

Optical control of each single container of ampoules, vials, and infusions?

  

82

IPC 6.129

Written IPC procedures and SOPs?

  

Particle testing of 6.130

• rooms

  

6.131

• primary packaging materials

  

6.132

• system of warning and action limits?

  

Microbiological monitoring of 6.133

• rooms

6.134

• personnel

6.135

• equipment

6.136

Residual O2 of ampoules, infusions, and syrups?

  

6.137

Endotoxin testing of water and packaging materials?

  

6.138

Calibration of equipment?

  

6.139

Regular revalidation of equipment?

  

7

PACKAGING Operations carried out: • • • • • • •

Blistering Foil packaging Filling into tablet glasses Effervescent packaging Powder filling Syrup/drops filling Ointment filling

      

Rooms 7.1

Suitable for the intended use?

  

3

7.2

• adequate size?

  

3

7.3

• clean?

  

3

7.4

Located and designed to exclude external contamination?

  

3.1

7.5

Appropriate level of maintenance?

  

3.2

7.6

Maintenance works possible without contamination risk?

  

3.2

7.7

Appropriate lighting and air-conditioning?

  

3.3

7.8

Recording of temperature and humidity?

  

7.9

Protection against the entry of insects or other animals?

  

3.4

7.10

Controlled access for authorized personnel only?

  

3.5

7.11

Adequate separation of the packaging lines?

  

3.15

7.12

Only one product per line?

  

5.44

Operations

GMP Audit Template, EU Guidelines

Compliance 1 2 3a

Remarks

EU-Guide

7.13

Check list for clearance before processing a new product/new batch?

  

5.45

7.14

Adequate labeling of the lines (product name and code)?

  

5.46

7.15

Check of all materials delivered to the line (quantity, identity, conformity with order)?

  

5.47

7.16

Cleaning of primary packaging materials?

  

5.48

7.17

Immediate labeling after filling?

  

5.49

7.18

Careful check of all printing processes (code, and expiry date)?

  

5.50

7.19

Special safety measures for off-line printing?

  

5.51

7.20

Regular checks of all control devices (code reader, counter etc.)?

  

5.52

7.21

Printings clear and durable?

  

5.53

7.22

Balancing of printed packaging materials and bulk?

  

5.56

7.23

Destruction of excessive coded packaging material after completion of an order?

  

5.57

7.24

Are the finished products kept in quarantine until final release?

  

5.58

7.25

Appropriate storage after release?

  

5.60

  

5.47

IPC 7.26

Checks on identity of bulk and packaging materials? Regular line checks on

7.27

• aspect of the packages

  

5.54a

7.28

• completeness

  

5.54b

7.29

• conformity of quantity and quality of materials with packaging order

  

5.54c

7.30

• correct imprint

  

5.54d

7.31

• correct function of control devices

  

5.54d

Are the following IPC checks performed? 7.32

• Leaking

  

7.33

• Release torque of screw caps

  

7.34

• pH, density, drop weight, viscosity, and sedimentation

  

8

DOCUMENTATION Specifications

8.1

Specifications for raw/packaging materials available?

  

4.10

Do they include 8.2

• internal name and code

  

4.11

8.3

• name of supplier and/or manufacturer?

  

4.11

8.4

• reference sample (printed pack. mat.)?

  

4.11

8.5

• sampling procedure?

  

4.11

8.6

• qualitative/quantitative specifications with limits?

  

4.11

8.7

• storage conditions?

  

4.11

8.8

• maximum storage period?

  

4.11

  

4.19

Goods receiving? 8.9

Written procedures for the reception of deliveries?

31

32

Handbook of Pharmaceutical Manufacturing Formulations: Over-the-Counter Products

Compliance 1 2 3a

Remarks

EU-Guide

Do records receipt include 8.10

• product name on labels and delivery note?

  

4.20

8.11

• internal name and code?

  

4.20

8.12

• receiving date?

  

4.20

8.13

• name of supplier and/or manufacturer?

  

4.20

8.14

• batch number of supplier?

  

4.20

8.15

• total quantity and number of containers?

  

4.20

• allocated internal batch number?

  

4.20

  

4.21

8.16 8.17

SOPs for labeling, quarantine, and storage conditions of all incoming goods available? SOPs include

8.18

• authorized sampling personnel?

  

4.22

8.19

• methods, equipment, and quantities?

  

4.22

8.20

• safety measures?

  

4.22

Master formulae 8.21

Are master formulae for each product and batch size available?

  

4.3

8.22

Is the master formula approved and signed by the authorized persons?

  

4.3

The master formula includes 8.23

• product name and code?

  

4.14a

8.24

• description of galenical form, dosage, and batch size?

  

4.14b

8.25

• all active ingredients with name, code, and weight?

  

4.14c

8.26

• all excipients used during manufacture with name, code, and weight?

  

4.14c

8.27

• yields with limits?

  

4.14d

Does the working procedure include 8.28

• the production line?

  

4.15a

8.29

• equipment to be used?

  

4.15a

8.30

• reference to methods for cleaning, assembling, and calibration of machines?

  

4.15b

8.31

• detailed stepwise manufacturing prescription?

  

4.15c

8.32

• IPCs to be performed with limits?

  

4.15d

8.33 8.34

• precautions to be followed? Are batch records kept for each batch processed?

  

4.15e

  

4.17

Do batch records include 8.35

• protocol of line clearance?

  

4.17

8.36

• name of the product and batch no.?

  

4.17a

8.37

• date and time of start and end of production?

  

4.17b

8.38

• name and initials of responsible workers for each step?

  

4.17c, d

8.39

• batch and analytical no. and actual weight of all starting materials?

  

4.17e

8.40

• equipment used?

  

4.17f

8.41

• results of IPCs with initials of person who carries them out?

  

4.17g

8.42

• yields of the relevant manufacturing steps?

  

4.17h

8.43

• detailed notes on problems and process deviations?

  

4.17i

GMP Audit Template, EU Guidelines

Compliance 1 2 3a 8.44

Records on reprocessing of batches?

Remarks

EU-Guide

  

Packaging instructions 8.45

Packaging instructions for each product, package size, and presentation?

  

4.16

Do they include 8.46

• product name?

  

4.16a

8.47

• description of galenical form and strength?

  

4.16b

8.48

• package size?

  

4.17c

8.49

• list of all packaging materials with code for a standard batch size?

  

4.17d

8.50

• samples of printed packaging materials?

  

4.17e

8.51

• special precautions?

  

4.17f

8.52

• description of the process and equipment?

  

4.17g

8.53

• IPCs to be performed with sampling instruction?

  

4.17h

  

4.18

8.54

Are packaging batch records kept for each batch or part batch? Do the packaging batch records include

8.55

• protocol of line clearance?

  

4.18

8.56

• name of the product?

  

4.18a

8.57

• date and time when operations have been performed?

  

4.18b

8.58

• name of the responsible person?

  

4.18c

8.59

• initials of workers carrying out operations?

  

4.18d

8.60

• notes on identity checks and conformity with packaging instructions?

  

4.18e

8.61

• results of IPCs

  

4.18e

8.62

• details of operations and equipment used?

  

4.18f

8.63

• samples of printed packaging materials with codes (MFD, EXP, batch no. etc.)?

  

4.18g

8.64

• record of problems and process deviations?

  

4.18h

8.65

• quantities of packaging materials delivered, used, destroyed, or returned?

  

4.18i

8.66

• no. of packs consumed?

  

4.18j

Testing Do the written testing procedures include 8.67

• test methods?

  

4.23

8.68

• equipment for testing?

  

4.23

  

4.23

8.69

Tests documented? Others

8.70

Procedures for release and rejection of materials and finished products?

  

4.24

8.71

Final release by authorized person?

  

4.24

8.72

Records about distribution of each batch?

  

4.25

  

4.26

Procedures and protocols about 8.73

• validation?

33

34

Handbook of Pharmaceutical Manufacturing Formulations: Over-the-Counter Products

Compliance 1 2 3a

Remarks

EU-Guide

8.74

• set up and calibration of equipment?

  

4.26

8.75

• maintenance, cleaning, and disinfection?

  

4.26

8.76

• training records?

  

4.26

8.77

• environmental monitoring of production areas?

  

4.26

8.78

• pest control?

  

4.26

8.79

• complaints?

  

4.26

8.80

• recalls?

  

4.26

• returned goods?

  

4.26

  

4.27

8.81 8.82

Instructions for use of manufacturing and testing equipment? Log books for major equipment incl. date and name of persons who performed

8.83

• validation?

  

4.28

8.84

• calibration?

  

4.28

8.85

• maintenance, cleaning, and repair works?

  

4.28

  

4.29

8.86

Chronological records of use of major equipment and manufacturing areas?

9

QUALITY CONTROL

6

General requirements 9.1

Independent QC department available?

  

6.1

9.2

Head of QC well qualified and sufficiently experienced?

  

6.1

9.3

Qualified personnel available?

  

2.1

9.4

Organization charts available?

  

2.2

9.5

Job descriptions available?

  

2.2

9.6

Responsibilities clearly defined?

  

2.2

9.7

Continuous training programs for QC staff?

  

2.2

9.8

Initial job training for all employees?

  

2.9

9.9

Training records?

  

9.10

QC personnel admitted to the production rooms for sampling etc.?

  

QC laboratories 9.11

Suitable for the intended use?

  

3.26

9.12

Laboratories of adequate size?

  

3.26

9.13

Appropriate level of maintenance?

  

3.1

9.14

Adequate separation from the production area?

  

3.26

9.15

Controlled access of authorized personnel only?

  

3.5

9.16

Special laboratory to handle biological samples available?

  

3.29

9.17

Special laboratory to handle radioactive material available?

  

3.29

9.18

Separate recreation rooms for the personnel available?

  

3.30

9.19

Animal laboratories present?

  

3.33

9.20

Animal laboratories separated from other areas?

  

3.33

9.21

Animal laboratories equipped with a separate air-handling system?

  

3.33

GMP Audit Template, EU Guidelines

Compliance 1 2 3a

Remarks

EU-Guide

QC Documentation 9.22

Do procedures exist for • self inspection? • release or rejection of products or raw material? • product complaints? • product recalls? • local stability testing? • storage of reference samples? • validation of analytical procedures?

                    

Specifications available for • raw materials? • bulk products? • packaging materials?

        

9.24

Analytical procedures for every product?

  

9.25

Are Basel methods followed?

  

9.26

Validation of locally developed test methods?

  

9.27

Sampling procedures available for • raw materials? • bulk products? • packaging materials?

     

9.28

Suppliers certificates available?

  

6.7

9.29

Calibration program for analytical instruments installed?

  

6.7

9.30

Maintenance program for analytical instruments?

  

6.7

9.31

Retention system for QC records?

  

6.8

9.32

Batch documents stored for expiry + 1 year or 5 years (EEC 75/319, article 22) minimum?

  

6.8

9.33

Are original data like notebooks stored in addition to the batch documents?

  

6.10

9.34

Can the original data be traced back easily and quickly from the analytical report number or batch number?

  

6.10

9.35

Are trend analyses being performed for • analytical results? • yields? • environmental monitoring data?

9.23

6.7

  

6.7   

6.9         

Sampling 9.36

Written procedures for taking samples?

9.37

Do procedures define • method of sampling? • necessary equipment? • quantity of the sample? • subdivision of the sample? • sample container? • labeling of samples? • storage conditions? • cleaning and storage of sampling equipment? • identification of containers sampled

  

6.11

                          

9.38

Are samples representative for the batch they are taken from (sampling plan)?

  

6.12

9.39

Are critical steps being surveilled and validated by additional sampling (e.g., beginning or end of a process).

  

6.12

35

36

Handbook of Pharmaceutical Manufacturing Formulations: Over-the-Counter Products

Compliance 1 2 3a 9.40

Remarks

EU-Guide

Sample containers labeled with • name of the content • batch number • date of sampling • batch containers sampled

6.13

     

9.41

Are samples taken by QC/QA?

  

9.42

Reference samples retained for validity +1 year?

  

6.14

9.43

Storage of reference samples under the recommended storage conditions?

  

6.14

9.44

Finished products stored in the final packaging?

  

6.14

9.45

Quantity of the reference sample makes 1 (better 2) complete reanalysis possible?

  

6.14

9.46

Sample room secure?

  

9.47

Sample room neatly organized and not overcrowded?

  

     

Testing 9.48

Are the applied analytical methods validated?

  

6.15

9.49

Analytical methods in compliance with the registration?

  

6.16

9.50

Are all results recorded and checked for correctness?

  

6.16

9.51

Are all calculations checked?

  

6.16

9.52

Do the testing protocols contain • name and galenical form of material? • batch number? • supplier if applicable? • specification reference? • method reference? • analytical results? • reference to analytical certificates? • date of the analysis? • name of the analyst? • name of the person verifying the data? • statement of release or rejection? • date and sign of the release person?

6.17                                    

9.53

Are all IPC methods in production approved by QC?

  

6.18

9.54

Are written methods available for the preparation of reagents and volumetric solutions?

  

6.19

9.55

Is a record maintained of standardization of volumetric solutions?

  

9.56

Are reagents for prolonged use labeled with • date of the preparation? • sign of the preparator?

9.57

9.58

9.59

     

Are unstable reagents labeled with • expiry date? • storage conditions?

  

Are volumetric solutions labeled with • the last date of standardization? • last current factor?

     

Are reference standards labeled with • name and potency • suppliers reference • date of receipt • date of expiry

6.2 6.20

6.20   

6.20

6.21            

37

GMP Audit Template, EU Guidelines

Compliance 1 2 3a 9.60

Are reference standards stored properly and under the control of a designated person?

9.61

Are animals used for testing of components, materials, or products • quarantined before use? • checked for suitability? • Are records maintained showing the history of their use?

10

Remarks

EU-Guide

  

        

COMPLAINTS AND PRODUCT RECALLS

8

Complaints

8.1

10.1

Does a written complaint procedure exist?

  

8.2

10.2

Are product complaints carefully reviewed?

  

8.1

10.3

Is a person designated to handle complaints and to decide on measures to be taken?

  

8.1

10.4

Is each complaint concerning a product recorded with all original details?

  

8.3

10.5

Are product complaints thoroughly investigated?

  

8.3

10.6

Is a responsible person of QC involved in the study?

  

8.3

10.7

Is it considered that other batches might be concerned as well?

  

8.4

10.8

Are decisions and measures as a result recorded?

  

8.5

10.9

Is this record added to the corresponding batch documents?

  

8.5

10.10

Are the complaint records regularly revised with respect to specific or recurring problems?

  

8.6

10.11

Are the authorities informed of serious quality problems with a product?

  

8.7

Recalls

8.8

10.12

Does a written recall procedure exist?

  

8.9

10.13

Is a person nominated responsible for the execution and coordination of a recall?

  

8.8

10.14

Responsible person independent of the marketing and sales organization?

  

8.8

10.15

Are the competent authorities informed of an imminent recall?

  

8.11

10.16

Does the person responsible for a recall have access to the distribution records?

  

8.12

10.17

Do the distribution records contain sufficient information on customers with • addresses? • phone numbers inside or outside working hours? • batches and amounts delivered? • medical samples?

  

8.12

        

10.18

Are recalled products stored separately in a secure area?

  

8.13

10.19

Is a final record made including a reconciliation between the delivered and recovered quantities?

  

8.14

10.20

Is the effectiveness of the arrangements for recalls checked critically from time to time?

  

8.15

11

SELF-INSPECTION

11.1

Does a self-inspection procedure exist which defines frequency and program?

  

9.1

11.2

Are self-inspections carried out to check compliance with GMP rules?

  

9.1

9

38

Handbook of Pharmaceutical Manufacturing Formulations: Over-the-Counter Products

Compliance 1 2 3a

Remarks

EU-Guide

Are self-inspections conducted in an independent and detailed way? by designated competent persons from the company or external experts?

  

11.4

Are self-inspections recorded?

  

9.3

11.5

Do reports contain • the observations made during a self-inspection? • proposals for corrective measures?

  

9.3

  

11.6

Are actions subsequently taken recorded?

  

12

CONTRACT MANUFACTURE AND ANALYSIS

12.1

Written contract between contract giver and contract acceptor available?

  

7.1

12.2

Are responsibilities and duties clearly defined?

  

7

12.3

All arrangements in accordance with the marketing authorization of the product concerned?

  

7.2

11.3

9.2

  

9.3 7

The contract giver 12.4

Competence of the acceptor to carry out the work successful and according to GMP assessed?

  

7.3

12.5

Acceptor provided with all the information necessary to carry out the contract work?

  

7.4

12.6

Acceptor informed of safety aspects?

  

7.4

12.7

Conformance of products supplied by the acceptor ensured?

  

7.5

12.8

Product released by a qualified person on the acceptor’s side?

  

7.5

12.9

Does the acceptor have • adequate premises and equipment? • knowledge and experience? • competent personnel? • a manufacturing authorization?

  

7.6

The contract acceptor

        

12.10

Does the acceptor ensure that all products or materials delivered to him are suitable?

  

7.7

12.11

There must be no work passed to a third party without the permission of the giver.

  

7.8

12.12

If a third party is involved it must have the necessary manufacturing and analytical information.

  

7.8

The contract 12.13

Does the written contract specify the responsibilities?

  

7.10

12.14

Have technical aspects been drawn up by competent persons?

  

7.10

12.15

Release of material and check for compliance with the marketing authorization defined?

  

7.11

12.16

Is defined who is responsible for • purchasing of materials? • IPC controls • testing and release of materials? • manufacturing and quality control? • sampling? • storage of batch documentation?

7.12                  

12.17

Are manufacturing, analytical, and distribution records available to the contract giver?

  

7.13

12.18

Contract permits the giver to visit the facilities of the acceptor?

  

7.14

GMP Audit Template, EU Guidelines

Compliance 1 2 3a 12.19

In the case of contract analysis: Does the contract acceptor understand that he is subject to inspection by the competent authorities?

13

AUDIT OF SUPPLIERS

13.1

Supplier audits performed for • excipients? • active substances? • packaging material?

a 1.

  

Remarks

39

EU-Guide 7.15

2.7         

Fulfilled or available; 2. partially fulfilled; 3. not fulfilled or not available.

GLOSSARY Acceptance Criteria—Numerical limits, ranges, or other suitable measures for acceptance of test results. Active Pharmaceutical Ingredient (API) (or Drug Substance)—Any substance or mixture of substances intended to be used in the manufacture of a drug (medicinal) product and that, when used in the production of a drug, becomes an active ingredient of the drug product. Such substances are intended to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease or to affect the structure and function of the body. Air lock—An enclosed space with two or more doors, which is interposed between two or more rooms, for example, of differing classes of cleanliness, for the purpose of controlling the airflow between those rooms when they need to be entered. An air lock is designed for use either by people or for goods and/or equipment. API Starting Material—A raw material, intermediate, or an API that is used in the production of an API and that is incorporated as a significant structural fragment into the structure of the API. An API Starting Material can be an article of commerce, a material purchased from one or more suppliers under contract or commercial agreement, or produced in house. API Starting Materials are normally of defined chemical properties and structure. Authorized Person—The person recognized by the national regulatory authority as having the responsibility for ensuring that each batch of finished product has been manufactured, tested, and approved for release in compliance with the laws and regulations in force in that country. Batch (or Lot)—A specific quantity of material produced in a process or series of processes so that it is expected to be homogeneous within specified limits. In the case of continuous production, a batch may correspond to a defined fraction of the production. The batch size can be defined either by a fixed quantity or by the amount produced in a fixed time interval. A defined quantity of starting material, packaging material, or product processed in a single process or series of processes so that it is expected to be homogeneous. It may sometimes be necessary to divide a batch into a number of subbatches, which are later brought together to form a final homogeneous batch. In the case of terminal sterilization, the batch size is determined by the capacity of the autoclave. In continuous manufacture, the batch must correspond to a defined fraction of the

production, characterized by its intended homogeneity. The batch size can be defined either as a fixed quantity or as the amount produced in a fixed time interval. Batch Number (or Lot Number)—A unique combination of numbers, letters, and/or symbols that identifies a batch (or lot) and from which the production and distribution history can be determined. A distinctive combination of numbers and/or letters which uniquely identifies a batch on the labels, its batch records and corresponding certificates of analysis, and so on. Batch Records—All documents associated with the manufacture of a batch of bulk product or finished product. They provide a history of each batch of product and of all circumstances pertinent to the quality of the final product. Bioburden—The level and type (e.g., objectionable or not) of microorganisms that can be present in raw materials, API starting materials, intermediates, or APIs. Bioburden should not be considered contamination unless the levels have been exceeded or defined objectionable organisms have been detected. Bulk Product—Any product that has completed all processing stages up to, but not including, final packaging. Calibration—The demonstration that a particular instrument or device produces results within specified limits by comparison with those produced by a reference or traceable standard over an appropriate range of measurements. The set of operations that establish, under specified conditions, the relationship between values indicated by an instrument or system for measuring (especially weighing), recording, and controlling, or the values represented by a material measure, and the corresponding known values of a reference standard. Limits for acceptance of the results of measuring should be established. Clean Area—An area with defined environmental control of particulate and microbial contamination, constructed, and used in such a way as to reduce the introduction, generation, and retention of contaminants within the area. Computer System—A group of hardware components and associated software, designed and assembled to perform a specific function or group of functions. A process or operation integrated with a computer system. Consignment (or delivery)—The quantity of a pharmaceutical(s), made by one manufacturer and supplied at one time in response to a particular request or order. A consignment may comprise one or more packages or containers and may include material belonging to more than one batch.

40

Handbook of Pharmaceutical Manufacturing Formulations: Over-the-Counter Products

Contamination—The undesired introduction of impurities of a chemical or microbiological nature, or of foreign matter, into or on to a starting material or intermediate during production, sampling, packaging or repackaging, and storage or transport. Contract Manufacturer—A manufacturer performing some aspect of manufacturing on behalf of the original manufacturer. Critical—Describes a process step, process condition, test requirement, or other relevant parameter or item that must be controlled within predetermined criteria to ensure that the API meets its specification. Critical Operation—An operation in the manufacturing process that may cause variation in the quality of the pharmaceutical product. Cross-Contamination—Contamination of a material or product with another material or product. Contamination of a starting material, intermediate product, or finished product with another starting material or product during production. Deviation—Departure from an approved instruction or established standard. Drug (Medicinal) Product—The dosage form in the final immediate packaging intended for marketing. (Reference Q1A). Drug Substance—See Active Pharmaceutical Ingredient. Expiry Date (or Expiration Date)—The date placed on the container/labels of an API designating the time during which the API is expected to remain within established shelf-life specifications if stored under defined conditions, and after which it should not be used. Finished Product—A finished dosage form that has undergone all stages of manufacture, including packaging in its final container and labeling. Impurity—Any component present in the intermediate or API that is not the desired entity. Impurity Profile—A description of the identified and unidentified impurities present in an API. In-process Control—Checks performed during production in order to monitor and, if necessary, to adjust the process to ensure that the product conforms to its specifications. The control of the environment or equipment may also be regarded as a part of in-process control. Intermediate—A material produced during steps of the processing of an API that undergoes further molecular change or purification before it becomes an API. Intermediates may or may not be isolated. Partly processed product that must undergo further manufacturing steps before it becomes a bulk product. Large-Volume Parenterals—Sterile solutions intended for parenteral application with a volume of 100 mL or more in one container of the finished dosage form. Lot—See Batch. Lot Number—See Batch Number. Manufacture—All operations of receipt of materials, production, packaging, repackaging, labeling, relabeling, quality control, release, storage, and distribution of APIs and related controls. Manufacturer—A company that carries out operations such as production, packaging, repackaging, labeling, and relabeling of pharmaceuticals. Marketing Authorization (Product License, Registration Certificate)—A legal document issued by the competent drug regulatory authority that establishes the detailed composition and formulation of the product and

the pharmacopoeial or other recognized specifications of its ingredients and of the final product itself, and includes details of packaging, labeling, and shelf life. Master Formula—A document or set of documents specifying the starting materials with their quantities and the packaging materials, together with a description of the procedures and precautions required to produce a specified quantity of a finished product as well as the processing instructions, including the in-process controls. Master Record—A document or set of documents that serve as a basis for the batch documentation (blank batch record). Material—A general term used to denote raw materials (starting materials, reagents, solvents), process aids, intermediates, APIs, and packaging and labeling materials. Mother Liquor—The residual liquid which remains after the crystallization or isolation processes. A mother liquor may contain unreacted materials, intermediates, levels of the API, and/or impurities. It may be used for further processing. Packaging—All operations, including filling and labeling, that a bulk product has to undergo in order to become a finished product. Filling of a sterile product under aseptic conditions or a product intended to be terminally sterilized, would not normally be regarded as part of packaging. Packaging Material—Any material intended to protect an intermediate or API during storage and transport. Any material, including printed material, employed in the packaging of a pharmaceutical, but excluding any outer packaging used for transportation or shipment. Packaging materials are referred to as primary or secondary according to whether or not they are intended to be in direct contact with the product. Pharmaceutical Product—Any material or product intended for human or veterinary use presented in its finished dosage form or as a starting material for use in such a dosage form, that is subject to control by pharmaceutical legislation in the exporting state and/or the importing state. Procedure—A documented description of the operations to be performed, the precautions to be taken and measures to be applied directly or indirectly related to the manufacture of an intermediate or API. Process Aids—Materials, excluding solvents, used as an aid in the manufacture of an intermediate or API that do not themselves participate in a chemical or biological reaction (e.g. filter aid, activated carbon, and so on). Process Control—See In-Process Control. Production—All operations involved in the preparation of a pharmaceutical product, from receipt of materials, through processing, packaging and repackaging, and labeling and relabeling, to completion of the finished product. Qualification—Action of proving and documenting that equipment or ancillary systems are properly installed, work correctly, and actually lead to the expected results. Qualification is part of validation, but the individual qualification steps alone do not constitute process validation. Quality Assurance (QA)—The sum total of the organised arrangements made with the object of ensuring that all APIs are of the quality required for their intended use and that quality systems are maintained.

GMP Audit Template, EU Guidelines

Quality Control (QC)—Checking or testing that specifications are met. Quality Unit(s)—An organizational unit independent of production which fulfills both Quality Assurance and Quality Control responsibilities. This can be in the form of separate QA and QC units or a single individual or group, depending upon the size and structure of the organization. Quarantine—The status of starting or packaging materials, intermediates, or bulk or finished products isolated physically or by other effective means while a decision is awaited on their release, rejection, or reprocessing. Raw Material—A general term used to denote starting materials, reagents, and solvents intended for use in the production of intermediates or APIs. Reconciliation—A comparison between the theoretical quantity and the actual quantity. Recovery—The introduction of all or part of previous batches (or of redistilled solvents and similar products) of the required quality into another batch at a defined stage of manufacture. It includes the removal of impurities from waste to obtain a pure substance or the recovery of used materials for a separate use. Reference Standard, Primary—A substance that has been shown by an extensive set of analytical tests to be authentic material that should be of high purity. Reference Standard, Secondary—A substance of established quality and purity, as shown by comparison to a primary reference standard, used as a reference standard for routine laboratory analysis. Reprocessing—Subjecting all or part of a batch or lot of an in-process drug, bulk process intermediate (final biological bulk intermediate) or bulk product of a single batch/lot to a previous step in the validated manufacturing process due to failure to meet pre-determined specifications. Reprocessing procedures are foreseen as occasionally necessary for biological drugs and, in such cases, are validated and preapproved as part of the marketing authorization. Retest Date—The date when a material should be reexamined to ensure that it is still suitable for use. Reworking—Subjecting an in-process or bulk process intermediate (final biological bulk intermediate) or final product of a single batch to an alternate manufacturing process due to a failure to meet predetermined specifications. Reworking is an unexpected occurrence and is not preapproved as part of the marketing authorization. Self-Contained Area—Premises which provide complete and total separation of all aspects of an operation,

41

including personnel and equipment movement, with well-established procedures, controls, and monitoring. This includes physical barriers as well as separate airhandling systems, but does not necessarily imply two distinct and separate buildings. Signature (Signed)—See definition for signed. Signed (Signature)—The record of the individual who performed a particular action or review. This record can be initials, full handwritten signature, personal seal, or authenticated and secure electronic signature. Solvent—An inorganic or organic liquid used as a vehicle for the preparation of solutions or suspensions in the manufacture of an intermediate or API. Specification—A list of detailed requirements with which the products or materials used or obtained during manufacture have to conform. They serve as a basis for quality evaluation. Standard Operating Procedure (SOP)—An authorized written procedure giving instructions for performing operations not necessarily specific to a given product or material (e.g., equipment operation, maintenance, and cleaning; validation; cleaning of premises and environmental control; sampling and inspection). Certain SOPs may be used to supplement product-specific master and batch production documentation. Starting Material—Any substance of a defined quality used in the production of a pharmaceutical product, but excluding packaging materials. Validation—A documented program that provides a high degree of assurance that a specific process, method, or system will consistently produce a result meeting predetermined acceptance criteria. Action of proving, in accordance with the principles of GMP, that any procedure, process, equipment, material, activity, or system actually leads to the expected results (see also qualification). Validation Protocol—A written plan stating how validation will be conducted and defining acceptance criteria. For example, the protocol for a manufacturing process identifies processing equipment, critical process parameters/operating ranges, product characteristics, sampling, test data to be collected, number of validation runs, and acceptable test results. Yield, Expected—The quantity of material or the percentage of theoretical yield anticipated at any appropriate phase of production based on previous laboratory, pilot scale, or manufacturing data. Yield, Theoretical—The quantity that would be produced at any appropriate phase of production, based upon the quantity of material to be used, in the absence of any loss or error in actual production.

4 WHO Good Manufacturing Guidelines

QUALITY MANAGEMENT IN THE DRUG INDUSTRY: PHILOSOPHY AND ESSENTIAL ELEMENTS

1. QUALITY ASSURANCE 1.1 Principle. “Quality assurance” is a wide-ranging concept covering all matters that individually or collectively influence the quality of a product. It is the totality of the arrangements made with the object of ensuring that pharmaceutical products are of the quality required for their intended use. Quality assurance therefore incorporates GMP and other factors, including those outside the scope of this guide such as product design and development. 1.2 The system of quality assurance appropriate to the manufacture of pharmaceutical products should ensure that (a) pharmaceutical products are designed and developed in a way that takes account of the requirements of GMP and other associated codes such as those of good laboratory practice (GLP) 1 and good clinical practice (GCP); (b) production and control operations are clearly specified in a written form and GMP requirements are adopted; (c) managerial responsibilities are clearly specified in job descriptions; (d) arrangements are made for the manufacture, supply, and use of the correct starting and packaging materials; (e) all necessary controls on starting materials, intermediate products, and bulk products and other inprocess controls, calibrations, and validations are carried out; (f) the finished product is correctly processed and checked, according to the defined procedures; (g) pharmaceutical products are not sold or supplied before the authorized persons (see also sections 9.11 and 9.12) have certified that each production batch has been produced and controlled in accordance with the requirements of the marketing authorization and any other regulations relevant to the production, control, and release of pharmaceutical products; (h) satisfactory arrangements exist to ensure, as far as possible, that the pharmaceutical products are stored by the manufacturer, distributed, and subsequently handled so that quality is maintained throughout their shelf life; (i) there is a procedure for self-inspection and/or quality audit that regularly appraises the effectiveness and applicability of the quality assurance system; (j) deviations are reported, investigated, and recorded; (k) there is a system for approving changes that may have an impact on product quality; and (l) regular evaluations of the quality of pharmaceutical products should be conducted with the objective of verifying the consistency of the process and ensuring its continuous improvement.

The WHO provides GMP guidelines and also offers a program of GMP compliance certification. One of the most valuable document is the WHO Technical Report 908, which is available at http://whqlibdoc.who.int/trs/WHO TRS 908. pdf#page=46. In addition, the WHO offers many very useful GMP training programs (http://healthtech.who.int/pq/ trainingresources/pq pres/gmptraining/GMPBasicTraining .htm) that can be of great benefit to companies who may not have access to the inspections by the U.S. FDA or EMEA. It is important to know that the U.S. FDA inspection triggers only when there is an application pending for marketing authorization in the United States, whereas the European as well as the WHO GMP audits can be invited otherwise. To assure that the interpretation of the WHO guidelines is properly understood, an appendix to this guideline includes the glossary of terms used. Also included at the end of the chapter is a description of the various types of inspections that the WHO offers. It is important to know that WHO will offer inspections regardless of the status of marketing authorization applications; most manufacturers will request these inspections in anticipation of participation in the WHO Essential Drugs Program and register as certified suppliers that will qualify the manufacturer to bid on various WHO-sponsored drug purchase programs. In the drug industry at large, quality management is usually defined as the aspect of management function that determines and implements the “quality policy,” that is, the overall intention and direction of an organization regarding quality, as formally expressed and authorized by top management. The basic elements of quality management are as follows:

r An appropriate infrastructure or “quality system,” encompassing the organizational structure, procedures, processes, and resources. r Systematic actions necessary to ensure adequate confidence that a product (or service) will satisfy given requirements for quality. The totality of these actions is termed “quality assurance.” Within an organization, quality assurance serves as a management tool. In contractual situations, quality assurance also serves to generate confidence in the supplier. The concepts of quality assurance, GMP, and quality control are interrelated aspects of quality management. They are described here in order to emphasize their relationship and their fundamental importance to the production and control of pharmaceutical products. 42

WHO Good Manufacturing Guidelines

1.3 The manufacturer must assume responsibility for the quality of the pharmaceutical products to ensure that they are fit for their intended use, comply with the requirements of the marketing authorization and do not place patients at risk due to inadequate safety, quality, or efficacy. The attainment of this quality objective is the responsibility of senior management and requires the participation and commitment of staff in many different departments and at all levels within the company, the company’s suppliers, and the distributors. To achieve the quality objective reliably, there must be a comprehensively designed and correctly implemented system of quality assurance incorporating GMP and quality control. It should be fully documented and its effectiveness monitored. All parts of the quality assurance system should be adequately staffed with competent personnel, and should have suitable and sufficient premises, equipment, and facilities.

43

(j) complaints about marketed products are examined, the causes of quality defects investigated, and appropriate measures taken in respect of the defective products to prevent recurrence.

3. SANITATION AND HYGIENE 3.1 A high level of sanitation and hygiene should be practiced in every aspect of the manufacture of drug products. The scope of sanitation and hygiene covers personnel, premises, equipment and apparatus, production materials and containers, products for cleaning and disinfection, and anything that could become a source of contamination to the product. Potential sources of contamination should be eliminated through an integrated comprehensive program of sanitation and hygiene. (For personal hygiene see section 11, and for sanitation see section 12, “Premises”.)

2. GMPs FOR PHARMACEUTICAL PRODUCTS 2.1 Good manufacturing practice is that part of quality assurance which ensures that products are consistently produced and controlled to the quality standards appropriate to their intended use and as required by the marketing authorization. GMPs are aimed primarily at diminishing the risks inherent in any pharmaceutical production. Such risks are essentially of two types: cross-contamination (in particular of unexpected contaminants) and mix-ups (confusion) caused by, for example, false labels being put on containers. Under GMP (a) all manufacturing processes are clearly defined, systematically reviewed in the light of experience, and shown to be capable of consistently manufacturing pharmaceutical products of the required quality that comply with their specifications; (b) qualification and validation are performed; (c) all necessary resources are provided, including (i) appropriately qualified and trained personnel; (ii) adequate premises and space; (iii) suitable equipment and services; (iv) appropriate materials, containers, and labels; (v) approved procedures and instructions; (vi) suitable storage and transport; and (vii) adequate personnel, laboratories, and equipment for in-process controls; (d) instructions and procedures are written in clear and unambiguous language, specifically applicable to the facilities provided; (e) operators are trained to carry out procedures correctly; (f) records are made (manually and/or by recording instruments) during manufacture to show that all the steps required by the defined procedures and instructions have, in fact, been taken and that the quantity and quality of the product are as expected; any significant deviations are fully recorded and investigated; (g) records covering manufacture and distribution, which enable the complete history of a batch to be traced, are retained in a comprehensible and accessible form; (h) the proper storage and distribution of the products minimize any risk to their quality; (i) a system is available to recall any batch of product from sale or supply;

4. QUALIFICATION AND VALIDATION 4.1 In accordance with GMP, each pharmaceutical company should identify what qualification and validation work is required to prove that the critical aspects of their particular operation are controlled. 4.2 The key elements of a qualification and validation program of a company should be clearly defined and documented in a validation master plan. 4.3 Qualification and validation should establish and provide documentary evidence that (a) the premises, supporting utilities, equipment, and processes have been designed in accordance with the requirements for GMP (design qualification or DQ); (b) the premises, supporting utilities, and equipment have been built and installed in compliance with their design specifications (installation qualification or IQ); (c) the premises, supporting utilities, and equipment operate in accordance with their design specifications (operational qualification or OQ); (d) a specific process will consistently produce a product meeting its predetermined specifications and quality attributes (process validation, or PV, also called performance qualification, or PQ). 4.4 Any aspect of operation, including significant changes to the premises, facilities, equipment, or processes, which may affect the quality of the product, directly or indirectly, should be qualified and validated. 4.5 Qualification and validation should not be considered as one-off exercises. An ongoing program should follow their first implementation and should be based on an annual review. 4.6 The commitment to maintain continued validation status should be stated in the relevant company documentation, such as the quality manual or validation master plan. 4.7 The responsibility of performing validation should be clearly defined. 4.8 Validation studies are an essential part of GMP and should be conducted in accordance with predefined and approved protocols. 4.9 A written report summarizing the results recorded and the conclusions reached should be prepared and stored.

44

Handbook of Pharmaceutical Manufacturing Formulations: Over-the-Counter Products

4.10 Processes and procedures should be established on the basis of the results of the validation performed. 4.11 It is of critical importance that particular attention is paid to the validation of analytical test methods, automated systems, and cleaning procedures.

5. COMPLAINTS 5.1 Principle. All complaints and other information concerning potentially defective products should be carefully reviewed according to written procedures and the corrective action should be taken. 5.2 A person responsible for handling the complaints and deciding the measures to be taken should be designated, together with sufficient supporting staff to assist him or her. If this person is different from the authorized person, the latter should be made aware of any complaint, investigation, or recall. 5.3 There should be written procedures describing the action to be taken, including the need to consider a recall, in the case of a complaint concerning a possible product defect. 5.4 Special attention should be given to establish whether a complaint was caused because of counterfeiting. 5.5 Any complaint concerning a product defect should be recorded with all the original details and thoroughly investigated. The person responsible for quality control should normally be involved in the review of such investigations. 5.6 If a product defect is discovered or suspected in a batch, consideration should be given to whether other batches should be checked in order to determine whether they are also affected. In particular, other batches that may contain reprocessed product from the defective batch should be investigated. 5.7 Where necessary, appropriate follow-up action, possibly including product recall, should be taken after investigation and evaluation of the complaint. 5.8 All decisions made and measures taken as a result of a complaint should be recorded and referenced to the corresponding batch records. 5.9 Complaints records should be regularly reviewed for any indication of specific or recurring problems that require attention and might justify the recall of marketed products. 5.10 The competent authorities should be informed if a manufacturer is considering action following possibly faulty manufacture, product deterioration, counterfeiting, or any other serious quality problems with a product.

6. PRODUCT RECALLS 6.1 Principle. There should be a system to recall from the market, promptly and effectively, products known or suspected to be defective. 6.2 The authorized person should be responsible for the execution and coordination of recalls. He or she should have sufficient staff to handle all aspects of the recalls with the appropriate degree of urgency. 6.3 There should be established written procedures, which are regularly reviewed and updated, for the organization of any recall activity. Recall operations should be capable of being initiated promptly down to the required level in the distribution chain.

6.4 An instruction should be included in the written procedures to store recalled products in a secure segregated area while their fate is decided. 6.5 All competent authorities of all countries to which a given product has been distributed should be promptly informed of any intention to recall the product because it is, or is suspected of being, defective. 6.6 The distribution records should be readily available to the authorized person, and they should contain sufficient information on wholesalers and directly supplied customers (including, for exported products, those who have received samples for clinical tests and medical samples) to permit an effective recall. 6.7 The progress of the recall process should be monitored and recorded. Records should include the disposition of the product. A final report should be issued, including a reconciliation between the delivered and recovered quantities of the products. 6.8 The effectiveness of the arrangements for recalls should be tested and evaluated from time to time.

7. CONTRACT PRODUCTION AND ANALYSIS 7.1 Principle. Contract production and analysis must be correctly defined, agreed, and controlled in order to avoid misunderstandings that could result in a product or work or analysis of unsatisfactory quality.

General 7.2 All arrangements for contract manufacture and analysis, including any proposed changes in technical or other arrangements, should be in accordance with the marketing authorization for the product concerned. 7.3 The contract should permit the contract giver to audit the facilities of the contract accepter. 7.4 In the case of contract analysis, the final approval for release must be given by the authorized person.

The Contract Giver 7.5 The contract giver is responsible for assessing the competence of the contract accepter in successfully carrying out the work or tests required, for approval for contract activities, and for ensuring by means of the contract that the principles of GMP described in this guide are followed. 7.6 The contract giver should provide the contract accepter with all the information necessary to carry out the contracted operations correctly in accordance with the marketing authorization and any other legal requirements. The contract giver should ensure that the contract accepter is fully aware of any problems associated with the product, work, or tests that might pose a hazard to premises, equipment, personnel, other materials, or other products. 7.7 The contract giver should ensure that all processed products and materials delivered by the contract accepter comply with their specifications or that the product has been released by the authorized person.

The Contract Accepter 7.8 The contract accepter must have adequate premises, equipment, knowledge, and experience and competent personnel to carry out satisfactorily the work ordered by the contract giver. Contract manufacture may be

WHO Good Manufacturing Guidelines

undertaken only by a manufacturer who holds a manufacturing authorization. 7.9 The contract accepter should not pass to a third party any of the work entrusted to him or her under the contract without the contract giver’s prior evaluation and approval of the arrangements. Arrangements made between the contract accepter and any third party should ensure that the manufacturing and analytical information is made available in the same way as between the original contract giver and contract accepter. 7.10 The contract accepter should refrain from any activity that may adversely affect the quality of the product manufactured and/or analyzed for the contract giver.

The Contract 7.11 There must be a written contract between the contract giver and the contract accepter which clearly establishes the responsibilities of each party. 7.12 The contract must clearly state the way in which the authorized person, in releasing each batch of product for sale or issuing the certificate of analysis, exercises his or her full responsibility and ensures that each batch has been manufactured in, and checked for, compliance with the requirements of the marketing authorization. 7.13 Technical aspects of the contract should be drawn up by competent persons suitably knowledgeable in pharmaceutical technology, analysis, and GMP. 7.14 All arrangements for production and analysis must be in accordance with the marketing authorization and agreed by both parties. 7.15 The contract should describe clearly who is responsible for purchasing, testing, and releasing materials and for undertaking production and quality controls, including in-process controls, and who has responsibility for sampling and analysis. In the case of contract analysis, the contract should state whether or not the contract accepter should take samples at the premises of the manufacturer. 7.16 Manufacturing, analytical, distribution records and reference samples should be kept by, or be available to, the contract giver. Any records relevant to assessing the quality of a product in the event of complaints or a suspected defect must be accessible and specified in the defect/recall procedures of the contract giver. 7.17 The contract should describe the handling of starting materials, intermediate and bulk products, and finished products if they are rejected. It should also describe the procedure to be followed if the contract analysis shows that the tested product must be rejected.

8. SELF-INSPECTION AND QUALITY AUDITS 8.1 Principle. The purpose of self-inspection is to evaluate the manufacturer’s compliance with GMP in all aspects of production and quality control. The self-inspection program should be designed to detect any shortcomings in the implementation of GMP and to recommend the necessary corrective actions. Self-inspections should be performed routinely, and may be, in addition, performed on special occasions, for example, in the case of product recalls or repeated rejections, or when an inspection by the health authorities is announced. The team responsible for self-inspection should consist of personnel who can evaluate the implementation of

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GMP objectively. All recommendations for corrective action should be implemented. The procedure for selfinspection should be documented, and there should be an effective follow-up program.

Items for Self-Inspection 8.2 Written instructions for self-inspection should be established to provide a minimum and uniform standard of requirements. These may include questionnaires on GMP requirements covering at least the following items: (a) Personnel (b) Premises including personnel facilities (c) Maintenance of buildings and equipment (d) Storage of starting materials and finished products (e) Equipment (f) Production and in-process controls (g) Quality control (h) Documentation (i) Sanitation and hygiene (j) Validation and revalidation programs (k) Calibration of instruments or measurement systems (l) Recall procedures (m) Complaints management (n) Labels control (o) Results of previous self-inspections and any corrective steps taken

Self-Inspection Team 8.3 Management should appoint a self-inspection team consisting of experts in their respective fields and familiar with GMP. The members of the team may be appointed from inside or outside the company.

Frequency of Self-Inspection 8.4 The frequency at which self-inspections are conducted may depend on company requirements but should preferably be at least once a year. The frequency should be stated in the procedure.

Self-Inspection Report 8.5 A report should be made at the completion of a selfinspection. The report should include (a) self-inspection results, (b) evaluation and conclusions, and (c) recommended corrective actions.

Follow-Up Action 8.6 There should be an effective follow-up program. The company management should evaluate both the selfinspection report and the corrective actions as necessary.

Quality Audit 8.7 It may be useful to supplement self-inspections with a quality audit. A quality audit consists of an examination and assessment of all or part of a quality system with the specific purpose of improving it. A quality audit is usually conducted by outside or independent specialists or a team designated by the management for this purpose. Such audits may also be extended to suppliers and contractors (see section 7, “Contract Production and Analysis”).

Suppliers’ Audits and Approval 8.8 The person responsible for quality control should have responsibility together with other relevant departments

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for approving suppliers who can reliably supply starting and packaging materials that meet established specifications. 8.9 Before suppliers are approved and included in the approved suppliers’ list or specifications, they should be evaluated. The evaluation should take into account a supplier’s history and the nature of the materials to be supplied. If an audit is required, it should determine the supplier’s ability to conform with GMP standards.

9. PERSONNEL 9.1 Principle. The establishment and maintenance of a satisfactory system of quality assurance and the correct manufacture and control of pharmaceutical products and active ingredients rely upon people. For this reason, there must be sufficient qualified personnel to carry out all the tasks for which the manufacturer is responsible. Individual responsibilities should be clearly defined and understood by the persons concerned and recorded as written descriptions.

General 9.2 The manufacturer should have an adequate number of personnel with the necessary qualifications and practical experience. The responsibilities placed on any one individual should not be so extensive so as to present any risk to quality. 9.3 All responsible staff should have their specific duties recorded in written descriptions and adequate authority to carry out their responsibilities. Their duties may be delegated to designated deputies of a satisfactory qualification level. There should be no gaps or unexplained overlaps in the responsibilities of personnel concerned with the application of GMP. The manufacturer should have an organization chart. 9.4 All personnel should be aware of the principles of GMP that affect them and receive initial and continuing training, including hygiene instructions, relevant to their needs. All personnel should be motivated to support the establishment and maintenance of high-quality standards. 9.5 Steps should be taken to prevent unauthorized people from entering production, storage, and quality control areas. Personnel who do not work in these areas should not use them as a passageway.

Key Personnel 9.6 Key personnel include the head of production, the head of quality control, and the authorized person. Normally, key posts should be occupied by full-time personnel. The heads of production and quality control should be independent of each other. In large organizations, it may be necessary to delegate some of the functions; however, the responsibility cannot be delegated. 9.7 Key personnel responsible for supervising the manufacture and quality control of pharmaceutical products should possess the qualifications of a scientific education and practical experience required by national legislation. Their education should include the study of an appropriate combination of (a) chemistry (analytical or organic) or biochemistry, (b) chemical engineering, (c) microbiology,

(d) (e) (f) (g)

pharmaceutical sciences and technology, pharmacology and toxicology, physiology, and other related sciences. They should also have adequate practical experience in the manufacture and quality assurance of pharmaceutical products. In order to gain such experience, a preparatory period may be required, during which they should exercise their duties under professional guidance. The scientific education and practical experience of experts should be such as to enable them to exercise independent professional judgment, based on the application of scientific principles and understanding to the practical problems encountered in the manufacture and quality control of pharmaceutical products. 9.8 The heads of the production and quality control generally have some shared, or jointly exercised, responsibilities relating to quality. These may include, depending on national regulations, (a) to ensure that products are produced and stored according to the appropriate documentation in order to obtain the required quality; (b) to approve the instructions relating to production operations, including the in-process controls, and to ensure their strict implementation; (c) to ensure that the production records are evaluated and signed by a designated person; (d) to check the maintenance of the department, premises, and equipment; (e) to ensure that the appropriate process validations and calibrations of control equipment are performed and recorded and the reports made available; and (f) to ensure that the required initial and continuing training of production personnel is carried out and adapted according to need. 9.9 The head of the production generally has the following responsibilities: (a) authorization of written procedures and other documents, including amendments; (b) monitoring and control of the manufacturing environment; (c) plant hygiene; (d) process validation and calibration of analytical apparatus; (e) training, including the application and principles of quality assurance; (f) approval and monitoring of suppliers of materials; (g) approval and monitoring of contract manufacturers; (h) designation and monitoring of storage conditions for materials and products; (i) performance and evaluation of in-process controls; (j) retention of records; (k) monitoring of compliance with GMP requirements; and (l) inspection, investigation, and taking of samples in order to monitor factors that may affect product quality. 9.10 The head of the quality control generally has the following responsibilities: (a) to approve or reject starting materials, packaging materials, and intermediate, bulk, and finished products in relation to their specifications; (b) to evaluate batch records; (c) to ensure that all necessary testing is carried out;

WHO Good Manufacturing Guidelines

9.11

9.12

9.13

9.14

(d) to approve sampling instructions, specifications, test methods, and other quality control procedures; (e) to approve and monitor analyses carried out under contract; (f) to check the maintenance of the department, premises, and equipment; (g) to ensure that the appropriate validations, including those of analytical procedures, and calibrations of control equipment are carried out; and (h) to ensure that the required initial and continuing training of quality control personnel is carried out and adapted according to need. Other duties of the quality control are summarized in sections 17.3 and 17.4. The authorized person is responsible for compliance with technical or regulatory requirements related to the quality of finished products and the approval of the release of the finished product for sale. The authorized person will also be involved in other activities, including (a) implementation (and, when needed, establishment) of the quality system, (b) participation in the development of the company’s quality manual, (c) supervision of the regular internal audits or selfinspections, (d) oversight of the quality control department, (e) participation in external audit (vendor audit), and (f) participation in validation programs. The function of the approval of the release of a finished batch or a product can be delegated to a designated person with appropriate qualifications and experience who will release the product in accordance with an approved procedure. This is normally done by quality assurance by means of batch review. The person responsible for approving a batch for release should always ensure that the following requirements have been met: (a) The marketing authorization and the manufacturing authorization requirements for the product have been met for the batch concerned. (b) The principles and guidelines of GMP, as laid down in the guidelines published by WHO, have been followed. (c) The principal manufacturing and testing processes have been validated, if different. (d) All the necessary checks and tests have been performed and account taken of the production conditions and manufacturing records. (e) Any planned changes or deviations in manufacturing or quality control have been notified in accordance with a well-defined reporting system before any product is released. Such changes may need notification to, and approval by, the drug regulatory authority. (f) Any additional sampling, inspection, tests, and checks have been carried out or initiated, as appropriate, to cover planned changes and deviations. (g) All necessary production and quality control documentation has been completed and endorsed by supervisors trained in appropriate disciplines. (h) Appropriate audits, self-inspections, and spotchecks are carried out by experienced and trained staff. (i) Approval has been given by the head of quality control.

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(j) All relevant factors have been considered, including any not specifically associated with the output batch directly under review (e.g., subdivision of output batches from a common input, factors associated with continuous production runs).

10. TRAINING 10.1 The manufacturer should provide training in accordance with a written program for all personnel whose duties take them into manufacturing areas or into control laboratories (including the technical, maintenance, and cleaning personnel) and for other personnel as required. 10.2 Besides basic training on the theory and practice of GMP, newly recruited personnel should receive training appropriate to the duties assigned to them. Continuing training should also be given, and its practical effectiveness periodically assessed. Approved training programs should be available. Training records should be kept. 10.3 Personnel working in areas where contamination is a hazard, for example, clean areas or areas where highly active, toxic, infectious, or sensitizing materials are handled, should be given specific training. 10.4 The concept of quality assurance and all the measures which aid its understanding and implementation should be fully discussed during the training sessions. 10.5 Visitors or untrained personnel should preferably not be taken into the production and quality control areas. If this is unavoidable, they should be given relevant information in advance (particularly about personal hygiene) and the prescribed protective clothing. They should be closely supervised. 10.6 Consultant and contract staff should be qualified for the services they provide. Evidence of this should be included in the training records.

11. PERSONAL HYGIENE 11.1 All personnel, prior to and during employment, as appropriate, should undergo health examinations. Personnel conducting visual inspections should also undergo periodic eye examinations. 11.2 All personnel should be trained in the practices of personal hygiene. A high level of personal hygiene should be observed by all those concerned with manufacturing processes. In particular, personnel should be instructed to wash their hands before entering production areas. Signs to this effect should be posted and instructions observed. 11.3 Any person shown at any time to have an apparent illness or open lesions that may adversely affect the quality of products should not be allowed to handle starting materials, packaging materials, in-process materials, or drug products until the condition is no longer judged to be a risk. 11.4 All employees should be instructed and encouraged to report to their immediate supervisor any conditions (relating to plant, equipment, or personnel) that they consider may adversely affect the products. 11.5 Direct contact should be avoided between the operator’s hands and starting materials, primary packaging materials, and intermediate or bulk product. 11.6 To ensure protection of the product from contamination, personnel should wear clean body coverings

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Handbook of Pharmaceutical Manufacturing Formulations: Over-the-Counter Products

appropriate to the duties they perform, including appropriate hair covering. Used clothes, if reusable, should be stored in separate closed containers until properly laundered and, if necessary, disinfected or sterilized. 11.7 Smoking, eating, drinking, chewing, and keeping plants, food, drink, smoking material, and personal medicines should not be permitted in production, laboratory, and storage areas, or in any other areas where they might adversely influence product quality. 11.8 Personal hygiene procedures including the use of protective clothing should apply to all persons entering production areas, whether they are temporary or fulltime employees or nonemployees, for example, contractors’ employees, visitors, senior managers, and inspectors.

12. PREMISES 12.1 Principle. Premises must be located, designed, constructed, adapted, and maintained to suit the operations to be carried out.

General 12.2 The layout and design of premises must aim to minimize the risk of errors and permit effective cleaning and maintenance in order to avoid cross-contamination, build-up of dust or dirt, and, in general, any adverse effect on the quality of products. 12.3 Where dust is generated (e.g., during sampling, weighing, mixing and processing operations, packaging of powder), measures should be taken to avoid crosscontamination and facilitate cleaning. 12.4 Premises should be situated in an environment that, when considered together with measures to protect the manufacturing process, presents minimum risk of causing any contamination of materials or products. 12.5 Premises used for the manufacture of finished products should be suitably designed and constructed to facilitate good sanitation. 12.6 Premises should be carefully maintained, and it should be ensured that repair and maintenance operations do not present any hazard to the quality of products. 12.7 Premises should be cleaned and, where applicable, disinfected according to detailed written procedures. Records should be maintained. 12.8 Electrical supply, lighting, temperature, humidity, and ventilation should be appropriate and such that they do not adversely affect, directly or indirectly, either the pharmaceutical products during their manufacture and storage or the accurate functioning of equipment. 12.9 Premises should be designed and equipped so as to afford maximum protection against the entry of insects, birds, or other animals. There should be a procedure for rodent and pest control. 12.10 Premises should be designed to ensure the logical flow of materials and personnel.

Ancillary Areas 12.11 Rest and refreshment rooms should be separate from manufacturing and control areas. 12.12 Facilities for changing and storing clothes and for washing and toilet purposes should be easily accessible and appropriate for the number of users. Toilets should not communicate directly with production or storage areas.

12.13 Maintenance workshops should if possible be separated from production areas. Whenever parts and tools are stored in the production area, they should be kept in rooms or lockers reserved for that use. 12.14 Animal houses should be well isolated from other areas, with separate entrance (animal access) and airhandling facilities.

Storage Areas 12.15 Storage areas should be of sufficient capacity to allow orderly storage of the various categories of materials and products with proper separation and segregation: starting and packaging materials; intermediates, bulk, and finished products; products in quarantine; and released, rejected, returned, or recalled products. 12.16 Storage areas should be designed or adapted to ensure good storage conditions. In particular, they should be clean, dry, sufficiently lit, and maintained within acceptable temperature limits. Where special storage conditions are required (e.g. temperature, humidity), these should be provided, controlled, monitored, and recorded where appropriate. 12.17 Receiving and dispatch bays should be separated and protect materials and products from the weather. Receiving areas should be designed and equipped to allow containers of incoming materials to be cleaned if necessary before storage. 12.18 Where quarantine status is ensured by storage in separate areas, these areas must be clearly marked and their access restricted to authorized personnel. Any system replacing the physical quarantine should give equivalent security. 12.19 Segregation should be provided for the storage of rejected, recalled, or returned materials or products. 12.20 Highly active and radioactive materials, narcotics, other dangerous drugs, and substances presenting special risks of abuse, fire, or explosion should be stored in safe and secure areas. 12.21 Printed packaging materials are considered critical to the conformity of the pharmaceutical product to its labeling and special attention should be paid to sampling and the safe and secure storage of these materials. 12.22 There should normally be a separate sampling area for starting materials. (If sampling is performed in the storage area, it should be conducted in such a way as to prevent contamination or cross-contamination.)

Weighing Areas 12.23 The weighing of starting materials and the estimation of yield by weighing should be carried out in separate weighing areas designed for that use, for example, with provisions for dust control. Such areas may be part of either storage or production areas.

Production Areas 12.24 In order to minimize the risk of a serious medical hazard due to cross-contamination, dedicated and selfcontained facilities must be available for the production of particular pharmaceutical products, such as highly sensitizing materials (e.g. penicillins) or biological preparations (e.g. live microorganisms). The production of certain other highly active products, such as some antibiotics, hormones, cytotoxic substances, and certain nonpharmaceutical products, should not be conducted in the same facilities. In exceptional cases, the principle of campaign working in the same facilities

WHO Good Manufacturing Guidelines

12.25

12.26

12.27

12.28

12.29

12.30

12.31 12.32

can be accepted provided that specific precautions are taken and the necessary validations (including cleaning validation) are made. The manufacture of technical poisons, such as pesticides and herbicides, should not be allowed in premises used for the manufacture of pharmaceutical products. Premises should preferably be laid out in such a way as to allow the production to take place in areas connected in a logical order corresponding to the sequence of the operations and to the requisite cleanliness levels. The adequacy of the working and in-process storage space should permit the orderly and logical positioning of equipment and materials so as to minimize the risk of confusion between different pharmaceutical products or their components, to avoid crosscontamination, and to minimize the risk of omission or wrong application of any of the manufacturing or control steps. Where starting and primary packaging materials and intermediate or bulk products are exposed to the environment, interior surfaces (walls, floors, and ceilings) should be smooth and free from cracks and open joints, should not shed particulate matter, and should permit easy and effective cleaning and, if necessary, disinfection. Pipework, light fittings, ventilation points, and other services should be designed and sited to avoid the creation of recesses that are difficult to clean. As far as possible, for maintenance purposes, they should be accessible from outside the manufacturing areas. Drains should be of adequate size and designed and equipped to prevent backflow. Open channels should be avoided where possible, but if they are necessary they should be shallow to facilitate cleaning and disinfection. Production areas should be effectively ventilated, with air-control facilities (including filtration of air to a sufficient level to prevent contamination and crosscontamination, as well as control of temperature and, where necessary, humidity) appropriate to the products handled, to the operations undertaken, and to the external environment. These areas should be regularly monitored during both production and nonproduction periods to ensure compliance with their design specifications. Premises for the packaging of pharmaceutical products should be specifically designed and laid out so as to avoid mix-ups or cross-contamination. Production areas should be well lit, particularly where visual online controls are carried out.

Quality Control Areas 12.33 Quality control laboratories should be separated from production areas. Areas where biological, microbiological, or radioisotope test methods are employed should be separated from each other. 12.34 Quality control laboratories should be designed to suit the operations to be carried out in them. Sufficient space should be given to avoid mix-ups and crosscontamination. There should be adequate suitable storage space for samples, reference standards (if necessary, with cooling), solvents, reagents, and records. 12.35 The design of the laboratories should take into account the suitability of construction materials, prevention of fumes, and ventilation. There should be separate air supply to laboratories and production areas. Separate

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air-handling units and other provisions are needed for biological, microbiological, and radioisotope laboratories. 12.36 A separate room may be needed for instruments to protect them against electrical interference, vibration, contact with excessive moisture, and other external factors, or where it is necessary to isolate the instruments.

13. EQUIPMENT 13.1 Equipment must be located, designed, constructed, adapted, and maintained to suit the operations to be carried out. The layout and design of equipment must aim to minimize the risk of errors and permit effective cleaning and maintenance in order to avoid crosscontamination, build-up of dust or dirt, and, in general, any adverse effect on the quality of products. 13.2 Equipment should be installed in such a way as to minimize any risk of error or of contamination. 13.3 Fixed pipework should be clearly labeled to indicate the contents and, where applicable, the direction of flow. 13.4 All service pipings and devices should be adequately marked and special attention paid to the provision of noninterchangeable connections or adaptors for dangerous gases and liquids. 13.5 Balances and other measuring equipment of an appropriate range and precision should be available for production and control operations and should be calibrated on a scheduled basis. 13.6 Production equipment should be thoroughly cleaned on a scheduled basis. 13.7 Laboratory equipment and instruments should be suited to the testing procedures undertaken. 13.8 Washing, cleaning, and drying equipment should be chosen and used so as not to be a source of contamination. 13.9 Production equipment should not present any hazard to the products. The parts of the production equipment that come into contact with the product must not be reactive, additive, or absorptive to an extent that would affect the quality of the product. 13.10 Defective equipment should be removed from production and quality control areas. If this is not possible, it should be clearly labeled as defective to prevent use. 13.11 Closed equipment should be used whenever appropriate. Where open equipment is used or equipment is opened, precautions should be taken to minimize contamination. 13.12 Nondedicated equipment should be cleaned according to validated cleaning procedures between production of different pharmaceutical products to prevent crosscontamination. 13.13 Current drawings of critical equipment and support systems should be maintained.

14. MATERIALS 14.1 Principle. The main objective of a pharmaceutical plant is to produce finished products for patients’ use from a combination of materials (starting and packaging). 14.2 Materials include starting materials, packaging materials, gases, solvents, process aids, reagents, and labeling materials.

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Handbook of Pharmaceutical Manufacturing Formulations: Over-the-Counter Products

General 14.3 No materials used for operations such as cleaning, lubrication of equipment, and pest control, should come into direct contact with the product. Where possible, such materials should be of a suitable grade (e.g. food grade) to minimize health risks. 14.4 All incoming materials and finished products should be quarantined immediately after receipt or processing, until they are released for use or distribution. 14.5 All materials and products should be stored under the appropriate conditions established by the manufacturer and in an orderly fashion to permit batch segregation and stock rotation by a first-expire, first-out rule. 14.6 Water used in the manufacture of pharmaceutical products should be suitable for its intended use.

14.14 There should be appropriate procedures or measures to ensure the identity of the contents of each container of starting material. Bulk containers from which samples have been drawn should be identified. 14.15 Only starting materials released by the quality control department and within their shelf life should be used. 14.16 Starting materials should be dispensed only by designated persons, following a written procedure, to ensure that the correct materials are accurately weighed or measured into clean and properly labeled containers. 14.17 Each dispensed material and its weight or volume should be independently checked and the check recorded. 14.18 Materials dispensed for each batch of the final product should be kept together and conspicuously labeled as such.

Starting Materials 14.7 The purchase of starting materials is an important operation that should involve staff who have a particular and thorough knowledge of the products and suppliers. 14.8 Starting materials should be purchased only from approved suppliers and, where possible, directly from the producer. It is also recommended that the specifications established by the manufacturer for the starting materials be discussed with the suppliers. It is of benefit that all critical aspects of the production and control of the starting material in question, including handling, labeling, and packaging requirements as well as complaints and rejection procedures, are contractually agreed between the manufacturer and the supplier. 14.9 For each consignment, the containers should be checked for at least integrity of package and seal and for correspondence between the order, the delivery note, and the supplier’s labels. 14.10 All incoming materials should be checked to ensure that the consignment corresponds to the order. Containers should be cleaned where necessary and labeled, if required, with the prescribed information. Where additional labels are attached to containers, the original information should not be lost. 14.11 Damage to containers and any other problem that might adversely affect the quality of a material should be recorded and reported to the quality control department and investigated. 14.12 If one delivery of material is made up of different batches, each batch must be considered as separate for sampling, testing, and release. 14.13 Starting materials in the storage area should be appropriately labeled. Labels should bear at least the following information: (a) the designated name of the product and the internal code reference where applicable; (b) the batch number given by the supplier and, on receipt, the control or batch number given by the manufacturer, if any, documented so as to ensure traceability; (c) the status of the contents (e.g. on quarantine, on test, released, rejected, returned, recalled); and (d) where appropriate, an expiry date or a date beyond which retesting is necessary. When fully validated computerized storage systems are used, not all of the above information need be in a legible form on the label.

Packaging Materials 14.19 The purchase, handling, and control of primary and printed packaging materials should be as for starting materials. 14.20 Particular attention should be paid to printed packaging materials. They should be stored in secure conditions so as to exclude the possibility of unauthorized access. Roll-feed labels should be used wherever possible. Cut labels and other loose printed materials should be stored and transported in separate closed containers so as to avoid mix-ups. Packaging materials should be issued for use only by designated personnel following an approved and documented procedure. 14.21 Each delivery or batch of printed or primary packaging material should be given a specific reference number or identification mark. 14.22 Outdated or obsolete primary packaging material or printed packaging material should be destroyed and its disposal recorded. 14.23 All products and packaging materials to be used should be checked on delivery to the packaging department for quantity, identity, and conformity with the packaging instructions.

Intermediate and Bulk Products 14.24 Intermediate and bulk products should be kept under appropriate conditions. 14.25 Intermediate and bulk products purchased as such should be handled on receipt as though they were starting materials.

Finished Products 14.26 Finished products should be held in quarantine until their final release, after which they should be stored as usable stock under conditions established by the manufacturer. 14.27 The evaluation of finished products and the documentation necessary for release of a product for sale are described in section 17, “Good Practices in Quality Control”.

Rejected, Recovered, Reprocessed, and Reworked Materials 14.28 Rejected materials and products should be clearly marked as such and stored separately in restricted areas. They should either be returned to the suppliers or, where appropriate, reprocessed or destroyed in a

WHO Good Manufacturing Guidelines

timely manner. Whatever action is taken should be approved by authorized personnel and recorded. 14.29 The reworking or recovery of rejected products should be exceptional. It is permitted only if the quality of the final product is not affected, if the specifications are met, and if it is done in accordance with a defined and authorized procedure after evaluation of the risks involved. A record should be kept of the reworking or recovery. A reworked batch should be given a new batch number. 14.30 The introduction of all or part of earlier batches, conforming to the required quality, into a batch of the same product at a defined stage of manufacture should be authorized beforehand. This recovery should be carried out in accordance with a defined procedure after evaluation of the risks involved, including any possible effect on shelf life. The recovery should be recorded. 14.31 The need for additional testing of any finished product that has been reprocessed, reworked or into which a recovered product has been incorporated, should be considered by the quality control department.

Recalled Products 14.32 Recalled products should be identified and stored separately in a secure area until a decision is taken on their fate. The decision should be made as soon as possible.

Returned Goods 14.33 Products returned from the market should be destroyed unless it is certain that their quality is satisfactory; in such cases they may be considered for resale or relabeling, or alternative action taken only after they have been critically assessed by the quality control function in accordance with a written procedure. The nature of the product, any special storage conditions it requires, its condition and history, and the time elapsed since it was issued should all be taken into account in this assessment. Where any doubt arises over the quality of the product, it should not be considered suitable for reissue or reuse. Any action taken should be appropriately recorded.

Reagents and Culture Media 14.34 There should be records for the receipt and preparation of reagents and culture media. 14.35 Reagents made up in the laboratory should be prepared according to written procedures and appropriately labeled. The label should indicate the concentration, standardization factor, shelf life, the date when restandardization is due, and the storage conditions. The label should be signed and dated by the person preparing the reagent. 14.36 Both positive and negative controls should be applied to verify the suitability of culture media each time they are prepared and used. The size of the inoculum used in positive controls should be appropriate to the sensitivity required.

Reference Standards 14.37 Whenever official reference standards exist, these should preferably be used. 14.38 Official reference standards should be used only for the purpose described in the appropriate monograph. 14.39 Reference standards prepared by the producer should be tested, released, and stored in the same way as offi-

14.40 14.41

14.42 14.43

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cial standards. They should be kept under the responsibility of a designated person in a secure area. Secondary or working standards may be established by the application of appropriate tests and checks at regular intervals to ensure standardization. Reference standards should be properly labeled with at least the following information: (a) name of the material, (b) batch or lot number and control number, (c) date of preparation, (d) shelf life, (e) potency, and (f) storage conditions. All in-house reference standards should be standardized against an official reference standard, when available, initially and at regular intervals thereafter. All reference standards should be stored and used in a manner that will not adversely affect their quality.

Waste Materials 14.44 Provision should be made for the proper and safe storage of waste materials awaiting disposal. Toxic substances and flammable materials should be stored in suitably designed, separate, enclosed cupboards, as required by national legislation. 14.45 Waste material should not be allowed to accumulate. It should be collected in suitable receptacles for removal to collection points outside the buildings and disposed of safely and in a sanitary manner at regular and frequent intervals.

Miscellaneous 14.46 Rodenticides, insecticides, fumigating agents, and sanitizing materials should not be permitted to contaminate equipment, starting materials, packaging materials, in-process materials, or finished products.

15. DOCUMENTATION 15.1 Principle. Good documentation is an essential part of the quality assurance system and, as such, should exist for all aspects of GMP. Its aims are to define the specifications and procedures for all materials and methods of manufacture and control, to ensure that all personnel concerned with manufacture know what to do and when to do it, to ensure that authorized persons have all the information necessary to decide whether or not to release a batch of a drug for sale, to ensure the existence of documented evidence, traceability, and to provide records and an audit trail that will permit investigation. It ensures the availability of the data needed for validation, review, and statistical analysis. The design and use of documents depend upon the manufacturer. In some cases, some or all of the documents described below may be brought together, but they will usually be separate.

General 15.2 Documents should be designed, prepared, reviewed, and distributed with care. They should comply with the relevant parts of the manufacturing and marketing authorizations. 15.3 Documents should be approved, signed, and dated by the appropriate responsible persons. No document

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15.4

15.5

15.6 15.7

15.8

15.9

Handbook of Pharmaceutical Manufacturing Formulations: Over-the-Counter Products

should be changed without authorization and approval. Documents should have unambiguous contents: the title, nature, and purpose should be clearly stated. They should be laid out in an orderly fashion and be easy to check. Reproduced documents should be clear and legible. The reproduction of working documents from master documents must not allow any error to be introduced through the reproduction process. Documents should be regularly reviewed and kept upto-date. When a document has been revised, a system should exist to prevent inadvertent use of the superseded version. Superseded documents should be retained for a specific period of time. Where documents require the entry of data, these entries should be clear, legible, and indelible. Sufficient space should be provided for such entries. Any alteration made to a document should be signed and dated; the alteration should permit the reading of the original information. Where appropriate, the reason for the alteration should be recorded. Records should be made or completed when any action is taken and in such a way that all significant activities concerning the manufacture of pharmaceutical products are traceable. Records should be retained for at least one year after the expiry date of the finished product. Data (and records for storage) may be recorded by electronic data-processing systems or by photographic or other reliable means. Master formulae and detailed standard operating procedures relating to the system in use should be available and the accuracy of the records should be checked. If documentation is handled by electronic data-processing methods, only authorized persons should be able to enter or modify data in the computer, and there should be a record of changes and deletions; access should be restricted by passwords or other means and the entry of critical data should be independently checked. Batch records stored electronically should be protected by back-up transfer on magnetic tape, microfilm, paper printouts, or other means. It is particularly important that, during the period of retention, the data are readily available.

Documents Required Labels 15.10 Labels applied to containers, equipment, or premises should be clear, unambiguous, and in the company’s agreed format. It is often helpful in addition to the wording on the labels to use colors to indicate status (e.g., quarantined, accepted, rejected, clean). 15.11 All finished drug products should be identified by labeling, as required by the national legislation, bearing at least the following information: (a) the name of the drug product; (b) a list of the active ingredients (if applicable, with the INNs), showing the amount of each present and a statement of the net contents (e.g., number of dosage units, weight, volume); (c) the batch number assigned by the manufacturer; (d) the expiry date in an uncoded form; (e) any special storage conditions or handling precautions that may be necessary; (f) directions for use, and warnings and precautions that may be necessary; and

(g) the name and address of the manufacturer or the company or the person responsible for placing the product on the market. 15.12 For reference standards, the label and/or accompanying document should indicate potency or concentration, date of manufacture, expiry date, date the closure is first opened, storage conditions, and control number, as appropriate.

Specifications and Testing Procedures 15.13 Testing procedures described in documents should be validated in the context of available facilities and equipment before they are adopted for routine testing. 15.14 There should be appropriately authorized and dated specifications, including tests on identity, content, purity, and quality, for starting and packaging materials and for finished products; where appropriate, they should also be available for intermediate or bulk products. Specifications for water, solvents, and reagents (e.g., acids and bases) used in production should be included. 15.15 Each specification should be approved, signed, and dated, and maintained by quality control, quality assurance unit, or documentation center. Specifications for starting materials, intermediates, and bulk, finished products, and packaging materials are referred to in sections 15.18–15.21. 15.16 Periodic revisions of the specifications may be necessary to comply with new editions of the national pharmacopoeia or other official compendia. 15.17 Pharmacopoeias, reference standards, reference spectra and other reference materials should be available in the quality control laboratory.

Specifications for Starting and Packaging Materials 15.18 Specifications for starting, primary, and printed packaging materials should provide, if applicable, a description of the materials, including (a) the designated name (if applicable, the INN) and internal code reference, (b) the reference, if any, to a pharmacopoeial monograph, and (c) qualitative and quantitative requirements with acceptance limits. Depending on the company’s practice, other data may be added to the specification, such as (a) the supplier and the original producer of the materials, (b) a specimen of printed materials, (c) directions for sampling and testing, or a reference to procedures, (d) storage conditions and precautions, and (e) the maximum period of storage before reexamination. Packaging material should conform to specifications, and should be compatible with the material and/or with the drug product it contains. The material should be examined for compliance with the specification, and for defects as well as for the correctness of identity markings. 15.19 Documents describing testing procedures should state the required frequency for reassaying each starting material, as determined by its stability.

Specifications for Intermediate and Bulk Products 15.20 Specifications for intermediate and bulk products should be available. The specifications should be

WHO Good Manufacturing Guidelines

similar to specifications for starting materials or for finished products, as appropriate.

Specifications for Finished Products 15.21 Specifications for finished products should include (a) the designated name of the product and the code reference, where applicable, (b) the designated name(s) of the active ingredient(s) [if applicable, with the INN(s)], (c) the formula or a reference to the formula, (d) a description of the dosage form and package details, (e) directions for sampling and testing or a reference to procedures, (f) the qualitative and quantitative requirements, with acceptance limits, (g) the storage conditions and precautions, where applicable, and (h) the shelf life.

Master Formulae 15.22 A formally authorized master formula should exist for each product and batch size to be manufactured. 15.23 The master formula should include (a) the name of the product, with a product reference code relating to its specification; (b) a description of the dosage form, strength of the product, and batch size; (c) a list of all starting materials to be used (if applicable, with the INNs), with the amount of each, described using the designated name and a reference that is unique to that material (mention should be made of any substance that may disappear in the course of processing); (d) a statement of the expected final yield with the acceptable limits, and of relevant intermediate yields, where applicable; (e) a statement of the processing location and the principal equipment to be used; (f) the methods, or reference to the methods, to be used for preparing and operating the critical equipment, for example, cleaning (especially after a change in product), assembling, calibrating, sterilizing, use; (g) detailed stepwise processing instructions (e.g., checks on materials, pretreatments, sequence for adding materials, mixing times, temperatures); (h) the instructions for any in-process controls with their limits; (i) where necessary, the requirements for storage of the products, including the container, the labeling, and any special storage conditions; and (j) any special precautions to be observed.

Packaging Instructions 15.24 Formally authorized packaging instructions should exist for each product, pack size, and type. These should normally include, or make reference to, (a) the name of the product; (b) a description of its pharmaceutical form, strength, and, where applicable, method of application; (c) the pack size expressed in terms of the number, weight, or volume of the product in the final container; (d) a complete list of all the packaging materials required for a standard batch size, including quan-

(e)

(f)

(g) (h)

53

tities, sizes, and types, with the code or reference number relating to the specifications for each packaging material; where appropriate, an example or reproduction of the relevant printed packaging materials and specimens, indicating where the batch number and expiry date of the product have been marked; special precautions to be observed, including a careful examination of the packaging area and equipment in order to ascertain the line clearance before and after packaging operations; a description of the packaging operation, including any significant subsidiary operations, and equipment to be used; and details of in-process controls with instructions for sampling and acceptance limits.

Batch Processing Records 15.25 A batch processing record should be kept for each batch processed. It should be based on the relevant parts of the currently approved specifications on the record. The method of preparation of such records should be designed to avoid errors. (Copying or validated computer programs are recommended. Transcribing from approved documents should be avoided.) 15.26 Before any processing begins, a check should be made that the equipment and workstation are clear of previous products, documents, or materials not required for the planned process, and that the equipment is clean and suitable for use. This check should be recorded. 15.27 During processing, the following information should be recorded at the time each action is taken, and after completion the record should be dated and signed by the person responsible for the processing operations: (a) the name of the product; (b) the number of the batch being manufactured; (c) dates and times of commencement, of significant intermediate stages, and of completion of production; (d) the name of the person responsible for each stage of production; (e) the initials of the operator(s) of different significant steps of production and, where appropriate, of the person(s) who checked each of these operations (e.g. weighing); (f) the batch number and/or analytical control number and the quantity of each starting material actually weighed (including the batch number and amount of any recovered or reprocessed material added); (g) any relevant processing operation or event and the major equipment used; (h) the in-process controls performed, the initials of the person(s) carrying them out, and the results obtained; (i) the amount of product obtained at different and pertinent stages of manufacture (yield), together with comments or explanations for significant deviations from the expected yield; and (j) notes on special problems including details, with signed authorization for any deviation from the master formula.

Batch Packaging Records 15.28 A batch packaging record should be kept for each batch or part batch processed. It should be based on the

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relevant parts of the approved packaging instructions, and the method of preparing such records should be designed to avoid errors. (Copying or validated computer programs are recommended. Transcribing from approved documents should be avoided.) 15.29 Before any packaging operation begins, checks should be made that the equipment and workstation are clear of previous products, documents, or materials not required for the planned packaging operations, and that equipment is clean and suitable for use. These checks should be recorded. 15.30 The following information should be recorded at the time each action is taken, and the date and the person responsible should be clearly identified by signature or electronic password: (a) the name of the product, the batch number, and the quantity of bulk product to be packed, as well as the batch number and the planned quantity of finished product that will be obtained, the quantity actually obtained, and the reconciliation; (b) the date(s) and time(s) of the packaging operations; (c) the name of the responsible person carrying out the packaging operation; (d) the initials of the operators of the different significant steps; (e) the checks made for identity and conformity with the packaging instructions, including the results of in-process controls; (f) details of the packaging operations carried out, including references to equipment and the packaging lines used, and, when necessary, the instructions for keeping the product unpacked or a record of returning product that has not been packaged to the storage area; (g) whenever possible, samples of the printed packaging materials used, including specimens bearing the approval for the printing of and regular check (where appropriate) of the batch number, expiry date, and any additional overprinting; (h) notes on any special problems, including details of any deviation from the packaging instructions, with written authorization by an appropriate person; (i) the quantities and reference number or identification of all printed packaging materials and bulk product issued, used, destroyed, or returned to stock and the quantities of product obtained to permit an adequate reconciliation.

Standard Operating Procedures and Records 15.31 Standard operating procedures and associated records of actions taken or, where appropriate, conclusions reached should be available for (a) equipment assembly and validation; (b) analytical apparatus and calibration; (c) maintenance, cleaning, and sanitization; (d) personnel matters including qualification, training, clothing, and hygiene; (e) environmental monitoring; (f) pest control; (g) complaints; (h) recalls; and (i) returns. 15.32 There should be standard operating procedures and records for the receipt of each delivery of starting material and primary and printed packaging material.

15.33 The records of the receipts should include (a) the name of the material on the delivery note and the containers, (b) the “in-house” name and/or code of the material if different from (a), (c) the date of receipt, (d) the supplier’s name and, if possible, manufacturer’s name, (e) the manufacturer’s batch or reference number, (f) the total quantity and number of containers received, (g) the batch number assigned after receipt, and (h) any relevant comment (e.g. state of the containers). 15.34 There should be standard operating procedures for the internal labeling, quarantine, and storage of starting materials, packaging materials, and other materials, as appropriate. 15.35 Standard operating procedures should be available for each instrument and piece of equipment (e.g., use, calibration, cleaning, maintenance) and placed in close proximity to the equipment. 15.36 There should be standard operating procedures for sampling, which specify the person(s) authorized to take samples. 15.37 The sampling instructions should include (a) the method of sampling and the sampling plan; (b) the equipment to be used; (c) any precautions to be observed to avoid contamination of the material or any deterioration in its quality; (d) the amount(s) of sample(s) to be taken; (e) instructions for any required subdivision of the sample; (f) the type of sample container(s) to be used, and whether they are for aseptic sampling or for normal sampling, and labeling; and (g) any specific precautions to be observed, especially in regard to the sampling of sterile or noxious material. 15.38 There should be a standard operating procedure describing the details of the batch (lot) numbering system, with the objective of ensuring that each batch of intermediate, bulk, or finished product is identified with a specific batch number. 15.39 The standard operating procedures for batch numbering that are applied to the processing stage and to the respective packaging stage should be related to each other. 15.40 The standard operating procedure for batch numbering should ensure that the same batch numbers will not be used repeatedly; this applies also to reprocessing. 15.41 Batch-number allocation should be immediately recorded, for example, in a logbook. The record should include at least the date of allocation, product identity, and size of batch. 15.42 There should be written procedures for testing materials and products at different stages of manufacture, describing the methods, and equipment to be used. The tests performed should be recorded. 15.43 Analysis records should include at least the following data: (a) the name of the material or product and, where applicable, dosage form; (b) the batch number and, where appropriate, the manufacturer and/or supplier;

WHO Good Manufacturing Guidelines

15.44

15.45 15.46

15.47 15.48

(c) references to the relevant specifications and testing procedures; (d) test results, including observations and calculations, and reference to any specifications (limits); (e) date(s) and reference number(s) of testing; (f) the initials of the persons who performed the testing; (g) the date and initials of the persons who verified the testing and the calculations, where appropriate; and (h) a clear statement of release or rejection (or other status decision) and the dated signature of the designated responsible person. Written release and rejection procedures should be available for materials and products, and in particular for the release for sale of the finished product by an authorized person. Records should be maintained of the distribution of each batch of a product in order, for example, to facilitate the recall of the batch if necessary. Records should be kept for major and critical equipment, as appropriate, of any validations, calibrations, maintenance, cleaning, or repair operations, including dates and the identity of the people who carried these operations out. The use of major and critical equipment and the areas where products have been processed should be appropriately recorded in chronological order. There should be written procedures assigning responsibility for cleaning and sanitation and describing in sufficient detail the cleaning schedules, methods, equipment and materials to be used, and facilities and equipment to be cleaned. Such written procedures should be followed.

16. GOOD PRACTICES IN PRODUCTION 16.1 Principle. Production operations must follow clearly defined procedures in accordance with manufacturing and marketing authorizations, with the objective of obtaining products of the requisite quality.

General 16.2 All handling of materials and products, such as receipt and cleaning, quarantine, sampling, storage, labeling, dispensing, processing, packaging, and distribution, should be done in accordance with written procedures or instructions and, where necessary, recorded. 16.3 Any deviation from instructions or procedures should be avoided as far as possible. If deviations occur, they should be done in accordance with an approved procedure. The authorization of the deviation should be approved in writing by a designated person, with the involvement of the quality control department, when appropriate. 16.4 Checks on yields and reconciliation of quantities should be carried out as necessary to ensure that there are no discrepancies outside acceptable limits. 16.5 Operations on different products should not be carried out simultaneously or consecutively in the same room or area unless there is no risk of mix-up or crosscontamination. 16.6 At all times during processing, all materials, bulk containers, major items of equipment, and where ap-

55

propriate, the rooms and packaging lines being used should be labeled or otherwise identified with an indication of the product or material being processed, its strength (where applicable) and the batch number. Where applicable, this indication should also mention the stage of production. In some cases, it may be useful to record also the name of the previous product that has been processed. 16.7 Access to production premises should be restricted to authorized personnel. 16.8 Normally, nonmedicinal products should not be produced in areas or with equipment destined for the production of pharmaceutical products. 16.9 In-process controls are usually performed within the production area. The performance of such in-process controls should not have any negative effect on the quality of the product or another product (e.g., crosscontamination or mix-up).

Prevention of Cross-Contamination and Bacterial Contamination During Production 16.10 When dry materials and products are used in production, special precautions should be taken to prevent the generation and dissemination of dust. Provision should be made for proper air control (e.g., supply and extraction of air of suitable quality). 16.11 Contamination of a starting material or of a product by another material or product must be avoided. This risk of accidental cross-contamination arises from the uncontrolled release of dust, gases, particles, vapors, sprays, or organisms from materials and products in process; from residues on equipment; from intruding insects; and from operators’ clothing, skin, etc. The significance of this risk varies with the type of contaminant and of the product being contaminated. Among the most hazardous contaminants are highly sensitizing materials, biological preparations such as living organisms, certain hormones, cytotoxic substances, and other highly active materials. Products in which contamination is likely to be most significant are those administered by injection or applied to open wounds and those given in large doses and/or over a long time. 16.12 Cross-contamination should be avoided by taking appropriate technical or organizational measures, for example, (a) carrying out production in dedicated and selfcontained areas (which may be required for products such as penicillins, live vaccines, live bacterial preparations, and certain other biologicals); (b) conducting campaign production (separation in time) followed by appropriate cleaning in accordance with a validated cleaning procedure; (c) providing appropriately designed airlocks, pressure differentials, and air supply and extraction systems; (d) minimizing the risk of contamination caused by recirculation or reentry of untreated or insufficiently treated air; (e) wearing protective clothing where products or materials are handled; (f) using cleaning and decontamination procedures of known effectiveness; (g) using a “closed system” in production; (h) testing for residues; and (i) using cleanliness status labels on equipment.

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16.13 Measures to prevent cross-contamination and their effectiveness should be checked periodically according to standard operating procedures. 16.14 Production areas where susceptible products are processed should undergo periodic environmental monitoring (e.g., for microbiological monitoring and particulate matter where appropriate).

16.27 16.28

Processing Operations 16.15 Before any processing operation is started, steps should be taken to ensure that the work area and equipment are clean and free from any starting materials, products, product residues, labels, or documents not required for the current operation. 16.16 Any necessary in-process controls and environmental controls should be carried out and recorded. 16.17 Means should be instituted of indicating failures of equipment or of services (e.g. water, gas) to equipment. Defective equipment should be withdrawn from use until the defect has been rectified. After use, production equipment should be cleaned without delay according to detailed written procedures and stored under clean and dry conditions in a separate area or in a manner that will prevent contamination. 16.18 Time limits for storage of equipment after cleaning and before use should be stated and based on data. 16.19 Containers for filling should be cleaned before filling. Attention should be given to avoiding and removing any contaminants such as glass fragments and metal particles. 16.20 Any significant deviation from the expected yield should be recorded and investigated. 16.21 Checks should be carried out to ensure that pipelines and other pieces of equipment used for the transportation of products from one area to another are connected in a correct manner. 16.22 Pipes used for conveying distilled or deionized water and, where appropriate, other water pipes should be sanitized and stored according to written procedures that detail the action limits for microbiological contamination and the measures to be taken. 16.23 Measuring, weighing, recording, and control equipment and instruments should be serviced and calibrated at prespecified intervals and records maintained. To ensure satisfactory functioning, instruments should be checked daily or prior to use for performing analytical tests. The date of calibration and servicing and the date when recalibration is due should be clearly indicated, preferably on a label attached to the instrument. 16.24 Repair and maintenance operations should not present any hazard to the quality of the products.

Packaging Operations 16.25 When the program for packaging operations is being set up, particular attention should be given to minimizing the risk of cross-contamination, mix-ups, or substitutions. Different products should not be packaged in close proximity unless there is physical segregation or an alternative system that will provide equal assurance. 16.26 Before packaging operations are begun, steps should be taken to ensure that the work area, packaging lines, printing machines, and other equipment are clean and free from any products, materials, or documents used previously and which are not required for the current

16.29

16.30

16.31 16.32

16.33

16.34

16.35

operation. The line clearance should be performed according to an appropriate procedure and checklist, and recorded. The name and batch number of the product being handled should be displayed at each packaging station or line. Normally, filling and sealing should be followed as quickly as possible by labeling. If labeling is delayed, appropriate procedures should be applied to ensure that no mix-ups or mislabeling could occur. The correct performance of any printing (e.g., of code numbers or expiry dates) done separately or in the course of the packaging should be checked and recorded. Attention should be paid to printing by hand, which should be rechecked at regular intervals. Special care should be taken when cut labels are used and when overprinting is carried out off-line, and in hand-packaging operations. Roll-feed labels are normally preferable to cut labels in helping to avoid mixups. Online verification of all labels by automated electronic means can be helpful in preventing mix-ups, but checks should be made to ensure that any electronic code readers, label counters, or similar devices are operating correctly. When labels are attached manually, in-process control checks should be performed more frequently. Printed and embossed information on packaging materials should be distinct and resistant to fading or erasing. Regular online control of the product during packaging should include at least checks on (a) the general appearance of the packages, (b) whether the packages are complete, (c) whether the correct products and packaging materials are used, (d) whether any overprinting is correct, and (e) the correct functioning of line monitors. Samples taken away from the packaging line should not be returned. Products that have been involved in an unusual event during packaging should be reintroduced into the process only after special inspection, investigation, and approval by authorized personnel. A detailed record should be kept of this operation. Any significant or unusual discrepancy observed during reconciliation of the amount of bulk product and printed packaging materials and the number of units produced should be investigated, satisfactorily accounted for, and recorded before release. Upon completion of a packaging operation, any unused batch-coded packaging materials should be destroyed and the destruction recorded. A documented procedure requiring checks to be performed before returning unused materials should be followed if uncoded printed materials are returned to stock.

17. GOOD PRACTICES IN QUALITY CONTROL 17.1 Quality control is the part of GMP concerned with sampling, specifications, and testing, and with the organization, documentation, and release procedures which ensure that the necessary and relevant tests are actually carried out and that materials are not released for use, nor products released for sale or supply, until their

WHO Good Manufacturing Guidelines

quality has been judged to be satisfactory. Quality control is not confined to laboratory operations but must be involved in all decisions concerning the quality of the product. 17.2 The independence of quality control from production is considered fundamental. 17.3 Each manufacturer (the holder of a manufacturing authorization) should have a quality control function. The quality control function should be independent of other departments and under the authority of a person with appropriate qualification and experience, who has one or several control laboratories at his or her disposal. Adequate resources must be available to ensure that all the quality control arrangements are effectively and reliably carried out. The basic requirements for quality control are as follows: (a) Adequate facilities, trained personnel, and approved procedures must be available for sampling, inspecting, and testing starting materials, packaging materials, and intermediate, bulk, and finished products, and where appropriate for monitoring environmental conditions for GMP purposes. (b) Samples of starting materials, packaging materials, intermediate products, bulk products, and finished products must be taken by methods and personnel approved of by the quality control department. (c) Qualification and validation must be performed. (d) Records must be made (manually and/or by recording instruments) demonstrating that all the required sampling, inspecting, and testing procedures have actually been carried out and that any deviations have been fully recorded and investigated. (e) The finished products must contain ingredients complying with the qualitative and quantitative composition of the product described in the marketing authorization; the ingredients must be of the required purity, in their proper container and correctly labeled. (f) Records must be made of the results of inspecting and testing the materials and intermediate, bulk, and finished products against specifications; product assessment must include a review and evaluation of the relevant production documentation and an assessment of deviations from specified procedures. (g) No batch of product is to be released for sale or supply prior to certification by the authorized person(s) that it is in accordance with the requirements of the marketing authorization. In certain countries, by law, the batch release is a task of the authorized person from production together with the authorized person from quality control. (h) Sufficient samples of starting materials and products must be retained to permit future examination of the product if necessary; the retained product must be kept in its final pack unless the pack is exceptionally large. 17.4 Quality control as a whole will also have other duties, such as to establish, validate, and implement all quality control procedures; to evaluate, maintain, and store the reference standards for substances; to ensure the correct labeling of containers of materials and products; to ensure that the stability of the active pharmaceutical ingredients and products is monitored; to participate in the investigation of complaints related to the qual-

57

ity of the product; and to participate in environmental monitoring. All these operations should be carried out in accordance with written procedures and, where necessary, recorded. 17.5 Assessment of finished products should embrace all relevant factors, including the production conditions, the results of in-process testing, the manufacturing (including packaging) documentation, compliance with the specification for the finished product, and an examination of the finished pack. 17.6 Quality control personnel must have access to production areas for sampling and investigation as appropriate.

Control of Starting Materials and Intermediate, Bulk, and Finished Products 17.7 All tests should follow the instructions given in the relevant written test procedure for each material or product. The result should be checked by the supervisor before the material or product is released or rejected. 17.8 Samples should be representative of the batches of material from which they are taken in accordance with the approved written procedure. 17.9 Sampling should be carried out so as to avoid contamination or other adverse effects on quality. The containers that have been sampled should be marked accordingly and carefully resealed after sampling. 17.10 Care should be taken during sampling to guard against contamination or mix-up of, or by, the material being sampled. All sampling equipment that comes into contact with the material should be clean. Some particularly hazardous or potent materials may require special precautions. 17.11 Sampling equipment should be cleaned and, if necessary, sterilized before and after each use and stored separately from other laboratory equipment. 17.12 Each sample container should bear a label indicating (a) the name of the sampled material, (b) the batch or lot number, (c) the number of the container from which the sample has been taken, (d) the number of the sample, (e) the signature of the person who has taken the sample, and (f) the date of sampling. 17.13 Out-of-specification results obtained during testing of materials or products should be investigated in accordance with an approved procedure. Records should be maintained.

Test Requirements Starting and Packaging Materials 17.14 Before releasing a starting or packaging material for use, the quality control manager should ensure that the materials have been tested for conformity with specifications for identity, strength, purity, and other quality parameters. 17.15 An identity test should be conducted on a sample from each container of starting material (see also section 14.14). 17.16 Each batch (lot) of printed packaging materials must be examined following receipt. 17.17 In lieu of testing by the manufacturer, a certificate of analysis may be accepted from the supplier, provided that the manufacturer establishes the reliability of the

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supplier’s analysis through appropriate periodic validation of the supplier’s test results (see sections 8.8 and 8.9) and through on-site audits of the supplier’s capabilities. (This does not affect section 17.15.) Certificates must be originals (not photocopies) or otherwise have their authenticity assured. Certificates must contain at least the following information: (a) identification (name and address) of the issuing supplier, (b) signature of the competent official, and statement of his or her qualifications, (c) the name of the material tested, (d) the batch number of the material tested, (e) the specifications and methods used, (f) the test results obtained, and (g) the date of testing.

(a) a complete description of the drug involved in the study; (b) the complete set of testing parameters and methods, describing all tests for potency, purity, and physical characteristics and documented evidence that these tests indicate stability; (c) provision for the inclusion of a sufficient number of batches; (d) the testing schedule for each drug; (e) provision for special storage conditions; (f) provision for adequate sample retention; and (g) a summary of all the data generated, including the evaluation and the conclusions of the study. 17.26 Stability should be determined prior to marketing and following any significant changes in processes, equipment, packaging materials, etc.

In-Process Control 17.18 In-process control records should be maintained and form a part of the batch records (see section 15.25).

Finished Products 17.19 For each batch of drug product, there should be an appropriate laboratory determination of satisfactory conformity to its finished product specification prior to release. 17.20 Products failing to meet the established specifications or any other relevant quality criteria should be rejected.

Batch Record Review 17.21 Production and quality control records should be reviewed as part of the approval process of batch release. Any divergence or failure of a batch to meet its specifications should be thoroughly investigated. The investigation should, if necessary, extend to other batches of the same product and other products that may have been associated with the specific failure or discrepancy. A written record of the investigation should be made and should include the conclusion and follow-up action. 17.22 Retention samples from each batch of finished product should be kept for at least one year after the expiry date. Finished products should usually be kept in their final packaging and stored under the recommended conditions. If exceptionally large packages are produced, smaller samples might be stored in appropriate containers. Samples of active starting materials should be retained for at least one year beyond the expiry date of the corresponding finished product. Other starting materials (other than solvents, gases, and water) should be retained for a minimum of two years if their stability allows. Retention samples of materials and products should be of a size sufficient to permit at least two full reexaminations.

Stability Studies 17.23 Quality control should evaluate the quality and stability of finished pharmaceutical products and, when necessary, of starting materials and intermediate products. 17.24 Quality control should establish expiry dates and shelflife specifications on the basis of stability tests related to storage conditions. 17.25 A written program for ongoing stability determination should be developed and implemented to include elements such as

BIBLIOGRAPHY Good Manufacturing Practices for pharmaceutical products. In: WHO Expert Committee on Specifications for Pharmaceutical Preparations. Thirty-second report. Geneva, World Health Organization, 1992, Annex 1 (WHO Technical Report Series, No. 823). Validation of analytical procedures used in the examination of pharmaceutical materials. In: WHO Expert Committee on Specifications for Pharmaceutical Preparations. Thirty-second report. Geneva, World Health Organization, 1992, Annex 5 (WHO Technical Report Series, No. 823). Good manufacturing practice for medicinal products in the European Community. Brussels, Commission of the European Communities, 1992. Pharmaceutical Inspection Convention, Pharmaceutical Inspection Co-operation Scheme (PIC/S). In: Guide to Good Manufacturing Practice for Medicinal Plants, Geneva, PIC/S Secretariat, 2000. Quality assurance of pharmaceuticals. A compendium of guidelines and related materials. Volume 2. Good manufacturing practices and inspection. Geneva, World Health Organization, 1999. Model certificate of analysis. In: WHO Expert Committee on Specifications for Pharmaceutical Preparations. Thirty-sixth report. Geneva, World Health Organization, 2002, Annex 10 (WHO Technical Report Series, No. 902).

WHO INSPECTIONS SUMMARY r Types of GMP Inspection ◦ ◦ ◦ ◦ ◦

Routine inspection Concise inspection Follow-up inspection Special inspection Quality systems review r Routine Inspection ◦ Full inspection of all components of GMP ◦ Newly established manufacturer ◦ Renewal of a license ◦ Changes: r New product or product lines r Modifications to manufacturing methods r Key personnel, premises, or equipment ◦ History of noncompliance with GMP ◦ Not inspected in the last 3–5 years r Concise Inspection ◦ Consistent record of compliance with GMP ◦ Focus on limited number of GMP requirements ◦ Selected as indicators ◦ Identify significant changes

WHO Good Manufacturing Guidelines ◦ Indicate attitude toward GMP ◦ Noncompliance ◦ Should trigger comprehensive inspection

r Duration of Inspections

◦ Depends on type of inspection ◦ Inspectorate resources (e.g., workload, number of in-

r Follow-up Inspection ◦ ◦ ◦ ◦ ◦ ◦ ◦ ◦

Reassessment or reinspection Monitor result of corrective actions weeks to 6 months after initial inspection Nature of defects Work undertaken Specific GMP requirements Not observed Not adequately implemented r Special Inspection ◦ Spot-check focusing on ◦ One product, a group of related products ◦ Specific operations, for example, mixing, labeling ◦ Complaints or recalls ◦ Adverse drug reactions ◦ Marketing approval or export certificate ◦ Information or investigation ◦ Specific information ◦ Advice on regulatory requirements r Quality Systems Review ◦ Assess the quality assurance (QA) system ◦ Description of the QA system (e.g., manual) ◦ Policy and standards to be observed ◦ Management structure ◦ Implementation ◦ Procedures ◦ Quality standards set for products ◦ Correctly defined manufacturing processes ◦ Records kept ◦ QC and QA functions are performed r Frequency of Inspections ◦ Depends on type of inspection ◦ Inspectorate resources (e.g. workload, number of inspectors) ◦ New facilities—before licensed ◦ All companies—regular schedule ◦ Ideally annual ◦ Large companies ◦ Several visits over a period, for example, 5 years ◦ Validity of manufacturing license or GMP certificate

59

r

r

r

r

spectors) Size of the company Purpose of the visit Days to weeks Number of inspectors Including specialist support Announced and Unannounced Inspections ◦ Depends on type of inspection ◦ Announced ◦ Comprehensive inspection ◦ Unannounced ◦ Routine inspection (depending on country policy) ◦ Concise inspection ◦ Follow-up inspection ◦ Special inspection Regulatory Actions ◦ Based on national regulations ◦ Correction of unsatisfactory situations ◦ Closing down of a factory ◦ Withholding of authorizations ◦ Product recall Group Session ◦ The inspectorate received a complaint that an injectable product [water for injection (WFI), 10 mL ampoule] is possibly contaminated with microorganisms. You have to organize an inspection of the company in question ◦ What type of inspection would be performed? ◦ Will the inspection be announced or unannounced? ◦ Who will be part of the inspection team? ◦ What will you consider in preparation for the inspection? Possible Issues ◦ Purpose of the inspection ◦ Notification (or not) of the company in advance ◦ Makeup of the team ◦ Program for the inspection ◦ Sterility test, leak test, and visual inspection ◦ Validation and qualification ◦ Documentation review ◦ ◦ ◦ ◦ ◦

5 Solid Oral Dosage Forms Validation

cable to both sterile and nonsterile drugs and devices. In 1984, the guideline was reissued as a draft guideline and was finalized in 1987. The 1987 Validation Guidelines merely points out the need to adequately develop and control manufacturing processes. It discusses microbiological issues and provides few specific and practical applications for the validation of manufacturing processes for a marketed solid oral dosage form. The issue of retrospective validation and its application to marketed products is frequently encountered. This concept of using historical data (test results), along with process control and process specificity was of value until more scientific methods for demonstrating process validation evolved. It should be pointed out that retrospective validation is not merely the review of test results. It also requires that the manufacturing process be specific and the same each time a batch is manufactured. Thus, specific raw-material specifications (including particle size when necessary), in-process specifications (tablet hardness, etc.), and specific manufacturing directions are required. Obviously, any failing batches attributed to the process would necessitate the conclusion that the process is not validated and is inadequate. Prospective process validation is required, particularly for those products introduced in the last 7 to 8 years or those for which manufacturing changes have been made; however, in some cases where older products have been on the market without sufficient premarket process validation, it may be possible to validate, in some measure, the adequacy of the process by examination of accumulated test data on the product and records of the manufacturing procedures used.

I. INTRODUCTION The Validation Guidelines issued by the FDA in 1987 define process validation as establishing documented evidence that provides a high degree of assurance that a specific process will consistently produce a product meeting its predetermined specifications and quality attributes. The three components of this definition include

r documented evidence, r consistency, and r predetermined specifications. Documented evidence includes the experiments, data, and analytical results that support the master formula, the in-process and finished product specifications, and the filed manufacturing process. With regard to consistency, several batches would have to be manufactured, using the full-scale batch size, to demonstrate that a process meets the consistency test. At least three batches are needed to demonstrate consistency. The development of a product and its manufacturing process and specifications, the design of the validation protocol, and the demonstration (validation) runs of the full-scale manufacturing process requires scientific judgment based on good scientific data. The FDA expects that in-process control and product specifications will be established during the product development process, with the test batch serving as the critical batch used for the establishment of specifications. Specifications, such as hardness and particle size, should be established prior to validation of the process; these specifications should be included in the validation protocol. Problems often arise when the product development runs of the process are used to establish both specifications and demonstrate that the system is validated. In these cases, more in-depth inspection and evaluation will be required; some of these process runs often produce failing product because the product specifications have not been fully established and tested.

III. PRODUCT DEVELOPMENT A. Product Development Reports No statute or regulation specifically requires a product development report, although companies are required to produce scientific data that justify the formulation and the manufacturing and control processes. Most companies use product development reports, technology transfer reports, and others to summarize the scientific data that justify the product and process. The product development report should satisfy the needs of the company. No specific format is required for the contents of the report. It is suggested that a company develop a product development standard operating procedure (SOP) that describes the development process, the documentation requirements, and the individuals responsible for approving the filed process. This SOP can be brief, and again no legal requirement exists stating that companies must produce such an SOP. Failure to have a formal development report is not a GMP deficiency, nor is it a filing requirement to have a formal development report; however, where such reports are written, the development data found in these reports should include the following.

II. BACKGROUND Two common complaints regarding validation issues have frequently been raised. The first concerns the misconception that the 1987 Validation Guideline represents a new requirement. The second concerns the lack of specificity in the FDA’s guides. In 1978, however, the current good manufacturing practice regulations (cGMPRs) were revised and provided for process validation, so this guideline does not represent a new requirement. Both the FDA and the industry have recognized the need to establish general guidance for the validation of manufacturing processes, and the FDA published a draft guideline in 1983. However, this draft guideline was a very general document that addressed general principles and was appli60

Solid Oral Dosage Forms Validation

1. Drug Substance Characterization Characterization of the chemical and physical properties of the drug substance is one of the most critical steps in the development of a solid dosage form. Chemical properties, especially the identification of impurities, are very important. In addition, the physical properties of the API, such as solubility, polymorphism, hygroscopicity, particle size, density, etc., must be addressed. The literature and actual experience demonstrate that the physical quality (e.g., particle size of raw materials) can sometimes have a significant impact on the availability and clinical effect of a dosage form drug; therefore, it is appropriate that the physical characteristics of a drug substance be characterized, that the impact of the physical characteristics be determined, and that a specification for the bulk drug product be established, if necessary. Development data will vary between new drugs and generics (e.g., characterization and establishment of specifications for the drug substance). In most cases, the manufacturing process for a new drug substance (new chemical entity) is developed and scaled up before the dosage form. In early development stages, very little information is available regarding polymorphic forms, solubility, etc. Consequently, changes to the manufacturing process for the drug substance may change the purity profile or physical characteristics and thus cause problems with the finished dosage form. Although these types of problems are expected, the firm must investigate and document batch failures for the API and dosage form product. On the other hand, generic manufacturers usually purchase drug substances from API manufacturers who may not be willing to supply information regarding the synthesis or analysis of the drug substance; therefore, the manufacturer of the finished dosage form must perform the appropriate tests to characterize the drug substance chemically and physically and establish appropriate specifications. This may require developing analytical methods to identify impurities. In some cases, this information can be obtained from literature searches. In either case, it is important that each firm compare the drug substance used to manufacture the biobatch or clinical batch(es) and the drug substances used for the commercial batches, including specifications, analytical methods, and test results for the lots of each drug substance. Remember that the safety of the drug may be based upon the type and level of impurities, and different physical characteristics may affect dissolution or content uniformity. This is particularly important for those drug substances that are poorly soluble in water. For those products on which biostudies have been conducted, the physical characteristics of the drug substance used for the study should serve as the basis for the physical specifications. It is widely recognized that when discussing in vivo release rates and drug absorption rates, fast and immediate release is not always best. For some “immediate”-release drug products, such as carbamazepine tablets, a slower release is desired; therefore, it is frequently desirable to have minimum and maximum particle size specifications to control the release rate. For example, micronizing or milling a drug substance to provide a greater surface area of the substance may also result in faster dissolution and possibly faster absorption and higher blood levels. Such changes to improve the dissolution may not always be desired. In addition to release or dissolution, variation in particle size, particle shape, and/or bulk density can also have an effect on the uniformity of dosage forms, particularly those manufactured by direct compression or direct encapsulation.

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Particulate solids, once mixed, have a tendency to segregate by virtue of differences in the shape, size, and density (other variables are also important) of the particles of which they are composed. This process of separation occurs during mixing, as well as during subsequent handling of the completed mix. Generally, large differences in particle size, density, or shape within the mixture result in instability in the mixture. The segregation process normally requires energy input and can be reduced following mixing by careful handling. Some manufacturers establish wide ranges for specifications. These must be established based on a GMP and validation perspective. Even though a wide range for a physical specification, such as particle size or surface area, may be established in a filing, it is expected that such ranges will be verified during validation of the process. In a recent court decision, the judge ruled that companies cannot hide behind approval of processes listed in an application when these processes do not work. In other words, the approval of a filing has no impact on processes that do not perform consistently. For example, in a particular filed process it was determined that particle size would have no effect on drug absorption and dissolution, and a wide-range particle size specification was established; however, during the GMP review, it was found that variation in particle size did have a major effect on content uniformity. Therefore, a tighter particle size specification had to be established. Control of the physical characteristics of the excipient is also important because variations in such characteristics may also affect the performance of the dosage form. Changes in particle size of some excipients, for example, may affect content uniformity. In other cases, a change in the supplier of an excipient or lubricant may affect dissolution or bioavailability. In fact, the release of the active ingredients in some products is timed by varying lubricant blending time and concentration. The literature contains many examples of lubricant processing causing major changes. Such changes in excipients illustrate deficiencies with the utilization of retrospective validation; for such validation to be satisfactory, control of all parameters and key steps in the process is necessary. The control of mixing times and physical characteristics of all ingredients is critical to successful validation of all formulations and processes. A major question that must be addressed is the need for testing physical characteristics (particle size) for each batch of excipient. For many single-source excipients, particle size is a supplier specification and is usually tightly controlled. Having established a specification and not testing each lot of excipient upon receipt may be satisfactory in such cases; however, for some multisource excipients and where the dosage formulator expects to shift sources of supply, some resulting differences in physical characteristics (particle size) may have an effect on dose uniformity and dissolution. Definite justification should exist for not testing lots of excipients for physical characteristics.

2. Manufacturing Procedures Procedures used to manufacture development batches must be specific and well documented. This is necessary for scaleup and subsequent comparison to the commercial process. This is another area where differences between new drug application (NDA)/new animal drug application (NADA) and abbreviated new drug application (ANDA)/abbreviated new animal drug application (ANADA) products arise. In the case of the NDA/NADA, there will be several clinical and/or test batches manufactured over a period of time showing

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Handbook of Pharmaceutical Manufacturing Formulations: Over-the-Counter Products

changes in the process as more is learned about the drug and the process. The level of documentation should increase as the process becomes more defined and the firm begins phase II and III studies. The generic product focus is on the biobatch. Again, the process used to manufacture the biobatch must be well defined and well documented; test batches must be manufactured to establish that biobatch manufactured is reproducible.

3. In-Process Testing Specific specifications required to control the manufacturing process must be established and justified. Doing so will require granulation studies, including blend uniformity, sieve analysis, and moisture.

4. Finished Product Testing Testing for standards given in FDA monographs such as content uniformity (when a specification applies), assay, hardness, friability, dissolution, and others are essential.

5. Dissolution Profile The dissolution profiles for the biobatch or pivotal clinical batches should be evaluated in the product development report. Good correlation should exist between the dissolution specifications and test results for the biobatch/clinical test batches and the full-scale commercial process.

6. Stability The Center for Drug Evaluation and Research (CDER) conducts an evaluation of stability data and approves proposed expiration dates. The product development report should contain an evaluation of the stability data that have been obtained. During postapproval inspections, stability data are reviewed by the field. An FDA inspection, therefore, inevitably includes an audit of underlying raw data and analytical worksheets to ensure the accuracy and authenticity of stability data contained in summary reports.

B. Preapproval Inspections Validation of three full-size commercial lots is not required for approval of the marketing application; however, the firm must have data that justify the full-scale commercial process filed in the NDA/ANDA or NADA/ANADA application. In other words, the firm should have sufficient research on the test batches to establish specifications for the manufacturing and control procedures listed in the application. These data and specifications form the basis for the validation protocol that may be developed following approval of the application. The final step in the process is demonstration (validation) runs to prove that the process will perform consistently. Firms should validate the process using the specifications listed in the filing. To evaluate the proposed manufacturing process, the following areas must be covered during the preapproval inspection:

2. History Section of the Application This section of the application is used to identify the biobatch or batches used for pivotal clinical studies. Any batches in which in vivo studies were carried out, particularly those for which in vivo studies showed a lack of equivalency, are subject to review.

3. Development Data (Product Development Report) The firm cannot logically proceed to the validation step without some prior evaluation of the process. During the development phase, the critical process parameters must be identified and specifications established. These predetermined specifications must be established during the development of the process, with the biobatch or pivotal clinical batch serving as the reference batch. Development of a solid dosage form will vary from firm to firm and will be dependent upon the specific product and process; however, the formula ranges, physical and chemical specifications of the drug substance and excipients, in-process variables, and interaction effects of the dosage form ingredients under normal and stress aging conditions should be confirmed by limited challenge in pilot-scale and production-size batches. Such development data serve as the foundation for the manufacturing procedures, specifications, and validation of the commercial process. In some cases, manufacturers establish specifications such as hardness and particle size during validation; however, as the validation definition states, specifications must be determined prior to validation of the process. When a manufacturer files a manufacturing process in an application, the FDA expects that the process will yield a product that is equivalent to the product on which the biostudy or pivotal clinical study was conducted; therefore, it is important that the development and scale-up of the process be well documented so that a link between the bio/clinical batches and the commercial process can be established. The firm should have data such as granulation studies, finished product test results, and dissolution profiles that may be used to document that the two processes are equivalent. In most cases, in vitro data alone will not be sufficient to document equivalency. The bioequivalency evaluation must be made by qualified individuals, and the firm should have a signed statement documenting that the processes are equivalent.

4. Inspection of the Facilities The FDA inspectors physically inspect the facility to ensure that the area and ancillary equipment such as air handling and water systems are suitable for the proposed manufacturing process. Construction of new walls, installation of new equipment, and other significant changes must be evaluated for their impact on the overall compliance with GMP requirements. These inspections include facilities used for development batches and to be used for full-scale production batches.

1. Master Formula This document must include specific manufacturing directions for the full-scale commercial process, including inprocess and finished product specifications. Make sure that the process filed in the application complies with the process used to manufacture the bio/clinical batch. In some cases, the process may be different after scale-up. This is acceptable if the firm has data showing the product produced by this process will be equivalent. Data such as granulation studies, finished product test results, and dissolution profiles are used to document that the two processes are equivalent.

5. Raw Materials The FDA inspectors review the information contained in the raw materials section of the product development report. Inventory records are a good source for identification of batches used for product development and biostudies.

6. Laboratory The regulatory inspection of a laboratory involves observations of the laboratory in operation and of the raw laboratory data to evaluate compliance with GMPs and to specifically

Solid Oral Dosage Forms Validation

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carry out the commitments in an application or Drug Master File (DMF). The raw laboratory data, laboratory procedures and methods, laboratory equipment, and methods validation data must be periodically reviewed to ensure overall quality of the laboratory operation and the ability to comply with GMP regulations. It is not uncommon for the FDA inspecting team to identify foreign peaks and impurities not filed or discussed in applications. Also, many inspections reveal laboratory test methods that are not validated. The transfer of laboratory methods and technology from the research and development department to the quality control department should be firmly established. Be aware that FDA inspectors are not bound by any rules to restrict their investigation to particular product files. They can and often do pick up data files, charts, and recordings that are lying around in the area and will raise queries. It is a good idea to keep these records properly secured to avoid unnecessary distractions in the inspection process.

cannot be written until the variables are identified in the development phase. In many of the FDA’s postapproval, premarketing inspections, validation (and consistency) are often not well established. Failures of production-size batches include dissolution, lack of content uniformity, and variable potency. Validation reports on batch scale-ups may also reflect selective reporting of data. Several parameters must be considered when ensuring validation of the manufacturing process for an oral solid dosage form. For example, at least eight major areas must be evaluated:

7. Equipment

1. Raw Materials

At the time of the preapproval inspection, the FDA expects that the equipment will be in place and qualified. New products, particularly potent drug products, can present cleaning problems for existing equipment. Manufacturers must validate their cleaning processes for the new drug/dosage form.

Physical characteristics of raw materials can vary among manufacturers of drug substances and, on occasion, have varied from lot to lot from the same manufacturer. The examination of retained samples of the lots of raw materials can reveal physical differences between the two lots and thus should become a routine measure. A quantitative compliance must be present for the raw material inventory records to evaluate the use of the drug substance in biobatch, clinical, and/or test batches. Make sure to account for the quantities and sources of materials used and the testing performed. Physical specifications for drug substances should be well established. If no such specifications are available, or only a very vague specification is, support data should exist to demonstrate that dissolution profiles and content uniformity will be satisfactory over a wide range of particle sizes. For example, a manufacturer may establish a specification that 90% of the particles must be less than 300 microns. For validation of this process, one would expect the use of micronized as well as nonmicronized material with particles close to 300 microns in size.

IV. VALIDATION PROTOCOLS Validation protocols are developed from the information obtained during product development research. These protocols list the specific manufacturing process and specifications that will be tested during the demonstration runs. Validation protocols are not required for the preapproval inspection but are required for postapproval inspections. Key processes and control specifications should have been established during product development research and should be carefully listed in the validation protocol.

V. DEMONSTRATION RUNS (VALIDATION OF THE PROCESS) A. Test Batch Relationships A validated process should produce a dosage form that is directly related to the dosage form on which equivalency and/or efficacy and safety data were determined. This is usually the test batch; therefore, ensure that the process used to make the test batch has been used for routine full-scale production batches. These processes and specifications must be equivalent, and the importance and need for good control of the manufacturing process used to produce the test and clinical batches cannot be overemphasized. Typically, the control of test batches includes, among other components, drug substance characterization, granulation analyses, and dose uniformity and dissolution profiles. The validation report should compare the manufacturing processes and specifications for the test batches to those for the full-scale batches; however, such findings may be contained in other documents, such as bioequivalency reports, and should be readily available.

B. Postapproval Prospective Validation Inspections In the postapproval, premarketing phase, the FDA reviews the validation protocol and validation report. Obviously, a validation protocol that lists all of the variables and parameters that should be controlled when the process is validated

r r r r r r r r

Biobatch relationship Raw materials Manufacturing procedures and equipment Granulation/mix analysis In-process controls Test results with validated methods Investigations/product failures Site review

2. Manufacturing Procedures and Equipment Regardless of the nature of the specificity of the manufacturing directions contained in the application, a detailed master formula with specific manufacturing directions and specifications must have been developed before any validation protocol is prepared and before the validation process begins. The basic premise of validation of a process is that a detailed process already exists that, it is hoped, will be shown to perform consistently and produces products in compliance with predetermined specifications; therefore, detailed manufacturing directions specifying equipment and operating parameters must be specified in the master formula. The importance of specific written directions and specifications cannot be overemphasized. For example, problem areas include

r failure to specify the amount of granulating solution, resulting in overwetting and dissolution failures of aged batches; r failure to specify the encapsulation machine and operating parameters, such as dosing discs, resulting in weight variation failures; and r failure to specify the compression machine(s) and operating parameters, resulting in content uniformity failures.

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Handbook of Pharmaceutical Manufacturing Formulations: Over-the-Counter Products

In addition to the concern about specific manufacturing directions, equipment presents its own set of unique problems that have to be considered in the control of the manufacturing and the validation processes. The following is a brief description of some issues associated with equipment. a. Blenders Many solid oral dosage forms are made by direct compression. The two types of mixers are low energy and high energy. The low-energy mixers represent the classical type of slow mixers, such as ribbon blenders, tumblers, and planetary pony pan; the high-energy mixers include some basic features of the low-energy mixers but also contain some type of high-speed blade, commonly termed an intensifier bar or chopper. The various types of mixers can be described as follows: 1. Pony pan type. This mixer has historically been used for the manufacture of wet granulations. Because of its open pan or pot, granulating agents such as starch paste can be added while mixing. Because the pan is open at the top to allow the mixing blades to penetrate the powder, mixing operations are usually dusty and can lead to potential cross-contamination problems. The usefulness of these mixers is limited to wet granulating. This type of mixer provides good horizontal (side-to-side) blending; however, vertical (top-to-bottom) mixing does not occur. Powder placed in the mixer first will be poorly mixed. Segregation or unmixing is also a recognized problem. To minimize this problem, some manufacturers have emptied the pan contents halfway through the mixing cycle in an attempt to turn the powder over at the bottom of the mixer. To alleviate the problem of the lack of mixing along the sides or walls of the pan, manufacturers have used a hand-held steel paddle at various times during mixing. This type of mixing is difficult to control and reproduce; thus, it would be difficult to validate. The potential for segregation and poor mixing along the sides and particularly the bottom of the pony blender makes this type of blender less desirable for the dry blending of granulations of drug products; consequently, whenever such dry blending is encountered, investigators will look for potential problems with blending validation and content uniformity. Whenever in-process samples of the granulation are collected as part of an investigation or inspection, the formula card and the weight of the dosage unit to be manufactured are needed for the calculations. 2. Ribbon blender. In the ribbon blender, powder is mixed both horizontally and vertically. Loading operations can be dusty, but during the actual blending the unit is enclosed, thereby limiting the amount of dust released to the environment. The major and potentially the most serious problem with the ribbon blender is the “dead spot” or zone at the discharge valve in some of these blenders. To compensate for this dead spot, manufacturers have to recycle the powder from this area at some point during the mixing process. Obviously, adequate and very specific directions and procedures should be available to ensure that this critical step is performed. Another concern with this mixer is the poor mixing at the ends of the center horizontal mixing bar and at the shell wall because of blade clearance. The level of powder placed in this mixer is normally at the top of the outer ribbon blade, and, as with other mixers, care must be taken not to overfill the mixer. Cleaning problems, particularly at the ends of the ribbon blender where the horizontal bar enters the blender, have

been identified. Manufacturers who do not disassemble and clean the seals/packing between batches should have data to demonstrate the absence of foreign contaminants between batches of different products processed in the blender. 3. Tumbler blender. Common mixers of this type include the twin shell and double cone. These mixers exert a gentle mixing action; because of this mild action, lumps of powder will not be broken up and mixed. Powders may also clump due to static charges and segregation can occur. Low humidity can contribute to this problem. Blending under very dry conditions has been found to lead to charge buildup and segregation, while blending of some products under humid conditions has led to lumping. More so than with other mixers, powder charge levels should not exceed 60% to 65% of the total volume of the mixer. Fabricators of tumbler-type blenders identify the volume as the actual working capacity and not the actual volume of the blender. It is important to correlate the bulk density of the granulation with the working capacity of the blender. 4. High-shear (high-energy) mixers. The several fabricators of these mixers include GRAL, Diosna, and Littleford/ Lodige. These mixers are highly efficient and ideally suited for wet granulations. End points of wet granulations can be determined by measurements on a gauge of the work required to agitate the blend. The mixing vessel is enclosed, and dust only enters the environment when loading. One of the problems associated with these mixers is the transfer or conversion of products blended in the older types of mixers to these blenders. Mixing times are going to be different, and the physical characteristics of the blend may also be different. These mixers are very efficient. For wet granulations, it is important to control the rate and amount of addition of the solvent. Because of their efficiency, drug substance may partially dissolve and recrystallize upon drying as a different physical form. An intensifier bar in the center of the blender rotates at very high speeds to break down the smaller, harder agglomerates. A major disadvantage of this type of blender is that the extremely high speed of the intensifier bar generates considerable heat, which can sometimes result in charring of some sugar-based granulations. It should be pointed out that these same comments are applicable to other highenergy mixers that also rely on high-speed choppers to disperse powders. Also, cleaning of the blender requires disassembly of the intensifier bar between products. 5. Plastic bag. Any discussion of mixers would not be complete without addressing the plastic bag. Firms have resorted to the blending or manufacture of a trituration in a plastic bag. Obviously, it is very difficult to reproduce such a process, and there is the potential for loss of powder as a result of breakage or handling. The use of a plastic bag cannot be justified in the manufacture of a pharmaceutical product. When the plastic bag has been used, directions are usually not specific, and one would not know by reading the directions that a plastic bag was employed. Some companies have been known to hide the use of plastic bags by indicating in the manufacturing records that a blender was used; these bags are easy to spot during an inspection, and the practice is highly discouraged. b. Dryers The two basic types of dryers are the oven dryer, in which the wet granulation is spread on trays and dried in an oven, and the fluid-bed dryer, in which the wet granulation is “fluidized” or suspended in air. Generally, the fluid-bed dryer

Solid Oral Dosage Forms Validation

yields a more uniform granulation with spherical particles; however, this may result in compression problems that may require additional compression force. It is not unusual to see manufacturers change from an oven dryer to the fluid-bed dryer; however, such a change should be examined for equivalency with in vitro testing such as hardness, disintegration, and comparative dissolution and stability testing. Other issues of concern with drying include moisture uniformity and cross-contamination. Tray dryers present more moisture uniformity problems than fluid-bed dryers. Obviously, a dryer should be qualified for heat uniformity and a program developed to ensure moisture uniformity in granulations at the end point of drying. With respect to fluidbed dryers, moisture problems can occur if the granulation is not completely fluidized. In regard to cross-contamination, oven dryers, particularly those in which air is recirculated, present crosscontamination problems because air recirculates through a common filter and duct. For fluid-bed dryers, the bag filters present cross-contamination problems. In order to minimize such problems, manufacturers should use product-dedicated bags. c. Tablet and Capsule Equipment Another important variable in the manufacturing process is the tablet press or encapsulating machine. The newer dosage form equipment requires granulations with good flow characteristics and good uniformity. The newer tablet presses control weight variation by compression force and require a uniform granulation to function correctly. Setup of the microprocessor-controlled tablet press usually includes some type of challenge to the system. For example, a short punch is sometimes placed among the other punches. If the press is operating correctly, it will alarm when a lower- or higherweight tablet is compressed. Different tablet compression equipment can cause dose uniformity, weight uniformity, and hardness problems. For example, vibrations during tablet compression can cause segregation of the granulation in the feed hopper. The speed of the machine can affect the fill of the die and tablet weight; therefore, as previously noted, it is important to have specific operating directions. Many unit operations now provide for blending in totes, with direct discharge of the tote into the tablet compression equipment. Because of segregation problems at the end of the discharge, tablets from the end of the compression should be tested for content uniformity. The use of inserts in totes has been shown to minimize segregation. With regard to the newer computer-controlled tablet compression equipment, buckets of tablets are often rejected because of potential weight variation problems. The disposition of these tablets, as well as the granulation and tablets used to set up the press, should be documented, and reworking processes must be validated. With regard to encapsulation operations, the hygroscopic nature of gelatin capsules and some of the granulations require humidity controls for storage of the empty capsules and their subsequent filling. Scale-up of capsule products has also presented some problems because of the different types of encapsulation equipment. Older equipment that operated on gravity fill, such as Lilly and Parke-Davis machines, was commonly used for manufacturing capsules in clinical manufacturing areas. When formulations were scaled up to high-speed encapsulation equipment, flow problems and weight variation resulted. Additionally, some of the newer

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equipment provides for the formation of a slug which could have an impact on dissolution. Many firms, in order to recondition (rework) batches, pass those particular batches through a sorter, such as the R MOCON VERICAP . This machine works on the principal of current (dielectric constant), and moisture variation in the filled capsules can cause inaccurate results. Manufacturers should qualify equipment and examine equipment logs for these sorting machines to identify batches with weight problems. Data supporting the accuracy of equipment in regard to rejecting low- or high-weight capsules should be available during an FDA inspection.

d. Coating Equipment Many tablets are now coated with an aqueous film coat that is usually very soluble. Current technology provides for fixed sprays of the coating solution. The volume of coating solution, rate, and temperature can be controlled by some of the more highly automated operations; however, for many sugar-coated, enteric-coated, and delayed-release products, some components of the coating are not highly soluble and that part of the process is performed manually. Generally, the shellac undercoat used for sugar-coated tablets has presented disintegration/dissolution problems, particularly in aged samples. With respect to poor disintegration, the example of ferrous sulfate tablets probably represents the classical example. Over the years, many different manufacturers have issued recalls for poor disintegration of coated ferrous sulfate tablets; likewise, problems with poor dissolution have been attributed to the coating process. Again, the shellac undercoat hardens and even sometimes cracks, resulting in poor dissolution. On many occasions the coating process has not been validated. The number of applications of coats, volume of coating solution in a specific application, and temperature of the solution during application are all parameters that must be addressed. For example, the temperature of application and even heat during drying has been found to cause dissolution failures in aged tablets. Another problem associated with the coating process concerns heat applied to products that are sensitive to heat. For example, it has been shown that estrogen tablets are heat sensitive and have exhibited stability problems; thus, it is important to control this phase of the process. For a few products, such as some of the antihistamine tablets or multivitamin tablets containing folic acid or cyanocobalamine, the drug substance is applied during the coating process. Some products require the active drug substance to be applied as a dust on tacky tablets as part of the coating process; for these products, it is particularly important to apply the drug in the coating solution through controlled applications. Again, it is important as part of the validation of these processes to demonstrate dose uniformity and dissolution and to control the parameters of the coating process.

3. Granulation/Mix Analysis A critical step in the manufacture of an oral solid dosage form is the blending of the final granulation. If uniformity is not achieved at this stage, then one could assume that some dosage units would not comply with uniformity requirements. The major advantage of blend analysis (from a

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Handbook of Pharmaceutical Manufacturing Formulations: Over-the-Counter Products

uniformity perspective) is that specific areas of the blender that have the greatest potential to be nonuniform can be sampled. This is particularly true of the ribbon-type blender and planetary or pony-type mixers. In some cases, such as for large or tumbler-type blenders, it is impractical to sample from the blender directly. In such cases, granulations or blends could be sampled at the time of blender discharge or directly from drums. If sampling from drums, samples from the top, middle, and bottom of each drum should be collected. In most cases, sampling thieves are readily available for sampling the small quantities that need to be taken from key areas of the blender or the drums. If samples larger than one dosage unit must be collected, however, adequate provisions must be made to prevent excessive handling manipulation between the time of sampling and the time of analysis. Good science and logic would seem to dictate that sample sizes of the approximate equivalent weight of the dosage unit should be sampled in order to test for uniformity. Many industrial pharmacy and engineering texts confirm this approach. Large granulation sample sizes (e.g., 1 oz) will provide little information with respect to uniformity. Generally, further mixing after sampling and prior to analysis can yield misleading results. The acceptance criteria for granulation dose uniformity testing must be established. Although many firms evaluate dose uniformity using the compendial dose uniformity specifications [85 to 115% with a relative standard deviation (RSD) of 6 to 7.8], such specifications should be tighter where supported by the firm’s historical data on the level of blend uniformity with its equipment for a given product. In many cases, compendial assay limits for the finished product (90 to 110% of label claim) are broad enough for this purpose, and most firms should be able to demonstrate blend assay results well within these limits. If larger sample sizes are taken for assay to evaluate total composite assay, then the specific U.S. Pharmacopeia (USP) or filed criteria for assay should be used. In addition to analysis of blends for dose uniformity and potency, blends are tested for physical characteristics. A major physical parameter used to demonstrate equivalence between batches is the particle size profile. This is particularly important for comparison of the biobatch with production batches and also when processes are modified or changed. The particle size profile will provide useful information for demonstrating comparability. Particle size profiles are particularly important for tablets made by a wet granulation process. The size and even the type of granule can affect the pore size in a tablet and have an effect on dissolution. For example, a recent dissolution failure was attributed to a change in the milling screen size, yielding a granulation with larger granules. It was a coated tablet, and the larger pores permitted increased penetration of the coating solution into the tablet, resulting in slower dissolution. Another test that is typically performed in regard to granulation, particularly when the wet granulation process is used, is loss on drying (LOD) and/or moisture content. If organic solvents are employed, then residual solvent residues are also tested. To validate a drying process, LOD levels are determined prior to, during, and after drying in order to demonstrate times and levels. As with processing variables, levels (specifications) are established in the development phase, with the validation phase being used to confirm the adequacy of the process.

4. In-Process Testing In-process testing is testing performed on dosage forms during their compression/encapsulation stages to ensure consistency throughout these operations. For tablets, individual tablet weight, moisture, hardness (compression force), and disintegration tests are performed. For capsules, individual weight and moisture tests are performed. In many of the validation reports, it has been found that manufacturers have neglected to supply results of individual (not composite) dosage unit weight tests that should be performed throughout compression/encapsulation. Such testing is particularly important for capsule products, which may exhibit weight variation problems. If not part of the validation reports, the individual dosage unit weights should be recorded and be available for FDA inspectors to review. With regard to individual capsule weights, a major question that arises concerns acceptable levels. Because most USP assay limits are 90% to 110%, it would seem reasonable that each unit manufactured complies with these specifications. It should be pointed out that 85% to 115% limits are established by the USP for variability in both blending and compression or encapsulation operations. Because hardness and disintegration specifications are established during development and biobatch production, testing is performed to demonstrate both equivalency (comparability) and consistency. With regard to moisture, some tablets set up upon aging as a result of poor moisture control and inadequate specifications. For example, this has been shown to be a major problem with carbamazepine tablets and often for ferrous sulfate tablets.

5. Test Results Finished product testing, particularly assay, content uniformity, and dissolution, should be carefully recorded. With regard to dissolution, it is important to establish dissolution profiles. Validation batches with dissolution profiles not comparable to biobatches indicate nonequivalency of the manufacturing process. Depending on the discriminating nature of the dissolution test, it may also indicate lack of equivalence of the dosage forms made during validation with the biobatch. In the review of dissolution test results, it is important to eventually see results very close to 100% dissolution. In some cases, manufacturers will profile the dissolution results only to the specification; however, if lower but still acceptable results are obtained (such as 85%), it is important to continue the test by increasing the speed of the apparatus. If a product completely dissolves, yet only results in a value of 85%, it may indicate some problem with the test. Likewise, high dissolution results (115%) also indicate some problem with the test. Obviously, unusual or atypical results should be explained in the validation report.

6. Investigations and Product Failures In any process validation exercise, a basic objective is to prove that a process is satisfactory; unfortunately, some processes are unsatisfactory and may sometimes yield unacceptable results. It is important, therefore, that when the final validation report is reviewed, all results, including failing results, are discussed and evaluated. Historically, reviews of manufacturing processes typically show that one out of every

Solid Oral Dosage Forms Validation

eight batches manufactured has failed content uniformity testing. Manufacturers often recognize that the process is unsatisfactory and not validated, but fail to draw this conclusion in the written validation report. This is a dangerous precedence and is often easily identified during FDA inspections.

67

7. Site Review A major aspect and possibly the most critical phase of process validation is the review of data to ensure that failing batches were not omitted without justification. Additionally, manufacturers must ensure that the raw data, including analytical raw data, are accurate.

6 Current Regulatory Status of Over-the-Counter Products

BACKGROUND

specific new drug application (NDA), or an abbreviated new drug application (ANDA). The OTC drug review was established to evaluate the safety and effectiveness of OTC drug products marketed in the United States before May 11, 1972. It is a three-phase public rulemaking process (each phase requiring a Federal Register publication) resulting in the establishment of standards (monographs or nonmonographs) for an OTC therapeutic drug category. The first phase was accomplished by advisory review panels. The panels were charged with reviewing the ingredients in nonprescription drug products to determine whether these ingredients could be generally recognized as safe and effective for use in selftreatment. They were also charged with reviewing claims and recommending appropriate labeling, including therapeutic indications, dosage instructions, and warnings about side effects and preventing misuse. According to the terms of the review, the panels classified ingredients in three categories are as follows:

Over-the-Counter (OTC) drug products are those drugs that are available to consumers without a prescription. There are more than 80 classes (therapeutic categories) of OTC drugs, ranging from acne drug products to weight control drug products. As with prescription drugs, CDER oversees OTC drugs to ensure that they are properly labeled and that their benefits outweigh their risks. OTC drugs play an increasingly vital role in America’s health-care system by providing easy access to certain drugs that can be used safely without the help of a health-care practitioner. This enables consumers to take control of their own health care in many situations. There are more than 100,000 OTC drug products marketed, encompassing about 800 significant active ingredients. Most OTC drug products have been marketed for many years, prior to the laws that require proof of safety and effectiveness before marketing. For this reason, FDA has been evaluating the ingredients and labeling of these products as part of “The OTC Drug Review Program.” The goal of this program is to establish OTC drug monographs for each class of products. OTC drug monographs are a kind of “recipe book” covering acceptable ingredients, doses, formulations, and labeling. Monographs will continually be updated adding additional ingredients and labeling as needed. Products conforming to a monograph may be marketed without further FDA clearance, while those that do not, must undergo separate review and approval through the “new drug approval system.” The NDA system—and not the monograph system—is also used for new ingredients entering the OTC marketplace for the first time. For example, the newer OTC products (previously available only by prescription) are first approved through the NDA system and their “switch” to OTC status is approved via the NDA system. FDA’s review of OTC drugs is primarily handled by CDER’s Division of Over-the-Counter Drug Products in the Office of Drug Evaluation V. However, scientists and regulators throughout CDER, the Office of General Counsel, and other Centers within FDA are routinely asked to assist in this massive effort. There is also an advisory committee, “The Nonprescription Drug Advisory Committee,” which meets regularly to assist the agency in evaluating issues surrounding these products.

Category I: generally recognized as safe and effective for the claimed therapeutic indication Category II: not generally recognized as safe and effective or unacceptable indications Category III: insufficient data available to permit final classification The second phase of the OTC drug review was the agency’s review of ingredients in each class of drugs, based on the panel’s findings, on public comment, and on new data that may have become available. The agency, in turn, publishes its conclusions in the Federal Register in the form of a tentative final monograph. After publication of the tentative final monograph, a period of time is allotted for objections to the agency’s proposal or for requests to be submitted for a hearing before the Commissioner of FDA. The publication of final regulations in the form of drug monographs is the third and last phase of the review process. The monographs establish conditions under which certain OTC drug products are generally recognized as safe and effective. The term human drug application means an application for approval of a new drug submitted under section 505(b)(1) of the Federal Food, Drug, and Cosmetic Act (FD&C Act) or approval of a new drug submitted under section 505(b)(2) of the FD&C Act or approval of an abbreviated new drug application under section 505(j) of the FD&C Act or licensure of certain biological products under section 351 of the Public Health Service Act. A 505(b)(1) application is an application that contains full reports of investigations of safety and effectiveness. The investigations the applicant relied on for approval were conducted by, or for the applicant, or the applicant has obtained a right of reference or use for the investigations.

REGULATORY DEFINITIONS An OTC drug product is a drug product marketed for use by the consumer without the intervention of a health-care professional in order to obtain the product. Two post-1938 regulatory pathways exist for the legal marketing of such products: (a) marketing in compliance with an OTC drug monograph; (b) marketing under the authority of an approved product-

68

Current Regulatory Status of Over-the-Counter Products

Appendix I to this chapter is a listing of OTC ingredients and their respective recommended uses and classification. The U.S. FDA has recently issued guidance on unproven safety of OTC drug components (current as of April 2008) [CITE: 21CFR310.545]. A number of active ingredients

have been present in OTC drug products for various uses, as described below. However, based on evidence currently available, there are inadequate data to establish general recognition of the safety and effectiveness of these ingredients for the specified uses. These ingredients are listed as Appendix II to this chapter.

Appendix I OTC Ingredient List Review Panel 2-Ethylhexyl salicylate [see octyl salicylate] = == = 2-Ethylhexyl-4-phenylbenzophenone-2carboxylic acid Topical analgesic 5-(3,3-Dimethyl-2-norbornyliden)3-pentene2-one [see bornelone] = == = 8-Hydroxyquinoline [see oxyquinoline] = == = Acetaminophen Internal analgesic Internal analgesic Internal analgesic Miscellaneous internal Miscellaneous internal

Report

Drug Category

ANPR

PR

FR

= == =

= == =

= == =

= == =

= == =

Sunscreen

Sunscreen

IISE

IISE

Pending

= == =

= == =

= == =

= == =

= == =

= == =

= == =

= == =

= == =

= == =

Internal analgesic Internal analgesic Internal analgesic Menstrual/diuretic Overindulgence in alcohol/food

I I IIE I I

I I Not OTC I I

Pending Pending n/a Pending Pending

IIE IISE = == =

IIE IISE = == =

[54 FR 6826] 310.519(a) = == =

Sedative Sedative = == = Acetanilide Internal analgesic Internal analgesic Internal analgesic Acetic acid = == =

Nighttime sleep aid Daytime sedative = == =

Analgesic Antipyretic Antirheumatic Analgesic Overindulgence remedies (hangover) Sleep aid Sedative = == =

Internal analgesic Internal analgesic Internal analgesic

Analgesic Antipyretic Antirheumatic

IIS IIS IISE

IIS IIS not OTC

Pending Pending n/a

Otic

n/a

IIIE

310.545(15)(i)

Contraceptive/vaginal Miscellaneous external Acetic acid, glacial Miscellaneous external Miscellaneous external Acetone Miscellaneous external Miscellaneous external Acidulated phosphate fluoride (sod fluoride/sod phos/phos acid) Dental Acidulated phosphate fluoride (sodium fluoride/hydrogen fluoride) Dental Acidulated phosphate fluoride (sodium fluoride/sodium phos dibasic/phos acid) Dental Agar Laxative Alanine Miscellaneous internal

Vaginal Wart remover

Swimmer’s ear prevention Alters vaginal pH Wart remover

IIIE IIISE

Withdraw IIISE

n/a [55 FR 33254]

Wart remover Corn/callus remover

Wart remover Corn/callus remover

IIIE IIIE

IIISE IIISE

[55 FR 33254] [55 FR 33261]

External analgesic Skin protectant

Astringent Astringent

IISE IISE

n/a IISE

Pending 310.545(18)(ii)

Anticaries

Anticavity dental rinse

I

I

355.10(a)(2)(ii)

Anticaries

Anticavity dental rinse

IIS

IIS

355.10(a)(2)(ii)

Anticaries

Anticavity dental rinse

I

I

355.10(a)(3)(ii)

Laxative

Bulk laxative

IIIE

IIIE

310.545(12)(i)

Benign prostatic hypertrophy

Benign prostatic hypertrophy

IIE

IIISE

310.532(a)

Acne Antifungal Anorectal Anorectal

Acne Antifungal Keratolytic (external) Keratolytic (intrarectal)

IIE IIIE I I

IIE IIIE I I

310.545(1) 310.545(22)(ii) 346.20(a) 346.20(a)

Alcloxa Antimicrobial II Antimicrobial II Hemorrhoidal Hemorrhoidal

69

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Handbook of Pharmaceutical Manufacturing Formulations: Over-the-Counter Products

Review Panel

Report

Drug Category

ANPR

PR

FR

Alcohol Miscellaneous external Miscellaneous external Miscellaneous external Miscellaneous external Miscellaneous external Miscellaneous external

Alcohols (topical) Mercury External analgesic External analgesic External analgesic External analgesic

I n/a IISE Defer IISE Defer

Defer I n/a Defer IISE IISE

n/a Pending Pending n/a 310.545(a)(10)(vi) 310.545(a)(10)(vii)

Miscellaneous external Miscellaneous external Miscellaneous external

Skin protectant Skin protectant Skin protectant

IISE IISE Defer

IISE IISE IISE

310.545(a)(18)(ii) 310.545(a)(18)(v) 310.545(a)(18)(vi)

Miscellaneous external Miscellaneous internal Miscellaneous internal Miscellaneous internal Oral cavity Alcohol, 14% [see Alcohol] ==== Alcohol, ethoxylated alkyl ==== Aldioxa Miscellaneous external Miscellaneous external Miscellaneous external Miscellaneous external Alfalfa Miscellaneous internal Alfalfa leaves Miscellaneous internal Alginic acid Antacid Miscellaneous internal Alkaloids of sabadilla [see sabadilla alkaloids] ==== Alkyl arylsulfonate Contraceptive/vaginal

Skin protectant Digestive aid Menstrual/diuretic Weight control Oral health care

Antiseptic First aid antiseptic Astringent Fever blister (topical) Insect bite/sting Poison ivy/oak/ sumac Astringent Insect bite/sting Poison ivy/oak/ sumac Fever blister (topical) Digestive aid (ippuad) Analgesic adjuvant Anorectic Antimicrobial

IISE n/a n/a IISE IIIE

IISE n/a IISE IISE IIISE

Pending 310.545(a)(18)(ii) 310.545(a)(24)(i) 310.545(a)(20) Pending

====

====

====

====

====

Insect bite/sting

Insect bite/sting

n/a

n/a

310.545(a)(18)(v)(A)

Antifungal Antimicrobial External analgesic Skin protectant

Diaper rash Diaper rash Diaper rash Diaper rash

Defer Defer Defer Defer

n/a n/a n/a IIISE

310.545(a)(22)(ii) Pending 310.545(a)(10)(iv) Pending

Weight control

Anorectic

IISE

IISE

310.545(a)(20)

Menstrual/diuretic

Diuretic

n/a

IISE

310.545(a)(24)(i)

Antacid Weight control

Antacid Anorectic

IIIE IIIE

IIIE IISE

[39 FR 19873] 310.545(a)(20)

====

====

====

====

====

Vaginal

Lowers surface tension mucolytic effects

IIIE

Withdraw

n/a

Gingivitis/plaque

Antiplaque/gingivitis

n/a

IIISE

Pending

Acne Dandruff/seborrheic dermatitis/psoriasis

Acne Dandruff

IISE IISE

IISE IIIE

310.545(a)(1) 310.545(a)(7)

====

====

====

====

====

Vaginal Oral mucosal injury Antifungal Antimicrobial Dandruff/seborrheic dermatitis/psoriasis

Minor irritations Wound healing agent Diaper rash Diaper rash Dandruff/seborrheic dermatitis/ psoriasis Diaper rash Fever blister (topical) Poison ivy/oak/ sumac Hair grower Diaper rash Fever blister (topical) Poison ivy/oak/ sumac

IIIE IIIE Defer Defer IIIE

Withdraw IIIE n/a n/a IIIE

n/a 310.534(a) 310.545(a)(22)(i) Pending 310.545(a)(7)

Defer Defer Defer

n/a n/a IISE

310.545(a)(10)(iv) Pending Pending

IISE Defer Defer Defer

n/a I I IISE

310.527(a) Pending Pending Pending

Alkyl dimethyl amine oxide and alkyl dimethyl glycine ==== Alkyl isoquinolinium bromide Antimicrobial II Miscellaneous external Alkyldimethyl benzylammonium chloride [see benzalkonium chloride] ==== Allantoin Contraceptive/vaginal Dental Miscellaneous external Miscellaneous external Miscellaneous external

Miscellaneous external Miscellaneous external Miscellaneous external

External analgesic External analgesic External analgesic

Miscellaneous external Miscellaneous external Miscellaneous external Miscellaneous external

Hair growth/loss Skin protectant Skin protectant Skin protectant

Current Regulatory Status of Over-the-Counter Products

71

Review Panel

Report

Drug Category

ANPR

PR

FR

Miscellaneous external Topical analgesic Topical analgesic Allantoin (with aminobenzoic acid) Topical analgesic Allyl isothiocyanate Cough/cold

Corn/callus remover Skin protectant Skin protectant

Corn/callus remover Skin protectant Wound healing agent

IISE I IIIE

IISE I IIIE

[55 FR 33261] 347.10(a) 310.545(a)(18)(i)(A)

Sunscreen

Sunscreen

IIIE

IIIE

[64 FR 27682]

Cough/cold (nasal decongestant) External analgesic External analgesic

Nasal decongestant (topical/inhalant) Fever blister (topical) Counterirritant

IISE

IISE

310.545(a)(6)(ii)(A)

Defer I

IISE I

310.545(a)(10)(v) Pending

Digestive aid

Digestive aid (ippuad)

IIIE

n/a

310.545(a)(8)(ii)

Skin protectant Vaginal Laxative Menstrual/diuretic

Diaper rash Minor irritations Stimulant laxative Diuretic

n/a IIIE I n/a

Withdraw Withdraw I/IIIS IISE

n/a n/a 310.545(a)(12)(iv)(C) 310.545(a)(24)(i)

Laxative

Stimulant laxative

n/a

n/a

310.545(a)(12)(iv)(C)

Laxative

Stimulant laxative

n/a

n/a

310.545(a)(12)(iv)(C)

Gingivitis/plaque

Antiplaque/gingivitis

n/a

IIIE

Pending

====

====

====

====

====

====

====

====

====

====

Laxative

Stimulant laxative

IIISE

IIISE

310.545(a)(12)(iv)(A)

====

====

====

====

====

====

====

====

====

====

====

====

====

====

====

Vaginal External analgesic Skin protectant Astringent Oral health care

Astringent Astringent Astringent Astringent Astringent

IIIE IISE IISE I I

Withdraw n/a IISE Defer I

n/a Pending 310.545(a)(18)(ii) n/a Pending

Antifungal Antiperspirant Vaginal External analgesic Skin protectant Oral health care

Antifungal Antiperspirant Astringent Astringent Astringent Astringent

IIIE IIISE IIIE IISE IISE I

IIIE IIISE Withdraw n/a IISE I

310.545(a)(22)(ii) 310.545(a)(4) n/a Pending 310.545(18)(ii) Pending

Antifungal Antimicrobial External analgesic External analgesic Skin protectant Skin protectant

Diaper rash Diaper rash Astringent Diaper rash Astringent Diaper rash

Defer Defer I Defer I Defer

n/a n/a I n/a I IIISE

310.545(a)(22)(i) Pending 347.12(a) 310.545(a)(10)(iv) 347.10(a) Pending

====

====

====

====

====

Antiperspirant

Antiperspirant

IISE

IISE

310.545(a)(4)

====

====

====

====

====

Antacid

Antacid

I

I

331.11(a)(1)

====

====

====

====

====

Miscellaneous external Topical analgesic Almadrate sulfate Miscellaneous internal Aloe ==== Contraceptive/vaginal Laxative Miscellaneous internal Aloe extract ==== Aloe flower extract ==== Aloe vera [see aloe] ==== Aloe vera stabilized [see aloe] ==== Aloes [see aloe] ==== Aloin Laxative Alum (powdered alum) [see alum, ammonium/alum, potassium] ==== Alum [see alum, ammonium/alum, potassium] ==== Alum ammonium [see alum, ammonium] ==== Alum, ammonium Contraceptive/vaginal Miscellaneous external Miscellaneous external Oral cavity Oral cavity Alum, potassium Antimicrobial II Antiperspirant Contraceptive/vaginal Miscellaneous external Miscellaneous external Oral cavity Aluminum acetate Miscellaneous external Miscellaneous external Miscellaneous external Miscellaneous external Miscellaneous external Miscellaneous external Aluminum aspirin [see aspirin, aluminum] ==== Aluminum bromohydrate Antiperspirant Aluminum carbonate (gel) [see aluminum hydroxide] ==== Aluminum carbonate gel (basic) Antacid Aluminum carbonate gel [see basic aluminum carbonate gel] ====

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Handbook of Pharmaceutical Manufacturing Formulations: Over-the-Counter Products

Review Panel Aluminum chlorhydroxy complex Miscellaneous external Miscellaneous external Aluminum chloride (aerosol) (15% or less aqueous solution) Antiperspirant Aluminum chloride (alcoholic solutions) Antiperspirant Aluminum chloride (nonaerosol) (15% or less aqueous solution) Antiperspirant Aluminum chloride hexahydrate Miscellaneous external Aluminum chlorohydrate (aerosol) Antiperspirant Aluminum chlorohydrate (nonaerosol) Antiperspirant Aluminum chlorohydrex Antimicrobial II Aluminum chlorohydrex polyethylene glycol (aerosol) Antiperspirant t Aluminum chlorohydrex polyethylene glycol (nonaerosol) Antiperspirant Aluminum chlorohydrex polyethylene glycol complex [see name with “complex”] ==== Aluminum chlorohydrex polyplene glycol (aerosol) Antiperspirant Aluminum chlorohydrex polyplene glycol (nonaerosol) Antiperspirant Aluminum dichlorohydrate Antiperspirant Aluminum dichlorohydrate (nonaerosol) Antiperspirant Aluminum dichlorohydrex polyethylene glycol (aerosol) Antiperspirant Aluminum dichlorohydrex polyethylene glycol (nonaerosol) Antiperspirant Aluminum dichlorohydrex polyethylene glycol complex [see name with “complex”] ==== Aluminum dichlorohydrex propylene glycol (aerosol) Antiperspirant Aluminum dichlorohydrex propylene glycol (nonaerosol) Antiperspirant Aluminum dichlorohydrex propylene glycol complex [see name with “complex”] ==== Aluminum dihydroxy allantoinate [see aldioxa] ==== Aluminum hydroxide Antimicrobial II Antimicrobial II Antacid Laxative Miscellaneous external Miscellaneous external Miscellaneous external Miscellaneous external

Report

Drug Category

ANPR

PR

FR

External analgesic Skin protectant

Astringent Astringent

IISE IISE

n/a IISE

Pending 310.545(a)(18)(ii)

Antiperspirant

Antiperspirant

IIIS

IIIS

310.545(a)(4)

Antiperspirant

Antiperspirant

IIS

IIS

310.545(a) (4)

Antiperspirant

Antiperspirant

I

I

350.10(a)

External analgesic

Astringent

n/a

IIIE

Pending

Antiperspirant

Antiperspirant

IIIS

I

350.10(b)

Antiperspirant

Antiperspirant

I

I

350.10(b)

Acne

Acne

IIE

IIE

310.545(a)(1)

Antiperspiran

Antiperspirant

IIIS

I

350.10(c)

Antiperspirant

Antiperspirant

I

I

350.10(c)

====

====

====

====

====

Antiperspirant

Antiperspirant

IIIS

I

350.10(d)

Antiperspirant

Antiperspirant

I

I

350.10(d)

Antiperspirant

Antiperspirant

IIIS

I

350.10(e)

Antiperspirant

Antiperspirant

I

I

350.10(e)

Antiperspirant

Antiperspirant

IIIS

I

350.10(f)

Antiperspirant

Antiperspirant

I

I

350.10(f)

====

====

====

====

====

Antiperspirant

Antiperspirant

IIIS

I

350.10(g)

Antiperspirant

Antiperspirant

I

I

350.10(g)

====

====

====

====

====

====

====

====

====

====

Acne Antifungal Antacid Antidiarrheal Antifungal Antimicrobial External analgesic Skin protectant

Acne Acne Antacid Antidiarrheal Diaper rash Diaper rash Diaper rash Diaper rash

IIE IIE I IIIE Defer Defer Defer Defer

IIE IIE I IIIE n/a n/a n/a IIISE

310.545(a)(1) 310.545(a)(1) 331.11(a)(2) 310.545(a)(3)(i) 310.545(a)(22)(i) Pending 310.545(a)(10)(iv) 310.545(a)(18)(iii)

Current Regulatory Status of Over-the-Counter Products

73

Review Panel

Report

Drug Category

ANPR

PR

FR

Miscellaneous internal Miscellaneous internal

Digestive aid Overindulgence in alcohol/food

IIIE I

n/a I

310.545(a)(8)(ii) Pending

Topical analgesic Aluminum hydroxide (gel) [see aluminum hydroxide gel] ==== Aluminum hydroxide gel ====

Skin protectant

Digestive aid (ippuad) Overindulgence remedies (hangover) Skin protectant

I

I

347.10(b)

====

====

====

====

====

Skin protectant

n/a

I

347.10(b)

Hemorrhoidal

Anorectal

I

I

346.14(1)

Hemorrhoidal Internal analgesic Miscellaneous internal

Anorectal Internal analgesic Overindulgence in alcohol/food

I I I

I n/a I

346.14(1) n/a Pending

Topical analgesic Aluminum hydroxide sucrose powder hydrated Antacid Aluminum hydroxide-hexitol, stabilized polymer Antacid Aluminum hydroxide-magnesium carbonate, co-dried gel Antacid Aluminum hydroxide-magnesium trisilicate, co-dried gel Antacid Aluminum phosphate (gel) [see aluminum phosphate gel] ==== Aluminum phosphate gel Antacid Miscellaneous internal

Skin protectant

Poison ivy/oak/ sumac Protectant (intrarectal) Protectant (external) Corrective Overindulgence remedies (hangover) Skin protectant

I

I

347.10(b)

Antacid

Antacid

I

I

331.11(a)(2)

Antacid

Antacid

I

I

331.11(a)(2)

Antacid

Antacid

I

I

331.11(a)(2)

Antacid

Antacid

I

I

331.11(a)(2)

====

====

====

====

====

Antacid Hypophosphatemia/ hyperphosphatemia

Antacid Hypophosphatemia

I IIS

I IIS

331.11(i)(1) 310.541(a)

Antacid

Antacid

I

I

331.11(a)(4)

Antiperspirant

Antiperspirant

IIIS

I

350.10(h)

Antiperspirant

Antiperspirant

I

I

350.10(h)

Antiperspirant

Antiperspirant

I

I

350.10(j)

====

====

====

====

====

Antiperspirant

Antiperspirant

IIIS

I

350.10(i)

Antiperspirant

Antiperspirant

I

I

350.10(i)

Antifungal Antiperspirant External analgesic Skin protectant

Antifungal Antiperspirant Astringent Astringent

IIIE IIISE IIIE IIIE

IIIE IIISE n/a I

310.545(a)(22)(ii) 310.545(a)(4) Pending 347.12(b)

Antiperspirant

Antiperspirant

IIIS

IIIS

310.545(a)(4)(ii)

Antiperspirant

Antiperspirant

I

I

310.545(a)(4)(ii)

Antiperspirant

Antiperspirant

IIS

IIS

310.502(a)(2)

Aluminum phosphate gel (when used as part of antacid combination) Antacid Aluminum sesquichlorohydrate (aerosol) Antiperspirant Aluminum sesquichlorohydrate (nonaerosol) Antiperspirant Aluminum sesquichlorohydrate propylene glycol (nonaerosol) Antiperspirant Aluminum sesquichlorohydrate propylene glycol complex [see name without “complex”] ==== Aluminum sesquichlorohydrate poylethylene glycol (aerosol) Antiperspirant Aluminum sesquichlorohydrate poylethylene glycol (nonaerosol) Antiperspirant Aluminum sulfate Antimicrobial II Antiperspirant Miscellaneous external Miscellaneous external Aluminum sulfate, buffered (aerosol) Antiperspirant Aluminum sulfate, buffered (nonaerosol) Antiperspirant Aluminum zirconium octachlorohydrate (aerosol) Antiperspirant

74

Handbook of Pharmaceutical Manufacturing Formulations: Over-the-Counter Products

Review Panel Aluminum zirconium octachlorohydrate (nonaerosol) Antiperspirant Aluminum zirconium octachlorohydrex glycine (aerosol) Antiperspirant Aluminum zirconium octachlorohydrex glycine (nonaerosol) Antiperspirant Aluminum zirconium octachlorohydrex glycine complex [see name without “complex”] ==== Aluminum zirconium pentachlorohydrate (aerosol) Antiperspirant Aluminum zirconium pentachlorohydrate (nonaerosol) Antiperspirant Aluminum zirconium pentachlorohydrex glycine (aerosol) Antiperspirant Aluminum zirconium pentachlorohydrex glycine (nonaerosol) Antiperspirant Aluminum zirconium pentachlorohydrex glycine complex [see name without “complex”] ==== Aluminum zirconium tetrachlorohydrate (aerosol) Antiperspirant Aluminum zirconium tetrachlorohydrate (nonaerosol) Antiperspirant Aluminum zirconium tetrachlorohydrex glycine (aerosol) Antiperspirant Aluminum zirconium tetrachlorohydrex glycine (nonaerosol) Antiperspirant Aluminum zirconium tetrachlorohydrex glycine complex [see name without “complex”] ==== Aluminum zirconium trichlorohydrate (aerosol) Antiperspirant Aluminum zirconium trichlorohydrate (nonaerosol) Antiperspirant Aluminum zirconium trichlorohydrex glycine (aerosol) Antiperspirant Aluminum zirconium trichlorohydrex glycine (nonaerosol) Antiperspirant Aluminum zirconium trichlorohydrex glycine complex [see name without “complex”] ==== Aluminum sesquichlorohydrate propylene glycol (aerosol) Antiperspirant Aminacrine hydrochloride Miscellaneous external Amiloxate n/a Amino acids Miscellaneous external Aminoacetic acid [see glycine] ====

Report

Drug Category

ANPR

PR

FR

Antiperspirant

Antiperspirant

I

I

350.10(k)

Antiperspirant

Antiperspirant

IIS

IIS

310.502(a)(2)

Antiperspirant

Antiperspirant

I

I

350.10(1)

====

====

====

====

====

Antiperspirant

Antiperspirant

IIS

IIS

350.10(m)

Antiperspirant

Antiperspirant

I

I

350.10(m)

Antiperspirant

Antiperspirant

IIS

IIS

310.502(a)(2)

Antiperspirant

Antiperspirant

I

I

350.10(m)

====

====

====

====

====

Antiperspirant

Antiperspirant

IIS

IIS

310.502(a)(2)

Antiperspirant

Antiperspirant

I

I

350.10(o)

Antiperspirant

Antiperspirant

IIS

IIS

310.502(a)(2)

Antiperspirant

Antiperspirant

I

I

350.10(p)

====

====

====

====

====

Antiperspirant

Antiperspirant

IIS

IIS

310.502(a)(2)

Antiperspirant

Antiperspirant

I

I

350.10(q)

Antiperspirant

Antiperspirant

IIS

IIS

310.502(a)(2)

Antiperspirant

Antiperspirant

I

I

350.10(r)

====

====

====

====

====

Antiperspirant

Antiperspirant

IIIS

I

350.10(r)

Boil treatment

Boil treatment

IISE

IISE

310.531(a)

TEA

Sunscreen

n/a

Hair growth/loss

Hair grower

IISE

IIE

310.527(a)

====

====

====

====

====

Current Regulatory Status of Over-the-Counter Products

Review Panel Aminoacridine hydrochloride [see aminacrine hydrochloride] ==== Aminobenzoic acid Internal analgesic Internal analgesic Internal analgesic Miscellaneous external Aminobenzoic acid (PABA) Topical analgesic Aminophylline Cough/cold Ammonia Miscellaneous external Miscellaneous external Ammonia solution, strong Miscellaneous external Miscellaneous external Topical analgesic Topical analgesic Ammonium alum [see alum, ammonium] ==== Ammonium bromide Sedative Sedative Ammonium carbonate Miscellaneous external Miscellaneous external Ammonium chloride Cough/cold Miscellaneous internal Oral cavity Sedative Ammonium hydroxide Miscellaneous external Miscellaneous external Amyl para-dimethylaminobenzoate [see padimate A] ==== Amylase Miscellaneous internal Amyltricresols, secondary Antimicrobial II Oral cavity Amylum [see starch] ==== Amyltricresol, secondary [see amyltricresols, secondary] ==== Anion and cation exchange resins buffered Miscellaneous external Miscellaneous external Anise Miscellaneous internal Anise oil Miscellaneous internal Anise seed Miscellaneous internal Antimony potassium tartrate Cough/cold

75

Report

Drug Category

ANPR

PR

FR

====

====

====

====

====

Internal analgesic Internal analgesic Internal analgesic

IISE IISE IISE

IISE IISE n/a

310.545(a)(23)(i) 310.545(a) (23)(i) 310.545(a) (23)(i)

Hair growth/loss

Analgesic adjuvant Antipyretic adjuvant Antirheumatic adjuvant Hair grower

n/a

IIE

310.527(a)

Sunscreen

Sunscreen

I

I

352.10(b)

Cough/cold (bronchodilator)

Bronchodilator

I

IIS

310.545(a)(6)(iv)(A)

Skin protectant External analgesic

Fever blister (topical) Fever blister (topical)

Defer Defer

n/a n/a

Pending Pending

External analgesic Skin protectant External analgesic External analgesic

Insect bite/sting Insect bite/sting Counterirritant Fever blister (topical)

IISE IISE I n/a

IISE IISE I IISE

310.545(a)(18)(v)(A) 310.545(a)(18)(v) Pending 310.545(a)(10)(v)

====

====

====

====

====

Daytime sedative Nighttime sleep aid

Sedative Sleep aid

IISE IISE

IISE IISE

310.519(a) [54 FR 6826]

External analgesic Skin protectant

Fever blister (topical) Fever blister (topical)

Defer Defer

n/a n/a

Pending Pending

Cough/cold (expectorant) Menstrual/diuretic Oral health care Stimulant

Expectorant

IIIE

IIIE

310.545(a)(6)(iii)

Diuretic Expectorant Stimulant

I IIIE IIE

I IIIE IIE

Pending 310.545(a)(6)(iii) [39 FR 6104]

External analgesic Skin protectant

Insect bite/sting Insect bite/sting

IIIE IIIE

IIIE IIISE

310.545(a)(18)(v)(A) 310.545(a)(18)(v)(A)

====

====

====

====

====

Digestive aid

Digestive aid (intestinal distress)

n/a

n/a

310.545(a)(8)(ii)

Antifungal Oral health care

Antifungal Antimicrobial

IIISE IIISE

IIISE IIISE

310.545(a)(22)(ii) Pending

====

====

====

====

====

====

====

====

====

====

External analgesic

Poison ivy/oak/ sumac Poison ivy/oak/ sumac

IIIE

IIIE

Pending

IIIE

IIIE

310.545(a)(10)(vii)(A)

Aphrodisiac

Aphrodisiac

n/a

n/a

310.528(a)

Weight control

Anorectic

IISE

IISE

310.545(a)(20)

Digestive aid

Digestive aid (ippuad)

n/a

n/a

310.545(a)(18)(ii)

Cough/cold (expectorant)

Expectorant

IISE

IISE

310.545(a)(6)(iii)

Skin protectant

76

Handbook of Pharmaceutical Manufacturing Formulations: Over-the-Counter Products

Review Panel Antipyrine Internal analgesic Internal analgesic Internal analgesic Oral cavity Ophthalmic Topical analgesic Aqua ammonia [see ammonium solution, strong] ==== Aqueous coconut oil soap [see coconut oil soap, aqueous] ==== Arginine Miscellaneous internal Aromatic oils Miscellaneous external Miscellaneous external Miscellaneous external Miscellaneous external Miscellaneous external Miscellaneous external Aromatic powder Miscellaneous internal Aromatics Miscellaneous external Miscellaneous external Asafetida Miscellaneous internal Asclepias tuberosa Miscellaneous internal Ascorbic acid Miscellaneous external Miscellaneous external Miscellaneous external Miscellaneous internal Asparagus Miscellaneous internal Aspergillus oryzae enzymes (except lactase enzyme from aspergillus oryzae) Miscellaneous internal Aspirin ==== ====

Report

Drug Category

ANPR

PR

FR

Internal analgesic Internal analgesic Internal analgesic Oral health care Ophthalmic Otic

Analgesic Antipyretic Antirheumatic Analgesic/anesthetic Analgesic/anesthetic Analgesic/anesthetic

IIISE IIISE IIISE IISE IIS IISE

IIISE IIISE not OTC IISE IIS IISE

310.545(a)(23)(i) 310.545(a)(23)(i) 310.545(a)(23)(i) 310.545(a)(14) 310.545(a)(21)(i) [51 FR 28660]

====

====

====

====

====

====

====

====

====

====

Weight control

Anorectic

IISE

IISE

310.545(a)(20)

Antifungal Antimicrobial External analgesic External analgesic Skin protectant Skin protectant

Diaper rash Diaper rash Diaper rash Fever blister (topical) Diaper rash Fever blister (topical)

Defer Defer Defer Defer Defer Defer

n/a n/a n/a n/a n/a n/a

310.545(a)(22)(i) Pending 310.545(a)(10)(iv) Pending Pending Pending

Digestive aid

Digestive aid (ippuad)

n/a

n/a

310.545(a)(18)(ii)

External analgesic Skin protectant

Astringent Astringent

IISE IISE

n/a IISE

Pending 310.545(a)(18)(ii)

Digestive aid

Digestive aid (ippuad)

n/a

n/a

310.545(a)(18)(ii)

Menstrual/diuretic

Dysmenorrhea

IISE

IISE

310.545(a)(24)(i)

Hair growth/loss Wart remover Corn/callus remover Weight control

Hair grower Wart remover Corn/callus remover Anorectic

IIIE IIIE IISE IISE

IIIE IIIE IISE IISE

310.527(a) [55 FR 33254] [55 FR 33261] 310.545(a)(20)

Menstrual/diuretic

Diuretic

n/a

IISE

310.545(a)(24)(i)

Digestive aid

Digestive aid (intestinal distress)

n/a

n/a

310.545(a)(18)(ii)

External analgesic External analgesic

n/a n/a

IIIE IIIE

310.545(a)(10)(v) 310.545(a)(10)(vii)

I I I I I

I I not OTC I I

Pending Pending n/a Pending Pending

I IIE IIE IIIE

IIIE IISE IIE IIIE

Pending 310.519(a) [54 FR 6826] 310.545(a)(10)(i)

Internal analgesic Internal analgesic Internal analgesic Miscellaneous internal Miscellaneous internal

Internal analgesic Internal analgesic Internal analgesic Menstrual/diuretic Overindulgence in alcohol/food

Oral cavity Sedative Sedative Topical analgesic Aspirin, aluminum Internal analgesic Internal analgesic Internal analgesic Aspirin, calcium Internal analgesic Internal analgesic Internal analgesic Miscellaneous internal

Oral health care Daytime sedative Nighttime sleep aid External analgesic

Fever blister (topical) Poison ivy/oak/ sumac Analgesic Antipyretic Antirheumatic Analgesic Overindulgence remedies (hangover) Analgesic/anesthetic Sedative Sleep aid Analgesic/anesthetic

Internal analgesic Internal analgesic Internal analgesic

Analgesic Antipyretic Antirheumatic

n/a IIIE IIIE

IISE IIIE Not OTC

310.545(a)(23)(i) 310.545(a)(23)(i) 310.545(a)(23)(i)

Internal analgesic Internal analgesic Internal analgesic Menstrual/diuretic

Analgesic Antipyretic Antirheumatic Analgesic

I I I I

I I Not OTC I

Pending Pending n/a Pending

Current Regulatory Status of Over-the-Counter Products

77

Review Panel

Report

Drug Category

ANPR

PR

FR

Atropine ==== ==== Hemorrhoidal

Menstrual/diuretic Internal analgesic Anorectal

n/a n/a IISE

n/a n/a IISE

310.545(a)(24)(ii) 310.545(a)(23)(ii) 310.545(a)(26)(i)

Hemorrhoidal

Anorectal

Menstrual Analgesic Anticholinergic (external) Anticholinergic (intrarectal)

IISE

IISE

310.545(a)(26)(i)

Cough/cold (anticholinergic) Antidiarrheal

Anticholinergic

IIIE

IIIE

310.533(a)

Antidiarrheal

IIISE

IIISE

310.545(a)(3)(i)

Antidiarrheal

Antidiarrheal

IIIE

I

310.545(a)(3)(ii)

n/a

Sunscreen

n/a

1

352.10(a)

Digestive aid

Digestive aid (intestinal distress)

n/a

n/a

310.545(a)(18)(ii)

Antibiotic Antibiotic

First aid antibiotic Skin wound antibiotic

n/a IIIE

I Defer

333.110(a) n/a

Antibiotic

First aid antibiotic

n/a

I

333.110(b)

====

====

====

====

====

====

====

====

====

====

Menstrual/diuretic

Diuretic

n/a

IISE

310.545(a)(24)(i)

Hypophosphatemia/ hyperphosphatemia

Hyperphosphatemia

IIS

IIS

310.541(a)

Antifungal

Antifungal

IIISE

IIISE

310.545(a)(22)(ii)

Digestive aid

Digestive aid (ippuad)

n/a

n/a

310.545(a)(18)(ii)

Weight control

Anorectic

IISE

IISE

310.545(a)(20)

Menstrual/diuretic

Diuretic

n/a

IISE

310.545(a)(24)(i)

Menstrual/diuretic

Diuretic

n/a

IISE

310.545(a)(24)(i)

Insect bite/sting Poison ivy/oak/sumac

Insect bite/sting Poison ivy/oak/ sumac Diaper rash Diaper rash Diaper rash Fever blister (topical) Diaper rash Fever blister (topical)

n/a n/a

n/a n/a

310.545(a)(18)(v)(B) 310.545(a)(18)(vi)(B)

Defer Defer Defer Defer Defer Defer

n/a n/a n/a n/a n/a n/a

310.545(a)(22)(i) Pending 310.545(a)(10)(iv) Pending 310.545(a)(18)(i)(B) Pending

Cough/cold (bronchodilator) Cough/cold (anticholinergic) Corn/callus remover Digestive aid

Bronchodilator (inhalation) Anticholinergic

IISE

IISE

310.545(a)(6)(iv)(A)

IIIE

IIIE

310.533(a)

Corn/callus remover Digestive aid (ippuad)

IISE n/a

IISE n/a

[55 FR 33261] 310.545(a)(18)(ii)

Cough/cold (anticholinergic)

Anticholinergic

IISE

IISE

310.533(a)

Belladonna extract Hemorrhoidal

Anorectal

IISE

IISE

310.545(a)(26)(i)

Hemorrhoidal

Anorectal

Anticholinergic (intrarectal) Anticholinergic (external)

IISE

IISE

310.545(a)(26)(i)

Atropine sulfate Cough/cold Laxative Attapulgite, activated Laxative Avobenzone ==== Bacillus acidophilus Miscellaneous internal Bacitracin Antimicrobial II Antimicrobial II Bacitracin zinc Antimicrobial II Balsam Peru [see Peruvian balsam] ==== Balsam Peru oil [see Peruvian balsam oil] ==== Barosma Miscellaneous internal Basic aluminum carbonate gel Miscellaneous internal Basic fuchsin Antimicrobial II Bean Miscellaneous internal Bearberry Miscellaneous internal Bearberry (extract of uva ursi) Miscellaneous internal Bearberry fluidextract (extract of bearberry) Miscellaneous internal Beeswax ==== ==== Miscellaneous external Miscellaneous external Miscellaneous external Miscellaneous external Miscellaneous external Miscellaneous external Belladonna alkaloids Cough/cold Cough/cold Miscellaneous external Miscellaneous internal Belladonna alkaloids (inhalation) atropa belladonna/datura stramonium Cough/cold

Antifungal Antimicrobial External analgesic External analgesic Skin protectant Skin protectant

78

Handbook of Pharmaceutical Manufacturing Formulations: Over-the-Counter Products

Review Panel Belladonna leaves, powdered extract Miscellaneous internal Bemotrizinol n/a Benzalkonium chloride Antimicrobial I Antimicrobial I Antimicrobial I Antimicrobial I Antimicrobial I Antimicrobial I Antimicrobial I Contraceptive/vaginal Miscellaneous external Miscellaneous external Miscellaneous external

Report

Drug Category

ANPR

PR

FR

Digestive aid

Digestive aid (ippuad)

n/a

n/a

310.545(a)(18)(ii)

TEA

Sunscreen

n/a

Antimicrobial Antimicrobial Antimicrobial Antimicrobial Antimicrobial Antimicrobial

Antimicrobial soap First aid antiseptic Preoperative skin prep Skin antiseptic Skin wound cleanser Skin wound protectant Surgical hand scrub Minor irritations Diaper rash Diaper rash Dandruff

n/a n/a IIISE IIISE I IIISE

IISE I IIISE IIISE I IIISE

Pending Pending Pending Pending Pending Pending

IIISE IIISE Defer Defer IIIE

IIISE Withdraw n/a IIISE IIIE

Pending n/a 310.545(a)(22)(i) Pending 310.545(a)(7)

Astringent Fever blister (topical) Insect bite/sting Astringent Diaper rash Fever blister (topical) Insect bite/sting Diaper rash

IISE Defer IISE IISE Defer Defer IISE Defer

n/a n/a IISE IISE n/a n/a IISE n/a

Pending Pending 310.545(a)(10)(vi) 310.545(a)(18)(ii) Pending Pending 310.545(a)(18)(v)(A) 310.545(a)(10)(iv)

First aid antiseptic Surgical hand scrub Skin antiseptic Skin wound cleanser Skin wound protectant Antimicrobial soap Preoperative skin prep Health care personnel handwash Antifungal Diaper rash Dandruff/cradle cap

n/a IIISE IIISE I IIISE

I IIISE IIISE I IIISE

Pending Pending Pending Pending Pending

n/a IISE IIIE

IISE IISE IIIE

Pending Pending Pending

IIISE Defer IIIE

IIISE IISE IIIE

310.545(a)(22)(ii) 310.545(a)(22)(i) 310.545(a)(7)

Astringent Poison ivy/oak/ sumac Astringent Diaper rash Poison ivy/oak/ sumac Diaper rash Diaper rash Antimicrobial

IISE Defer

n/a IISE

310.545(a)(18)(ii) 310.545(a)(10)(vii)

IISE Defer Defer

IISE n/a IISE

310.545(a)(18)(ii) Pending 310.545(a)(10)(vii)(A)

Defer Defer IIISE

n/a n/a IIISE

310.545(a)(22)(i) 310.545(a)(10)(iv) Pending

IISE IIIE I

IISE Withdraw I

310.545(a)(1) n/a Pending

Antimicrobial Vaginal Antifungal Antimicrobial Dandruff/seborrheic dermatitis/psoriasis External analgesic External analgesic External analgesic Skin protectant Skin protectant Skin protectant Skin protectant External analgesic

Miscellaneous external Miscellaneous external Miscellaneous external Miscellaneous external Miscellaneous external Miscellaneous external Miscellaneous external Miscellaneous external Benzethonium chloride Antimicrobial I Antimicrobial I Antimicrobial I Antimicrobial I Antimicrobial I

Antimicrobial Antimicrobial Antimicrobial Antimicrobial Antimicrobial

Antimicrobial I Antimicrobial I Antimicrobial I

Antimicrobial Antimicrobial Antimicrobial

Antimicrobial II Miscellaneous external Miscellaneous external Miscellaneous external Miscellaneous external

Antifungal Antifungal Dandruff/seborrheic dermatitis/psoriasis External analgesic External analgesic

Miscellaneous external Miscellaneous external Miscellaneous external

Skin protectant Skin protectant Skin protectant

Miscellaneous external Miscellaneous external Oral cavity Benzocaine Antimicrobial II Contraceptive/vaginal Dental

External analgesic External analgesic Oral health care Acne Vaginal Relief of oral discomfort

Dental Hemorrhoidal

Relief of oral discomfort Anorectal

Hemorrhoidal Miscellaneous external Miscellaneous external Miscellaneous external Miscellaneous external

Anorectal Antifungal Antimicrobial Boil treatment Dandruff/seborrheic dermatitis/psoriasis External analgesic External analgesic

Miscellaneous external Miscellaneous external

Acne Minor irritations Oral mucosal analgesic Toothache relief Anesthetic (intrarectal) Anesthetic (external) Diaper rash Diaper rash Boil treatment Psoriasis

IIIE IIIE

IIIE IIIE

Pending [55 FR 1779]

I Defer Defer IISE IIE

I n/a n/a IIISE IIE

346.10(a) 310.545(a)(22)(i) Pending 310.531(a) [56 FR 63567]

Astringent Diaper rash

IISE Defer

n/a IISE

Pending 310.545(a)(10)(iv)

Current Regulatory Status of Over-the-Counter Products

Review Panel

Report

Drug Category

ANPR

PR

FR

Miscellaneous external Miscellaneous external Miscellaneous external

I IIIE I

Pending Pending 348.10(a)(1)

Defer

I

Pending

Miscellaneous external Miscellaneous external Miscellaneous external Miscellaneous external Miscellaneous external Miscellaneous external

External analgesic Pediculicide Skin protectant Skin protectant Skin protectant Skin protectant

Defer IISE IISE Defer Defer Defer

IIIE IISE IISE n/a DEF n/a

IISE (0.5–1.25%) 310.545(a)(25)(i) 310.545(a)(18)(ii) Pending Pending 310.545(a)(10)(vii)

Miscellaneous external Miscellaneous internal Oral cavity Topical analgesic Topical analgesic Topical analgesic

Wart remover Weight control Oral health care External analgesic Otic External analgesic

Fever blister (topical) Insect bite/sting Male genital desensitizer Poison ivy/oak/ sumac Poison/ivy/oak/sumac Pediculicide Astringent Diaper rash Fever blister (topical) Poison ivy/oak/ sumac Wart remover Anorectic Analgesic/anesthetic Analgesic/anesthetic Analgesic/anesthetic Poison ivy/oak/ sumac

Defer n/a I

Miscellaneous external

External analgesic External analgesic Male genital desensitizer External analgesic

IISE I I I IISE IIIE

IISE IISE I I IISE n/a

[55 FR 33254] Pending Pending Pending [51 FR 28660] 310.545(a)(10)(vii)

Benzoic acid Antimicrobial II Antimicrobial II Miscellaneous external Miscellaneous external Miscellaneous external Oral cavity Benzoin tincture, compound Cough/cold Dental Benzoin, tincture Cough/cold Benzonatate Cough/cold

Acne Antifungal External analgesic Hair growth/loss Skin protectant Oral health care

Acne Antifungal Astringent Hair grower Astringent Antimicrobial

IIE IIIE IISE IIE IISE IIIE

IIE IIIE n/a IIE IISE IIIE

310.545(a)(1) 310.545(a)(22)(ii) n/a 310.527(a) 310.545(a)(18)(ii) Pending

Cough/cold (expectorant) Relief of oral discomfort

Expectorant (topical/inhalant) Oral mucosal protectant

IIIE

IIIE

310.545(a)(6)(iii)

I

I

Pending

Cough/cold (expectorant)

Expectorant

n/a

n/a

310.545(a)(6)(iii)

Cough/cold (antitussive)

Antitussive

n/a

I

310.533(a)

Antifungal

Antifungal

IISE

IISE

310.545(a)(22)(ii)

79

Benzoxiquine Antimicrobial II Benzoyl peroxide Antimicrobial II Benzyl alcohol Dental Dental

Acne

Acne

I

I

Pending

Relief of oral discomfort Relief of oral discomfort

IIISE IIISE

IIISE I

Pending Pending

Hemorrhoidal Hemorrhoidal

Anorectal Anorectal

IIIE IIIE

I IIIE

346.10(b) [55 FR 1779]

Miscellaneous external Miscellaneous external Miscellaneous external

IIE Defer IISE

Defer I IISE

n/a Pending 310.545(a)(10)(iii)

Miscellaneous external

Alcohols (topical) External analgesic Male genital desensitizer External analgesic

Defer

I

Pending

Miscellaneous external Miscellaneous external

Pediculicide Skin protectant

IISE Defer

IISE IISE

310.545(a)(25)(i) 310.545(a)(10)(vii)(A)

Oral cavity Topical analgesic Benzyl benzoate Miscellaneous external Betaine hydrochloride Miscellaneous internal

Oral health care External analgesic

Toothache relief Oral mucosal analgesic Anesthetic (external) Anesthetic (intrarectal) Antiseptic Fever blister (topical) Male genital desensitizer Poison ivy/oak/ sumac Pediculicide Poison ivy/oak/ sumac Analgesic/anesthetic Analgesic/anesthetic

I I

I I

Pending Pending

Pediculicide

Pediculicide

IISE

IISE

310.545(a)(25)(i)

Digestive aid

n/a

n/a

310.545(a)(18)(ii)

Stomach acidifier

Digestive aid (intestinal distress) Stomach acidifier

IIE

IIE

310.540(a)

Antacid

Antacid

n/a

n/a

331.11(b)

Miscellaneous internal Bicarbonate Antacid

80

Handbook of Pharmaceutical Manufacturing Formulations: Over-the-Counter Products

Review Panel Bicarbonate of soda [see sodium bicarbonate] ==== Bile salts/acids Laxative Biotin Miscellaneous external Miscellaneous internal Bisacodyl Laxative Bismuth aluminate Antacid Bismuth carbonate Antacid Bismuth oxide Hemorrhoidal Hemorrhoidal Bismuth sodium tartrate Miscellaneous external Miscellaneous external Miscellaneous internal Bismuth subcarbonate Antacid Hemorrhoidal Hemorrhoidal Miscellaneous external Miscellaneous external Miscellaneous external Miscellaneous internal Bismuth subgallate Antacid Hemorrhoidal Hemorrhoidal Miscellaneous internal Miscellaneous internal Bismuth subnitrate ==== ==== ==== ==== Antacid Hemorrhoidal Laxative Miscellaneous external Miscellaneous external Miscellaneous external Miscellaneous external Miscellaneous external Miscellaneous external Topical analgesic Bismuth subsalicylate Laxative Laxative Miscellaneous internal Bisoctrizole n/a Bithionol Miscellaneous external Miscellaneous external Black radish powder Miscellaneous internal Blessed thistle (cnicus benedictus) Miscellaneous internal Miscellaneous internal

Report

Drug Category

ANPR

PR

FR

====

====

====

====

====

Laxative

Stimulant laxative

IIISE

IIISE

310.545(a)(12)(iv)(A)

Hair growth/loss Weight control

Hair grower Anorectic

n/a IISE

IISE IISE

310.527(a) 310.545(a)(20)

Laxative

Stimulant laxative

I

I/IIIS

Pending

Antacid

Antacid

I

I

331.11(c)(1)

Antacid

Antacid

I

I

331.11(c)(2)

Anorectal Anorectal

Protectant (external) Protectant (intrarectal)

IIIE IIIE

IIIE IIIE

310.545(a)(26)(viii) 310.545(a)(26)(viii)

External analgesic Skin protectant Digestive aid

Fever blister (topical) Fever blister (topical) Digestive aid (intestinal distress)

Defer Defer IISE

IIISE Defer IISE

310.545(a)(10)(v) Pending 310.545(a)(8)(i)

Antacid Anorectal Anorectal Antifungal Antimicrobial Skin protectant Digestive aid

Antacid Protectant (intrarectal) Protectant (external) Diaper rash Diaper rash Diaper rash Digestive aid (ippuad)

I IIIE IIIE Defer Defer Defer n/a

I IIIE IIIE n/a n/a n/a n/a

331.11(c)(3) 310.545(a)(26)(viii) 310.545(a)(26)(viii) 310.545(a)(22)(i) Pending Pending 310.545(a)(18)(ii)

Antacid Anorectal Anorectal Deodorants for internal use Digestive aid

Antacid Protectant (external) Protectant (intrarectal) Internal deodorant

I IIIE IIIE IIIE

I IIIE IIIE I

331.11(c)(4) 310.545(a)(26)(viii) 310.545(a)(26)(viii) 357.810(a)

Digestive aid (ippuad)

n/a

n/a

310.545(a)(18)(ii)

Insect bite/sting Poison ivy/oak/sumac Skin protectant Skin protectant Antacid Anorectal Antidiarrheal Anorectal Antifungal Antimicrobial Boil treatment External analgesic Skin protectant Skin protectant

Insect bite/sting Poison ivy/oak/sumac Fever blister (topical) Poison ivy/oak/sumac Antacid Protectant (external) Antidiarrheal Protectant (intrarectal) Diaper rash Diaper rash Boil treatment Diaper rash Diaper rash Skin protectant

n/a n/a n/a n/a I IIS IIISE IIS Defer Defer IISE Defer Defer IISE

n/a n/a IISE IISE I IIS IIISE IIS n/a n/a IISE n/a IISE IISE

310.545(a)(18)(v)(B) 310.545(a)(18)(vi)(B) 310.545(a)(10)(iv) 310.545(a)(10)(vii)(A) 331.11(c)(5) 310.545(a)(26)(viii) Pending 310.545(a)(26)(viii) 310.545(a)(22)(i) Pending 310.531(a) 310.545(a)(10)(iv) Pending Pending

Antidiarrheal Antiemetic Overindulgence in alcohol/food

Antidiarrheal Antiemetic Upset stomach

IIIE IIIE I

IIIE IIIE I

335.10(a) Defer (overindulgence) Pending

TEA

Sunscreen

n/a

External analgesic Skin protectant

Poison ivy/oak/sumac Poison ivy/oak/sumac

Defer Defer

IISE IISE

310.545(a)(10)(vii) 310.545(a)(18)(vi)(A)

Digestive aid

Digestive aid (intestinal distress)

n/a

n/a

310.545(a)(18)(ii)

Digestive aid Menstrual/diuretic

Digestive aid (intestinal distress) Menstrual

n/a n/a

n/a IISE

310.545(a)(18)(ii) 310.545(a)(24)(i)

Current Regulatory Status of Over-the-Counter Products

Review Panel Bone marrow, red Miscellaneous internal Borax [see sodium borate] ==== Boric acid ==== ==== ==== ==== Antimicrobial II Antimicrobial II Contraceptive/vaginal Contraceptive/vaginal Contraceptive/vaginal Contraceptive/vaginal Hemorrhoidal Hemorrhoidal Miscellaneous external Miscellaneous external Miscellaneous external Miscellaneous external Miscellaneous external Miscellaneous external Miscellaneous external Oral cavity Ophthalmic Topical analgesic Bornelone Topical analgesic Bornyl acetate Cough/cold Boroglycerin Contraceptive/vaginal Contraceptive/vaginal Contraceptive/vaginal Contraceptive/vaginal Hemorrhoidal Hemorrhoidal Oral cavity Boroglycerin glycerite [see boroglycerin] ==== Bran Laxative Bran, dietary [see bran] ==== Bran, tablets [see bran] ==== Bromopheniramine maleate Cough/cold Buchu Miscellaneous internal Buchu powdered extract (extract of buchu) Miscellaneous internal Buchu, extract Miscellaneous internal Buckthorn Miscellaneous internal Buffered mixture anion/cation exchange resin [see anion/cation exchange resins] ====

81

Report

Drug Category

ANPR

PR

FR

Weight control

Anorectic

IISE

IISE

310.545(a)(20)

====

====

====

====

====

Insect bite/sting Poison ivy/oak/sumac Skin protectant Skin protectant Acne Antifungal Vaginal Vaginal Vaginal Vaginal Anorectal Anorectal Antifungal Antimicrobial Dandruff/seborrheic dermatitis/psoriasis External analgesic External analgesic Skin protectant Skin protectant Oral health care Ophthalmic Skin protectant

Insect bite/sting Poison ivy/oak/sumac Fever blister (topical) Poison ivy/oak/sumac Acne Antifungal Astringent Alters vaginal pH Lowers surface tension mucolytic effects Minor irritations Antiseptic (external) Antiseptic (intrarectal) Diaper rash Diaper rash Dandruff/seborrheic dermatitis

n/a n/a n/a n/a IIE IIIE IIISE IIISE IIISE IIISE IISE IISE Defer Defer IISE

n/a n/a IISE IISE IIE IIIE Withdraw Withdraw Withdraw Withdraw IISE IISE IISE IISE IISE

310.545(a)(18)(v)(B) 310.545(a)(18)(vi)(B) 310.545(a)(18)(iv) 310.545(a)(10)(vii)(A) 310.545(a)(1) 310.545(a)(22)(ii) n/a n/a n/a n/a 310.545(a)(26)(ii) 310.545(a)(26)(ii) 310.545(a)(22)(ii) Pending 310.545(a)(7)

Astringent Diaper rash Astringent Diaper rash Antimicrobial Anti-infective Skin protectant

IISE Defer IISE Defer IISE IIIE IISE

n/a n/a IISE IIS IISE IIE IISE

Pending 310.545(a)(10)(iv) 310.545(a)(18)(ii) Pending Pending 310.545(a)(21)(ii) 310.545(a)(18)(i)(B)

Sunscreen

Sunscreen

IIIE

IIIE

[64 FR 27682]

Cough/cold (nasal decongestant)

Nasal decongestant (topical)

IIIE

IIIE

310.545(a)(6)(ii)(B)

Vaginal Vaginal Vaginal Vaginal Anorectal Anorectal Oral health care

Minor irritations Alters vaginal pH Astringent Lowers surface tension mucolytic effects Antiseptic (external) Antiseptic (intrarectal) Antimicrobial

IIISE IIISE IIISE IIISE IISE IISE IISE

Withdraw Withdraw Withdraw Withdraw IISE IISE IISE

n/a n/a n/a n/a 310.545(a)(26)(ii) 310.545(a)(26)(ii) Pending

====

====

====

====

====

Laxative

Bulk laxative

I

I

Pending

====

====

====

====

====

====

====

====

====

====

Cough/cold (antihistamine)

Antihistamine

I

I

341.12(a)

Weight control

Anorectic

IISE

IISE

310.545(a)(20)

Menstrual/diuretic

Diuretic

n/a

IISE

310.545(a)(24)(i)

Weight control

Anorectic

IISE

IISE

310.545(a)(20)

Digestive aid

Digestive aid (intestinal distress)

n/a

n/a

310.545(a)(18)(ii)

====

====

====

====

====

82

Handbook of Pharmaceutical Manufacturing Formulations: Over-the-Counter Products

Review Panel

Report

Drug Category

ANPR

PR

FR

Butacaine sulfate Dental

Relief of oral discomfort

Oral mucosal analgesic Toothache relief

I

I

Pending

IIISE

IIISE

Pending

n/a n/a

I I

Pending Pending

I

I

Pending

Dental Butamben picrate ==== ====

Relief of oral discomfort

Topical analgesic Butylated hydroxyanisole ==== ==== Caffeine Cough/cold

External analgesic

Fever blister (topical) Poison ivy/oak/ sumac Analgesic/anesthetic

External analgesic Skin protectant

Fever blister (topical) Fever blister (topical)

n/a n/a

n/a n/a

Pending Pending

Cough/cold (miscellaneous) Internal analgesic Internal analgesic Internal analgesic

Corrective

IIIE

IIIE

Pending

Analgesic adjuvant Antipyretic adjuvant Antirheumatic adjuvant Analgesic adjuvant Diuretic Overindulgence remedies (hangover) Anorectic Stimulant

IIIE IIIE IIIE

IIIE IIIE n/a

Pending Pending Pending

IIIE I I

IIIE I I

Pending Pending Pending

IISE I

IISE I

310.545(a)(20) 340.10

I I

I I

346.18(a) 346.18(a)

I

I

346.14(b)(1)

I Defer Defer Defer IISE Defer

I n/a n/a n/a IISE IISE

346.14(b)(1) 310.545(a)(22)(ii) Pending 310.545(a)(10)(iv) 310.545(a)(10)(vi) 310.545(a)(10)(vii)

I Defer IISE Defer

I I IISE I

347.10(c) Pending 310.545(a)(10)(vi) 347.10(c)

I

I

347.10(c)

I

I

346.14(b)(1)

Anorectal

Protectant (intrarectal) Protectant (external)

I

I

346.14(b)(1)

Weight control

Anorectic

IISE

IISE

310.545(a)(20)

Skin protectant External analgesic

Astringent Astringent

IISE IISE

IISE n/a

310.545(a)(18)(ii) Pending

====

====

====

====

====

Antacid Digestive aid Weight control

Antacid Digestive aid (ippuad) Anorectic

I IIIE IISE

I IIIE IISE

331.11(d) 310.545(a)(8)(i) 310.545(a)(20)

Antidiarrheal Antifungal Antimicrobial External analgesic Skin protectant

Antidiarrheal Diaper rash Diaper rash Diaper rash Diaper rash

IIIE Defer Defer Defer Defer

IIIE n/a n/a n/a n/a

310.545(a)(3) 310.545(a)(22)(i) Pending 310.545(a)(10)(iv) Pending

Weight control

Anorectic

IISE

IISE

310.545(a)(20)

Internal analgesic Internal analgesic Internal analgesic

External analgesic External analgesic

Miscellaneous internal Miscellaneous internal Miscellaneous internal

Menstrual/diuretic Menstrual/diuretic Overindulgence in alcohol/food

Miscellaneous internal Sedative Calamine Hemorrhoidal Hemorrhoidal

Weight control Stimulant

Hemorrhoidal

Anorectal

Hemorrhoidal Miscellaneous external Miscellaneous external Miscellaneous external Miscellaneous external Miscellaneous external

Anorectal Antifungal Antimicrobial External analgesic External analgesic External analgesic

Miscellaneous external Miscellaneous external Miscellaneous external Miscellaneous external

Skin protectant Skin protectant Skin protectant Skin protectant

Topical analgesic Calamine (in combination only) Hemorrhoidal

Skin protectant

Hemorrhoidal Calcium Miscellaneous internal Calcium acetate ==== Miscellaneous external Calcium carbaspirin [see carbaspirin calcium] ==== Calcium carbonate Antacid Miscellaneous internal Miscellaneous internal Calcium carbonate, precipitated Laxative Miscellaneous external Miscellaneous external Miscellaneous external Miscellaneous external Calcium casinate Miscellaneous internal

Anorectal Anorectal

Anorectal

Astringent (external) Astringent (intrarectal) Protectant (intrarectal) Protectant (external) Diaper rash Diaper rash Diaper rash Insect bite/sting Poison ivy/oak/ sumac Skin protectant Diaper rash Insect bite/sting Poison ivy/oak/ sumac Skin protectant

Current Regulatory Status of Over-the-Counter Products

Review Panel Calcium gluconate Miscellaneous internal Calcium hydroxide Laxative Calcium iodide, anhydrous Cough/cold Calcium lactate Miscellaneous internal Miscellaneous internal Calcium pantothenate Laxative Miscellaneous external Miscellaneous internal Miscellaneous internal Calcium phosphate Antacid Calcium phosphate, dibasic Dental Internal analgesic Calcium phosphate, tribasic Antacid Calcium polysulfide Antimicrobial II Calcium propionate Contraceptive/vaginal Calcium salicylate Internal analgesic Internal analgesic Calcium salt (mono or dibasic) Antacid Calcium silicate Miscellaneous external Miscellaneous external Calcium sucrose phosphate Dental Calcium thiosulfate Antimicrobial II Calcium undecylenate Antimicrobial II Miscellaneous external Miscellaneous external Miscellaneous external Miscellaneous external Miscellaneous external Calomel Laxative Miscellaneous external Miscellaneous external Calomel (mercurous chloride) Miscellaneous external Calomel [see mercuric chloride] ==== Camphor Antimicrobial II Antimicrobial II Cough/cold Cough/cold Cough/cold Cough/cold Cough/cold

83

Report

Drug Category

ANPR

PR

FR

Digestive aid

Digestive aid (intestinal distress)

n/a

n/a

310.545(a)(18)(ii)

Antidiarrheal

Antidiarrheal

IIIE

IIIE

310.545(a)(3)(ii)

Cough/cold (expectorant)

Expectorant

IISE

IISE

310.545(a)(6)(iii)

Menstrual/diuretic Weight control

Diuretic Anorectic

n/a IISE

IISE IISE

310.545(a)(24)(i) 310.545(a)(20)

Laxative Wart remover Menstrual/diuretic Weight control

Stimulant laxative Wart remover Premenstrual/menstrual period Anorectic

IIIE IIIE n/a IISE

IIIE IIIE IISE IISE

310.545(a)(12)(iv)(A) [55 FR 33254] 310.545(a)(24)(i) 310.545(a)(20)

Antacid

Antacid

I

I

331.11(d)

Anticaries Internal analgesic

Anticavity agent Corrective

IIE I

n/a n/a

[60 FR 52504] n/a

Antacid

Antacid

I

I

331.11(d)

Acne

Acne

IIE

IIE

310.545(a)(1)

Vaginal

Minor irritations

I

Withdraw

n/a

Internal analgesic Internal analgesic

Analgesic Antirheumatic

n/a n/a

IISE Not OTC

310.545(a)(23)(i) 310.545(a)(23)(i)

Antacid

Antacid

n/a

n/a

331.11(i)(2)

External analgesic Skin protectant

Fever blister (topical) Fever blister (topical)

Defer Defer

n/a n/a

Pending Pending

Anticaries

Anticavity agent

IIE

n/a

310.545(a)(2)(ii)

Acne

Acne

IIE

IIE

310.545(a)(1)

Antifungal Antifungal Antimicrobial Dandruff/seborrheic dermatitis/psoriasis External analgesic Skin protectant

Antifungal Diaper rash Diaper rash Dandruff/seborrheic dermatitis/psoriasis Diaper rash Diaper rash

I Defer Defer IIISE

I IISE IIISE IIISE

333.210(f) 310.545(a)(22)(i) Pending 310.545(a)(7)

Defer Defer

n/a n/a

310.545(a)(10)(iv) Pending

Laxative Boil treatment Mercury

Stimulant laxative Boil treatment Antiseptic

IIS IISE IISE

IIS IISE IISE

310.545(a)(12)(iv)(A) 310.531(a) 310.545(a)(27)(i)

Antimicrobial

First aid antiseptic

n/a

IIIE

310.545(a)(27)(i)

====

====

====

====

====

Acne Antifungal Cold/cough (antitussive) Cough/cold (expectorant) Cough/cold (expectorant) Cough/cold (nasal decongestant) Cough/cold (nasal decongestant)

Acne Antifungal Antitussive (topical/inhalant)

IIE IIE IIIE

IIE IIE I

310.545(a)(1) 310.545(a)(22)(ii) 341.14(b)(1)

Expectorant (lozenge)

IIIE

IIIE

310.545(a)(6)(iii)

Expectorant (topical/inhalant)

IIIE

IIIE

310.545(a)(6)(iii)

Nasal decongestant (topical/inhalant) Nasal decongestant (lozenge)

IIIE

IIIE

[59 FR 43408]

IIIE

IIIE

310.545(a)(6)(ii)(A)

84

Handbook of Pharmaceutical Manufacturing Formulations: Over-the-Counter Products

Review Panel

Report

Drug Category

ANPR

PR

FR

Dental

Relief of oral discomfort

IISE

IISE

Pending

Hemorrhoidal Miscellaneous external Miscellaneous external Miscellaneous external Miscellaneous external Miscellaneous external Miscellaneous external

Anorectal Antifungal Antimicrobial Boil treatment External analgesic External analgesic External analgesic

n/a Defer Defer IISE Defer IISE Defer

I IISE n/a IIISE IISE I I

346.16(a) 310.545(a)(22)(ii) Pending 310.531(a) 310.545(a)(10)(iv) Pending Pending

Miscellaneous external Miscellaneous external Miscellaneous external Miscellaneous external

Skin protectant Skin protectant Skin protectant Skin protectant

Defer Defer IISE Defer

n/a Defer IISE IISE

Pending Pending 310.545(a)(18)(v)(A) 310.545(a)(10)(vii)(A)

Miscellaneous external Miscellaneous external

Wart remover External analgesic

IISE I

IISE I

[55 FR 33254] Pending

Miscellaneous external

External analgesic

IISE

IISE

Pending

Oral cavity Oral cavity Topical analgesic Topical analgesic Topical analgesic Topical analgesic Topical analgesic Camphor (>3–11%) Miscellaneous external Camphor (0.1–3%) Miscellaneous external Camphor (greater than 3–11%) Hemorrhoidal

Oral health care Oral health care External analgesic External analgesic External analgesic Sunscreen External analgesic

Oral mucosal analgesic Analgesic (external) Diaper rash Diaper rash Boil treatment Diaper rash Insect bite/sting Poison ivy/oak/ sumac Diaper rash Fever blister (topical) Insect bite/sting Poison ivy/oak/ sumac Wart remover External analgesic (less than 2.5%) External analgesic (greater than 2.5%) Antimicrobial Analgesic/anesthetic Counterirritant Analgesic/anesthetic External analgesic Sunscreen Antipyretic

IISE IISE I I I IISE n/a

IISE IISE I I I IISE I

Pending 310.545(a)(14) Pending Pending Pending [64 FR 27682] Pending

External analgesic

Fever blister (topical)

Defer

IISE

310.545(a)(10)(v)

External analgesic

Fever blister (topical)

Defer

I

Pending

Anorectal

IISE

IISE

310.545(a)(26)(iv)

Hemorrhoidal

Anorectal

Counterirritant (intrarectal) Counterirritant (external)

IISE

IISE

310.545(a)(26)(iv)

External analgesic Skin protectant

Astringent Astringent

IISE IISE

n/a IISE

n/a 310.545(a)(18)(ii)

External analgesic External analgesic

n/a n/a

I I

Pending Pending

Antifungal Male genital desensitizer External analgesic

Fever blister (topical) Poison ivy/oak/ sumac Antifungal Male genital desensitizer Analgesic/anesthetic

IIISE n/a

IIISE IISE

310.545(a)(22)(iv) 310.545(a)(10)(iii)

IIISE

I

Pending

Camphorated oil

Counterirritant

IIS

n/a

310.502(a)(4)

====

====

====

====

====

Antifungal

Anticandidial

IISE

IISE

310.545(a)(22)(ii)

Aphrodisiac

Aphrodisiac

IISE

IISE

310.528(a)

Camphor gum Miscellaneous external Miscellaneous external Camphorated metacresol ==== ==== Antimicrobial II Miscellaneous external Topical analgesic Camphorated oil Miscellaneous external Candelillia wax [see wax, candelilla] ==== Candicidin Antimicrobial II Cantharides Miscellaneous internal Capsaicin Miscellaneous external Topical analgesic Capsicum Dental

External analgesic External analgesic

Fever blister (topical) Counterirritant

Defer I

IISE I

310.545(a)(10)(v) Pending

Relief of oral discomfort

IIIE

IIIE

Pending

Dental Miscellaneous external Miscellaneous internal Topical analgesic

Relief of oral discomfort External analgesic Digestive aid External analgesic

Counterirritant (external) Toothache relief Fever blister (topical) Digestive aid (ippuad) Counterirritant

IISE Defer n/a I

IISE IISE n/a I

Pending 310.545(a)(10)(v) 310.545(a)(8)(ii) Pending

Current Regulatory Status of Over-the-Counter Products

Review Panel Capsicum oleoresin Miscellaneous external Miscellaneous internal Topical analgesic Capsicum, fluid extract of Miscellaneous internal Captan Miscellaneous external Caramiphen edisylate Cough/cold Carbamide peroxide Miscellaneous external Miscellaneous external Oral cavity Oral cavity Carbamide peroxide (in anhydrous glycerin) Dental Dental Carbamide peroxide 6.5% (in anhydrous glycerin) Topical analgesic Carbaspirin calcium Internal analgesic Internal analgesic Internal analgesic Miscellaneous internal Carbetapentane citrate Cough/cold Carbon Miscellaneous internal Carbon dioxide, released Laxative Carboxymethylcellulose Antacid Carboxymethylcellulose sodium Laxative Laxative Miscellaneous internal Ophthalmic Carnauba wax [see wax, carnauba] ==== Carrageenan Miscellaneous internal Carrageenan (degraded) [see carrageenan, degraded] ==== Carrageenan (native) [see carrageenan, native] ==== Carrageenan, degraded Laxative Carrageenan, native Laxative Casanthranol Laxative Cascara fluidextract aromatic [see cascara fluidextract, aromatic] ==== Cascara fluidextract, aromatic Laxative Miscellaneous internal Cascara sagrada Laxative

85

Report

Drug Category

ANPR

PR

FR

External analgesic Menstrual/diuretic External analgesic

Fever blister (topical) Diuretic Counterirritant

Defer n/a I

IISE IISE I

310.545(a)(10)(v) 310.545(a)(24)(i) Pending

Digestive aid

Digestive aid (ippuad)

n/a

n/a

310.545(a)(18)(ii)

Dandruff/seborrheic dermatitis/psoriasis

Dandruff

IIIE

IIIE

310.545(a)(7)

Cold/cough (antitussive)

Antitussive

IIIE

IIIE

[52 FR 30054]

External analgesic Skin protectant Oral health care Oral health care

Fever blister (topical) Fever blister (topical) Debriding agent Antimicrobial

Defer Defer III IIIE

Defer Defer III IIIE

Pending Pending Pending Pending

Oral mucosal injury Oral mucosal injury

Wound cleanser Wound healing agent

I IIIE

I IIIE

Pending 310.534(a)

Otic

Ear wax softening agent

I

I

344.10

Internal analgesic Internal analgesic Internal analgesic Menstrual/diuretic

Antipyretic Analgesic Antirheumatic Analgesic

I I I I

I I Not OTC I

Pending Pending n/a Pending

Cold/cough (antitussive)

Antitussive

IIIE

IIIE

[52 FR 30054]

Digestive aid

Digestive aid (ippuad)

n/a

n/a

310.545(a)(18)(ii)

Laxative

Laxative

I

I

Pending

Antacid

Antacid

IIIE

IIIE

[39 FR 19874]

Antidiarrheal Laxative Weight control Ophthalmic

Antidiarrheal Bulk laxative Anorectic Demulcent

IIIE I IIIE I

IIIE I IISE I

310.545(a)(3)(i) Pending 310.545(a)(20) 349.12(a)(1)

====

====

====

====

====

Weight control

Anorectic

IIIE

IISE

310.545(a)(20)

====

====

====

====

====

====

====

====

====

====

Laxative

Bulk laxative

IIS

IIS

310.545(a)(12)(i)

Laxative

Bulk laxative

IIIE

IIIE

310.545(a)(12)(i)

Laxative

Stimulant laxative

I

I/IIIS

Pending

====

====

====

====

====

Laxative Menstrual/diuretic

Stimulant laxative Diuretic

I n/a

I/IIIS IISE

310.545(a)(12)(iv)(C) 310.545(a)(24)(i)

Laxative

Stimulant laxative

I

I/IIIS

310.545(a)(12)(iv)(C)

86

Handbook of Pharmaceutical Manufacturing Formulations: Over-the-Counter Products

Review Panel Cascara sagrada bark [see cascara sagrada] ==== Cascara sagrada extract Miscellaneous internal Cascarasagrada extract Laxative Cascarasagrada fluid extract Laxative Casein Miscellaneous external Miscellaneous external Miscellaneous external Miscellaneous external Castor oil Laxative Miscellaneous external Miscellaneous external Miscellaneous external Catechu, tincture Miscellaneous internal Catnip Miscellaneous internal Cedar leaf oil Cough/cold Cellulase Miscellaneous internal Miscellaneous internal Cellulose Miscellaneous external Miscellaneous external Miscellaneous external Miscellaneous external Cellulose, microporous Miscellaneous external Miscellaneous external Miscellaneous external Miscellaneous external Cetalkonium chloride Miscellaneous external Miscellaneous external Oral cavity Cetyl alcohol ==== ==== ==== Miscellaneous external Miscellaneous external Cetylpyridinium chloride ==== Oral cavity Chamomile flowers Miscellaneous internal Charcoal, activated Antacid Laxative Miscellaneous internal Miscellaneous internal Miscellaneous internal Miscellaneous internal Miscellaneous internal Charcoal, wood Miscellaneous internal Chlophedianol hydrochloride Cough/cold

Report

Drug Category

ANPR

PR

FR

====

====

====

====

====

Digestive aid

Digestive aid (ippuad)

n/a

n/a

310.545(a)(18)(ii)

Laxative

Stimulant laxative

I

I/IIIS

310.545(a)(12)(iv)(C)

Laxative

Stimulant laxative

I

I/IIIS

310.545(a)(12)(iv)(C)

Antifungal Antimicrobial External analgesic Skin protectant

Diaper rash Diaper rash Diaper rash Diaper rash

Defer Defer Defer Defer

n/a n/a n/a Withdraw

310.545(a)(22)(i) n/a 310.545(a)(10)(iv) n/a

Laxative External analgesic Skin protectant Wart remover

Stimulant laxative Fever blister (topical) Fever blister (topical) Wart remover

I Defer Defer IISE

I n/a n/a IISE

Pending n/a n/a [55 FR 33254]

Digestive aid

Digestive aid (ippuad)

n/a

n/a

310.545(a)(18)(ii)

Digestive aid

Digestive aid (ippuad)

n/a

n/a

310.545(a)(18)(ii)

Cough/cold (nasal decongestant)

Nasal decongestant (topical)

IIIE

IIIE

310.545(a)(6)(ii)(B)

Digestive aid Digestive aid

Digestive aid (intestinal distress) Digestive aid (ippuad)

IIIE IIE

IIIE IIE

310.545(a)(8)(i) 310.545(a)(8)(i)

Antifungal Antimicrobial External analgesic Skin protectant

Diaper rash Diaper rash Diaper rash Diaper rash

Defer Defer Defer Defer

n/a n/a n/a n/a

310.545(a)(22)(i) n/a 310.545(a)(10)(iv) n/a

Antifungal Antimicrobial External analgesic Skin protectant

Diaper rash Diaper rash Diaper rash Diaper rash

Defer Defer Defer Defer

n/a n/a n/a IIISE

310.545(a)(22)(i) Pending 310.545(a)(10)(iv) Pending

External analgesic Skin protectant Oral health care

Poison ivy/oak/sumac Poison ivy/oak/sumac Antimicrobial

Defer Defer IIIE

IISE IISE IIIE

310.545(a)(10)(vii) 310.545(a)(18)(vii)(A) Pending

Insect bite/sting Poison ivy/oak/sumac Skin protectant External analgesic Skin protectant

Insect bite/sting Poison ivy/oak/sumac Skin protectant Fever blister (topical) Fever blister (topical)

n/a n/a n/a n/a Defer

n/a n/a n/a n/a n/a

310.545(a)(18)(v)(B) 310.545(a)(18)(vi)(B) 310.545(a)(18)(i)(B) n/a Pending

Antigingivitis/antiplaque Oral health care

Antigingivitis/antiplaque Antimicrobial

I IIISE

==== IIISE

Pending Pending

Digestive aid

Digestive aid (ippuad)

n/a

n/a

310.545(a)(18)(ii)

Antacid Antidiarrheal Deodorants for internal use Digestive aid Overindulgence in alcohol/food Poison treatment Acute toxic ingestion

Antacid Antidiarrheal Internal deodorant Digestive aid (intestinal distress) Minimize hangover symptoms

IIE IIIE IIIE IIIE IIIE

IIE IIIE IIIE IIIE IIIE

[39 FR 19873] 310.545(a)(3)(ii) [55 FR 19864] 310.545(a)(8)(iii) [48 FR 32873]

Poison absorbent Poison treatment

n/a I

I I

Pending Pending

Digestive aid

Digestive aid (intestinal distress)

IIIE

IIIE

310.545(a)(18)(ii)

Cold/cough (antitussive)

Antitussive

n/a

I

341.14(a)(1)

Current Regulatory Status of Over-the-Counter Products

87

Review Panel

Report

Drug Category

ANPR

PR

FR

Chloral hydrate ==== Miscellaneous external

External analgesic External analgesic

n/a Defer

IIE IIE

310.545(a)(10)(v) 310.545(a)(10)(vii)

Miscellaneous external

Skin protectant

Defer

IISE

310.545(a)(10)(vii)(A)

Topical analgesic Topical analgesic Chlorcyclizine hydrochloride Cough/cold

External analgesic External analgesic

Fever blister (topical) Poison ivy/oak/ sumac Poison ivy/oak/ sumac Analgesic/anesthetic Counterirritant

IIE n/a

IIE n/a

310.545(a)(10)(i) 310.545(a)(10)(ii)

Cough/cold (antihistamine)

Antihistamine

n/a

I

341.12(b)

====

====

====

====

====

External analgesic External analgesic

Fever blister (topical) Poison ivy/oak/ sumac Antiseptic Corn/callus remover Analgesic/anesthetic

n/a n/a

IIIE IIIE

310.545(a)(10)(v) 310.545(a)(10)(vii)

IIE IISE IIIE

Defer IISE IIIE

n/a [55 FR 33261] 310.545(a)(10)(i)

Cough/cold (expectorant) Digestive aid

Expectorant

IISE

IISE

310.545(a)(6)(iii)

Digestive aid (ippuad)

n/a

n/a

310.545(a)(18)(ii)

Pediculicide

Pediculicide

IISE

IISE

310.545(a)(25)(i)

====

====

====

====

====

Relief of oral discomfort

Oral mucosal analgesic

n/a

IIISE

Pending

Oral mucosal injury Deodorants for internal use Oral health care

Wound healing agent Internal deodorant

IIIE IIIE

IIIE I

310.534(a) 357.810(b)

Antimicrobial

IIIE

IIIE

Pending

====

====

====

====

====

Antifungal

Antifungal

IIISE

IIISE

310.545(a)(22)(ii)

Antimicrobial Antimicrobial Antimicrobial Antimicrobial Antimicrobial

First aid antiseptic Antimicrobial soap Preoperative skin prep Skin wound cleanser Skin wound protectant Skin antiseptic Surgical hand scrub Health care personnel handwash Acne Antifungal Diaper rash Diaper rash Dandruff/seborrheic dermatitis Diaper rash Ingrown toenail Diaper rash

n/a IIISE IIISE IIISE IIISE

IIIE IIISE IIISE IIISE IIISE

Pending Pending Pending Pending Pending

IIISE IIISE IIIE

IIISE IIISE IIIE

Pending Pending Pending

IIE IIIE Defer Defer IIISE

IIE IIIE IISE IIISE IIISE

310.545(a)(1) 310.545(a)(22)(iv) 310.545(a)(22)(i) Pending 310.545(a)(7)

Defer IISE Defer

n/a IISE n/a

310.545(a)(10)(iv) 310.538(a) Pending

Antihistamine

I

I

341.12(c)

Poison ivy/oak/ sumac Poison ivy/oak/ sumac

Defer

IISE

310.545(a)(10)(vii)

Defer

IISE

310.545(a)(10)(vii)(A)

Chlorhydroxyquinoline [see cloxyquin] ==== Chlorobutanol ==== ==== Miscellaneous external Miscellaneous external Topical analgesic Chloroform Cough/cold Miscellaneous internal Chlorophenothane Miscellaneous external Chlorophyll [see chlorophyllin copper complex] ==== Chlorophyllin Dental Chlorophyllin copper complex Dental Miscellaneous internal Oral cavity Chlorophyllins, water-soluble [see chlorophyllin copper complex] ==== Chlorothymol Antimicrobial II Chloroxlyneol Antimicrobial I Antimicrobial I Antimicrobial I Antimicrobial I Antimicrobial I

Alcohols (topical) Corn/callus remover External analgesic

Antimicrobial I Antimicrobial I Antimicrobial I

Antimicrobial Antimicrobial Antimicrobial

Antimicrobial II Antimicrobial II Miscellaneous external Miscellaneous external Miscellaneous external

Acne Antifungal Antifungal Antimicrobial Dandruff/seborrheic dermatitis/psoriasis External analgesic Ingrown toenail Skin protectant

Miscellaneous external Miscellaneous external Miscellaneous external Chlorpheniramine maleate Cough/cold Miscellaneous external

Cough/cold (antihistamine) External analgesic

Miscellaneous external

Skin protectant

88

Handbook of Pharmaceutical Manufacturing Formulations: Over-the-Counter Products

Review Panel Chlorprophenpyridamine maleate Miscellaneous internal Chlortetracycline hydrochloride Antimicrobial II Antimicrobial II Antimicrobial II Chloxyquin Antimicrobial II Cholecalciferol Hemorrhoidal Hemorrhoidal Miscellaneous external Miscellaneous external Miscellaneous external Miscellaneous external Miscellaneous internal Cholesterol Miscellaneous external Choline Miscellaneous internal Choline salicylate Internal analgesic Internal analgesic Internal analgesic Miscellaneous internal Chondrus Miscellaneous internal Cimicifuga racemosa Miscellaneous internal Cinnamedrine hydrochloride Miscellaneous internal Cinnamon oil Miscellaneous internal Cinnamon tincture Miscellaneous internal Cinoxate Topical analgesic Citric acid Contraceptive/vaginal Dental Internal analgesic Miscellaneous internal Miscellaneous internal Miscellaneous internal Citric acid/salt Antacid Citrus pectin Miscellaneous internal Climbazole n/a Clioquinol Antimicrobial II Cloflucarban Antimicrobial I Antimicrobial I Antimicrobial I Antimicrobial I Antimicrobial I Antimicrobial I Antimicrobial I Antimicrobial I Clotrimazole n/a

Report

Drug Category

ANPR

PR

FR

Menstrual/diuretic

Menstrual

n/a

IISE

310.545(a)(24)(i)

Antibiotic Antibiotic Antibiotic

First aid antibiotic Skin wound antibiotic Skin wound protectant

n/a IIE I

I Defer Defer

333.110(c) n/a n/a

Acne

Acne

IISE

IISE

310.545(a)(1)

Anorectal Anorectal Antifungal Antimicrobial External analgesic Skin protectant Weight control

Wound healing agent (external) Wound healing agent (intrarectal) Diaper rash Diaper rash Diaper rash Diaper rash Anorectic

IIIE IIIE Defer Defer Defer Defer IISE

IIIE IIIE n/a n/a n/a IIISE IISE

310.545(a)(26)(x) 310.545(a)(26)(x) 310.545(a)(22)(i) Pending 310.545(a)(10)(iv) Pending 310.545(a)(20)

Boil treatment

Boil treatment

IISE

IISE

310.531(a)

Weight control

Anorectic

IISE

IISE

310.545(a)(20)

Internal analgesic Internal analgesic Internal analgesic Menstrual/diuretic

Analgesic Antipyretic Antirheumatic Analgesic

I I I I

I I Not OTC I

Pending Pending n/a Pending

Weight control

Anorectic

IIIE

IISE

310.545(a)(20)

Menstrual/diuretic

Dysmenorrhea

IISE

IISE

310.545(a)(24)(i)

Menstrual/diuretic

Smooth muscle relaxant

IIIE

IIIE

Pending

Digestive aid

Digestive aid (ippuad)

n/a

n/a

310.545(a)(18)(ii)

Digestive aid

Digestive aid (ippuad)

n/a

n/a

310.545(a)(18)(ii)

Sunscreen

Sunscreen

I

I

352.10(c)

Vaginal Relief of oral discomfort

IIIE IIIE

Withdraw IIIE

n/a Pending

Internal analgesic Digestive aid Digestive aid Weight control

Alters vaginal pH Tooth desensitizer (in combination only) Corrective Digestive aid (intestinal distress) Digestive aid (ippuad) Anorectic

I IIIE IIIE IISE

n/a n/a n/a IISE

n/a 310.545(a)(18)(ii) 310.545(a)(18)(ii) 310.545(a)(20)

Antacid

Antacid

I

I

331.11(e)

Digestive aid

Digestive aid (intestinal distress)

n/a

n/a

310.545(a)(18)(ii)

TEA

Dandruff

n/a

Antifungal

Antifungal

I

I

333.210(a)

Antimicrobial Antimicrobial Antimicrobial Antimicrobial Antimicrobial Antimicrobial Antimicrobial Antimicrobial

Skin antiseptic Skin wound protectant First aid antiseptic Antimicrobial soap Skin wound cleanser Preoperative skin prep Surgical hand scrub Health care personnel handwash

n/a IISE IISE IIIS IISE IISE IISE IIISE

IISE IISE IISE IIIS IIISE IISE IISE IIISE

Pending Pending Pending Pending Pending Pending Pending Pending

n/a

Antifungal

n/a

I

[67 FR 5942]

Current Regulatory Status of Over-the-Counter Products

Review Panel

Report

Drug Category

ANPR

PR

FR

Smoking deterrent

Smoking deterrent

IIE

IIE

310.544(d)

External analgesic Skin protectant

Astringent Astringent

IISE IISE

n/a IISE

Pending 310.545(a)(18)(ii)

====

====

====

====

====

Weight control

Anorectic

IISE

IISE

310.545(a)(20)

Acne Antifungal Dandruff/seborrheic dermatitis/psoriasis

Acne Antifungal Psoriasis

IISE IISE I

IISE IISE I

310.545(a)(1) 310.545(a)(22)(ii) 358.710(c)(1)

Dandruff/seborrheic dermatitis/psoriasis

Dandruff

I

I

358.710(a)(1)

Dandruff/seborrheic dermatitis/psoriasis

Seborrheic dermatitis

IIIE

I

358.710(b)(1)

Skin protectant Skin protectant Anorectal Anorectal Skin protectant

Diaper rash Fever blister (topical) Protectant (external) Protectant (intrarectal) Skin protectant

Defer n/a I I I

IIISE I I I I

310.545(a)(18)(iii) Pending 346.14(2) 346.14(2) 347.10(d)

====

====

====

====

====

Pediculicide

Pediculicide

IISE

IISE

310.545(a)(25)(i)

Skin protectant Antitussive

n/a IIIE

n/a IIIE

347.10(e) [52 FR 30054]

Hemorrhoidal

Skin protectant Cold/cough (antitussive) Anorectal

IIISE

IIISE

310.545(a)(26)(x)

Hemorrhoidal

Anorectal

IIISE

IIISE

310.545(a)(26)(x)

Miscellaneous external Miscellaneous external Miscellaneous external Miscellaneous external Cod liver oil (in combination only) Hemorrhoidal Hemorrhoidal Codeine ==== Cough/cold

Antifungal Antimicrobial External analgesic Skin protectant

Wound healing agent (intrarectal) Wound healing agent (external) Diaper rash Diaper rash Diaper rash Diaper rash

Defer Defer Defer Defer

n/a n/a n/a I

310.545(a)(22)(i) Pending 310.545(a)(10)(iv) Pending

Anorectal Anorectal

Protectant (external) Protectant (intrarectal)

I I

I I

346.14(b)(2) 346.14(b)(2)

Menstrual/diuretic Cold/cough (antitussive) Internal analgesic Internal analgesic Menstrual/diuretic

Menstrual Antitussive

n/a I

n/a I

310.545(a)(24)(i) 341.14(a)(2)(i)

Analgesic Antipyretic Analgesic

IISE IISE IIS

IISE IISE IISE

310.545(a)(23)(i) 310.545(a)(23)(i) 310.545(a)(24)(i)

Cold/cough (antitussive) Internal analgesic

Antitussive

I

I

341.14(a)(2)(ii)

Analgesic

IISE

n/a

310.545(a)(23)(i)

Cold/cough (antitussive) Internal analgesic

Antitussive

I

I

341.14(a)(2)(iii)

Analgesic

IISE

n/a

310.545(a)(23)(i)

====

====

====

====

====

Anorectal Anorectal Menstrual/diuretic

Anorectal (external) Anorectal (intrarectal) Diuretic

IISE IISE n/a

IISE IISE IISE

310.545(a)(26)(vii) 310.545(a)(26)(vii) 310.545(a)(24)(i)

Clove Miscellaneous internal Clove oil Miscellaneous external Miscellaneous external Cloves, ground [see clove] ==== Cnicus benedictus Miscellaneous internal Coal tar Antimicrobial II Antimicrobial II Miscellaneous external Coal tar (shampoo) Miscellaneous external Coal tar (nonshampoo) Miscellaneous external Cocoa butter ==== ==== Hemorrhoidal Hemorrhoidal Topical analgesic Cocoa butter substitutes [see hard fat] ==== Coconut oil soap, aqueous Miscellaneous external Cod liver oil ==== Cough/cold

Internal analgesic Internal analgesic Miscellaneous internal Codeine phosphate Cough/cold Internal analgesic Codeine sulfate Cough/cold Internal analgesic Codeine, alkaloid [see codeine] ==== Collinsonia extract Hemorrhoidal Hemorrhoidal Miscellaneous internal

89

90

Handbook of Pharmaceutical Manufacturing Formulations: Over-the-Counter Products

Review Panel Colloidal oatmeal ==== ==== Miscellaneous external Miscellaneous external Miscellaneous external Miscellaneous external Colocynth Laxative Compound white pine syrup [see white pine syrup, compound] ==== Copper Miscellaneous internal Copper gluconate Miscellaneous internal Copper oleate Miscellaneous external Copper undecylenate Antimicrobial II Coriander Miscellaneous internal Coriander, ground [see coriander] ==== Corn oil Miscellaneous internal Corn oil, aqueous emulsion Miscellaneous internal Corn silk Miscellaneous internal Corn silk, potassium extract Miscellaneous internal Corn starch [see starch, corn] ==== Corn syrup Miscellaneous internal Couch grass Miscellaneous internal Creosote Dental Miscellaneous external Creosote, beechwood ==== Cough/cold Cough/cold Cough/cold Cough/cold Dental Miscellaneous external Cresol Antimicrobial II Dental Miscellaneous external Miscellaneous external Miscellaneous external Oral cavity Oral cavity Oral cavity Cresol saponated Miscellaneous external

Report

Drug Category

ANPR

PR

FR

Skin protectant Skin protectant Dandruff/seborrheic dermatitis/psoriasis External analgesic Skin protectant Skin protectant

Skin protectant Poison ivy/oak/sumac Dandruff

n/a n/a IIE

n/a I IIE

347.10(f) 347.10(f) 310.545(a)(7)

Astringent Astringent Diaper rash

IISE IISE Defer

n/a IIE IISE

Pending 310.545(a)(18)(ii) Pending

Laxative

Stimulant laxative

IIS

IIS

310.545(a)(12)(iv)(A)

====

====

====

====

====

Weight control

Anorectic

IISE

IISE

310.545(a)(20)

Weight control

Anorectic

IISE

IISE

310.545(a)(20)

Pediculicide

Pediculicide

IISE

IISE

310.545(a)(25)(i)

Antifungal

Antifungal

I

I

333.210(f)

Smoking deterrent

Smoking deterrent

IIE

IIE

310.544(d)

====

====

====

====

====

Weight control

Anorectic

IISE

IISE

310.545(a)(20)

Cholecystokinetic

Cholecystokinetic

I

I

357.210(a)

Menstrual/diuretic

Diuretic

n/a

IISE

310.545(a)(24)(i)

Weight control

Anorectic

IISE

IISE

310.545(a)(20)

====

====

====

====

====

Weight control

Anorectic

IISE

IISE

310.545(a)(20)

Menstrual/diuretic

Diuretic

n/a

IISE

310.545(a)(24)(i)

Relief of oral discomfort Skin protectant

Toothache relief Poison ivy/oak/sumac

IIIE Defer

IIIE IISE

Pending 310.545(a)(10)(vii)(A)

Skin protectant Cold/cough (antitussive) Cough/cold (expectorant) Cough/cold (nasal decongestant) Cough/cold (nasal decongestant) Relief of oral discomfort External analgesic

Poison ivy/oak/sumac Antitussive

n/a IIIE

IISE IIIE

310.545(a)(18)(vi) [52 FR 30054]

Expectorant

IIIE

IIIE

310.545(a)(6)(iii)

Nasal decongestant (oral)

IIIE

IIIE

310.545(a)(6)(ii)(A)

Nasal decongestant (topical)

IIIE

IIIE

310.545(a)(6)(ii)(B)

Toothache relief Poison ivy/oak/sumac

IIISE Defer

IIISE IISE

Pending 310.545(a)(10)(vii)

Antifungal Relief of oral discomfort External analgesic Astringent Skin protectant Oral health care Oral health care Relief of oral discomfort

Antifungal Toothache relief Astringent Antiseptic Astringent Antimicrobial Analgesic/anesthetic Oral mucosal analgesic

IIISE IIISE IISE IIE IISE IIS IISE IIISE

IIISE IIISE n/a Defer IISE IISE IISE IIISE

310.545(a)(22)(iv) Pending Pending n/a 310.545(a)(18)(ii) Pending 310.545(a)(14) Pending

Dandruff/seborrheic dermatitis/psoriasis

Psoriasis

IIE

IIE

310.545(a)(7)

Current Regulatory Status of Over-the-Counter Products

Review Panel Cupric sulfate Miscellaneous external Miscellaneous external Miscellaneous internal Cyanocobalamin (vitamin B12) Miscellaneous internal Cyclizine hydrochloride Laxative Cyclomethycaine sulfate ==== ==== Internal analgesic Cysteine hydrochloride Miscellaneous external Miscellaneous external Miscellaneous external Miscellaneous external Cystine Miscellaneous internal Danthron Laxative D-Calcium pantothenate [see calcium pantothenate] ==== Dehydrocholic acid Laxative Miscellaneous internal Miscellaneous internal Denatonium benzoate Miscellaneous external Dequalinium chloride Oral cavity Desoxyephedrine, L-[see levomethamphetamine] ==== Dexbromopheniramine maleate Cough/cold Cough/cold Dexchlorpheniramine maleate Cough/cold Dexpanthenol ==== Miscellaneous external Miscellaneous external Miscellaneous external Miscellaneous external Miscellaneous external Dextran 70 Ophthalmic Dextromethorphan Cough/cold Dextromethorphan hydrobromide Cough/cold Dextrose Miscellaneous internal Diastase Miscellaneous internal Diastase malt Miscellaneous internal Dibenzothiophene Antimicrobial II

91

Report

Drug Category

ANPR

PR

FR

External analgesic Skin protectant Weight control

Astringent Astringent Anorectic

IISE IISE IISE

n/a IISE IISE

Pending 310.545(a)(18)(ii) 310.545(a)(20)

Weight control

Anorectic

IISE

IISE

310.545(a)(20)

Antiemetic

Antiemetic

I

I

336.10(a)

External analgesic External analgesic

n/a n/a

IIIE IIIE

310.545(a)(10)(v) 310.545(a)(10)(vii)

External analgesic

Fever blister (topical) Poison ivy/oak/ sumac Analgesic/anesthetic

IIIE

IIIE

310.545(a)(10)(i)

Antifungal Antimicrobial External analgesic Skin protectant

Diaper rash Diaper rash Diaper rash Diaper rash

Defer Defer Defer Defer

n/a n/a n/a IIISE

310.545(a)(22)(i) Pending 310.545(a)(10)(iv) 310.545(a)(18)(iii)

Weight control

Anorectic

IISE

IISE

310.545(a)(20)

Laxative

Stimulant laxative

I

IIS

310.545(a)(12)(iv)(B)

====

====

====

====

====

Laxative Digestive aid

Stimulant laxative Digestive aid (intestinal distress) Digestive aid (ippuad)

I IIE

I IIE

Pending 310.545(a)(8)(i)

IIE

IIE

310.545(a)(8)(i)

Nailbiting/thumbsucking

Nailbiting/thumbsucking IIIE deterrent

IIIE

310.536(a)

Oral health care

Antimicrobial

IIISE

IIISE

Pending

====

====

====

====

====

Cough/cold (antihistamine) Cough/cold (antihistamine)

Antihistamine Antihistamine

IIISE n/a

I I

341.12(d) 341.12(f)

Cough/cold (antihistamine)

Antihistamine

n/a

I

341.12(e)

External analgesic

n/a

IIIE

310.545(a)(10)(vii)

Antifungal External analgesic External analgesic Hair growth/loss Skin protectant

Poison ivy/oak/ sumac Diaper rash Diaper rash Insect bite/sting Hair grower Diaper rash

Defer Defer n/a n/a Defer

n/a n/a IIIE IIE IIISE

310.545(a)(22)(i) 310.545(a)(10)(iv) Pending 310.527(a) Pending

Ophthalmic

Demulcent

I

I

349.12(b)

Cold/cough (antitussive)

Antitussive

I

I

341.14(a)(3)

Cough/cold (antitussive)

Antitussive

n/a

n/a

341.14(a)(4)

Weight control

Anorectic

IISE

IISE

310.545(a)(20)

Digestive aid

Digestive aid (ippuad)

n/a

n/a

310.545(a)(18)(ii)

Digestive aid

Digestive aid (intestinal distress)

n/a

n/a

310.545(a)(18)(ii)

Acne

Acne

IIS

IIS

310.545(a)(1)

Digestive aid

92

Handbook of Pharmaceutical Manufacturing Formulations: Over-the-Counter Products

Review Panel

Report

Drug Category

ANPR

PR

FR

Dibucaine ====

External analgesic

n/a

I

Pending

Hemorrhoidal

Anorectal

IIISE

IIISE

[55 FR 1779]

Hemorrhoidal Miscellaneous external Miscellaneous external Miscellaneous external Miscellaneous external Miscellaneous external Oral cavity Topical analgesic Dibucaine hydrochloride ==== ====

Anorectal Antifungal Antimicrobial External analgesic External analgesic Skin protectant Oral health care External analgesic

Poison ivy/oak/ sumac Anesthetic (intrarectal) Anesthetic (external) Diaper rash Diaper rash Diaper rash Fever blister (topical) Diaper rash Analgesic/anesthetic Analgesic/anesthetic

IIIS Defer Defer Defer Defer Defer IIS I

I n/a n/a IISE I n/a IIS I

346.10(d) 310.545(a)(22)(i) Pending 310.545(a)(10)(iv) Pending Pending 310.545(a)(14) Pending

External analgesic External analgesic

n/a n/a

I I

Pending Pending

Hemorrhoidal Hemorrhoidal

Anorectal Anorectal

IIIS IIISE

I IIISE

346.10(c) [55 FR 1779]

Oral cavity Topical analgesic Dicalcium phosphate dihydrate [see calcium phosphate, dibasic] ==== Dichlorodiphenyl trichloroethane [see chorophenothane] ==== Dichlorophen Antimicrobial II Miscellaneous external Diethanolamine methoxycinnamate Topical analgesic Diethanolamine p-methoxy-cinnamate [see diethanolamine methoxycinnamate] ==== Diethylhexyl butamido triazone (Uvasorb HEB) n/a TEA Digalloyltrioleate Topical analgesic Dihydroxyaluminum aminoacetate Antacid Dihydroxyaluminum aminoacetic acid Antacid Internal analgesic Dihydroxyaluminum sodium carbonate Antacid Internal analgesic Miscellaneous internal Dimenhydrinate Laxative Dimethicone ==== ==== Topical analgesic Dimethisoquin hydrochloride ====

Oral health care External analgesic

Fever blister (topical) Poison ivy/oak/ sumac Anesthetic (external) Anesthetic (intrarectal) Analgesic/anesthetic Analgesic/anesthetic

IIS I

IIS I

310.545(a)(14) Pending

Gingivitis/plaque

Gingivitis/antiplaque

n/a

IIIE

Pending

====

====

====

====

====

Antifungal Hair growth/loss

Antifungal Hair grower

IIISE IISE

IIISE n/a

310.545(a)(22)(ii) 310.527(a)

Sunscreen

Sunscreen

I

I

310.545(a)(29)

====

====

====

====

====

Sunscreen

n/a

Sunscreen

Sunscreen

I

I

310.545(a)(29)

Antacid

Antacid

I

I

331.11(a)(3)

Antacid Internal analgesic

Antacid Corrective

n/a I

n/a n/a

331.11(a)(3) n/a

Antacid Internal analgesic Digestive aid

Antacid Corrective Digestive aid (ippuad)

I I IIIE

I n/a IIIE

331.11(a)(5) n/a 310.545(a)(8)(i)

Antiemetic

Antiemetic

I

I

336.10(b)

Skin protectant Skin protectant Skin protectant

Diaper rash Fever blister (topical) Skin protectant

n/a n/a I

I I I

Pending Pending 347.10(g)

External analgesic

n/a

I

Pending

External analgesic External analgesic

Poison ivy/oak/ sumac Fever blister (topical) Analgesic/anesthetic

n/a I

I I

Pending Pending

Sunscreen

Sunscreen

I

I

352.10(e)

Anorectal

Anesthetic (intrarectal) Anesthetic (external)

IIISE

IIISE

310.545(a)(26)(vi)

IIE

IIIE

310.545(a)(26)(vi)

==== Topical analgesic Dioxybenzone Topical analgesic Diperodon Hemorrhoidal Hemorrhoidal

Anorectal

Current Regulatory Status of Over-the-Counter Products

Review Panel Diperodon hydrochloride Miscellaneous external Miscellaneous external Miscellaneous external Miscellaneous external Miscellaneous external Miscellaneous external Miscellaneous external Diphenhydramine citrate Cough/cold Cough/cold Sedative Diphenhydramine hydrochloride ==== Cough/cold Cough/cold Laxative Miscellaneous external Miscellaneous external Sedative Sedative Topical analgesic Diphenhydramine monocitrate [see diphenhydramine citrate] ==== Dipropylene glycol salicylate Topical analgesic DL-Methionine [see racemethionine] ==== Docusate calcium Laxative Docusate potassium Laxative Docusate sodium Contraceptive/vaginal Laxative Miscellaneous external Miscellaneous internal Dodecaethylene glycol monolaurate Contraceptive/vaginal Dodecaethyleneglycol monolaurate [see dodecaethylene glycol monolaurate] ==== Dog grass Miscellaneous internal Dog grass extract Miscellaneous internal Domiphen bromide Oral cavity Don qual Miscellaneous internal Doxylamine succinate Cough/cold Sedative Sedative Duodenal substance Miscellaneous internal Dyclonine hydrochloride ==== ==== Hemorrhoidal Hemorrhoidal Oral cavity Topical analgesic

93

Report

Drug Category

ANPR

PR

FR

Antifungal Antimicrobial External analgesic External analgesic Skin protectant Skin protectant Corn/callus remover

Diaper rash Diaper rash Diaper rash Poison ivy/oak/sumac Diaper rash Poison ivy/oak/sumac Corn/callus remover

Defer Defer Defer Defer Defer Defer IISE

n/a n/a n/a IISE n/a IISE IISE

310.545(a)(22)(i) Pending 310.545(a)(10)(iv) 310.545(a)(10)(vii) Pending 310.545(a)(10)(vii)(A) [55 FR 33261]

Cough/cold (antitussive) Cough/cold (antihistamine) Nighttime sleep aid

Antitussive Antihistamine Sleep aid

n/a n/a n/a

n/a n/a n/a

341.14(a)(5) 341.12(f) 338.10(b)

External analgesic Cough/cold (antitussive) Cough/cold (antihistamine) Antiemetic External analgesic Skin protectant Daytime sedative Nighttime sleep aid External analgesic

Fever blister (topical) Antitussive Antihistamine Antiemetic Poison ivy/oak/sumac Poison ivy/oak/sumac Sedative Sleep aid Analgesic/anesthetic

n/a I I IIIE Defer Defer IISE IIISE I

I IIIE I IIIE I IISE IISE IIISE I

Pending 341.14(a)(6) 341.12(g) 336.10(c) Pending 310.545(a)(18)(vi)(A) 310.519(a) 336.10(a) Pending

====

====

====

====

====

Sunscreen

Sunscreen

IIISE

IIISE

[64 FR 27682]

====

====

====

====

====

Laxative

Stool softener

I

I

Pending

Laxative

Stool softener

I

I

Pending

Vaginal

I

Withdraw

n/a

Laxative Pediculicide Weight control

Lowers surface tension mucolytic effects Stool softener Pediculicide Anorectic

I IISE IISE

I IISE IISE

Pending 310.545(a)(25)(i) 310.545(a)(20)

Contraceptive (vaginal)

Contraceptive

IIIE

Withdraw

310.545(a)(28)

====

====

====

====

====

Digestive aid

Digestive aid (ippuad)

n/a

n/a

310.545(a)(18)(ii)

Menstrual/diuretic

Diuretic

n/a

IISE

310.545(a)(24)(i)

Oral health care

Antimicrobial

IIISE

IIISE

Pending

Aphrodisiac

Aphrodisiac

IISE

IISE

310.528(a)

Cough/cold (antihistamine) Daytime sedative Nighttime sleep aid

Antihistamine Sedative Sleep aid

I IISE IIISE

I IISE IIISE

341.12(h) 310.519(a) [54 FR 6826]

Digestive aid

Digestive aid (intestinal distress)

IISE

IISE

310.545(a)(8)(i)

External analgesic External analgesic Anorectal Anorectal Oral health care External analgesic

Fever blister (topical) Poison ivy/oak/sumac Anesthetic (external) Anesthetic (intrarectal) Analgesic/anesthetic Analgesic/anesthetic

n/a n/a IIIE IIIE I I

I I I IIIE I I

Pending Pending 346.10(e) [55 FR 1779] Pending Pending

94

Handbook of Pharmaceutical Manufacturing Formulations: Over-the-Counter Products

Review Panel E. coli vaccines Hemorrhoidal Hemorrhoidal Edetate disodium Contraceptive/vaginal Dental Edetate sodium Contraceptive/vaginal Elaterin resin Laxative Elecampane Miscellaneous internal Elm bark Cough/cold Oral cavity Endothermic hectorite [see hectorite] ==== Ensulizole Topical analgesic Enzacamene n/a Ephedrine Cough/cold Cough/cold Cough/cold Ephedrine (any ingredient) ==== ==== Ephedrine hydrochloride Cough/cold Miscellaneous external Ophthalmic Cough/cold Cough/cold Ephedrine sulfate Cough/cold Cough/cold Hemorrhoidal Hemorrhoidal Cough/cold Epinephrine Cough/cold Hemorrhoidal Hemorrhoidal Epinephrine bitartrate Cough/cold Epinephrine hydrochloride Hemorrhoidal Hemorrhoidal Epinephrine hydrochloride (racemic) [see epinephine hydrochloride] ==== Epinephrine undecylenate Hemorrhoidal Hemorrhoidal Ergocalciferol Contraceptive/vaginal

Report

Drug Category

ANPR

PR

FR

Anorectal Anorectal

Anorectal (External) Anorectal (intrarectal)

IISE IISE

IISE IISE

310.545(a)(26)(vii) 310.545(a)(26)(vii)

Vaginal Relief of oral discomfort

Minor irritations Tooth desensitizer (in combination only)

IIISE IISE

Withdraw IISE

n/a Pending

Vaginal

Minor irritations

IIISE

Withdraw

n/a

Laxative

Stimulant laxative

IIS

IIS

310.545(a)(12)(iv)(A)

Digestive aid

Digestive aid (ippuad)

n/a

n/a

310.545(a)(18)(ii)

Cough/cold (antitussive) Oral health care

Antitussive Demulcent

IIIE I

IIIE I

[52 FR 30054] Pending

====

====

====

====

====

Sunscreen

Sunscreen

I

I

352.10(n)

TEA

Sunscreen

n/a

Cough/cold (bronchodilator) Cough/cold (nasal decongestant) Cough/cold (nasal decongestant)

Bronchodilator Nasal decongestant (topical/inhalant) Nasal decongestant (oral)

I I

I I

341.16(a) 341.20(b)(1)

IIIE

IIIE

310.545(a)(6)(ii)(B)

Menstrual/diuretic Internal analgesic

Menstrual Analgesic

n/a n/a

n/a n/a

310.545(a)(24)(ii) 310.545(a)(23)(ii)

Cough/cold (bronchodilator) Male genital desensitizer Ophthalmic Cough/cold (nasal decongestant) Cough/cold (nasal decongestant)

Bronchodilator Male genital desensitizer Vasoconstrictor Nasal decongestant (oral)

I IISE I IIIE

I IISE I IIIE

341.16(b) 310.545(a)(10)(iii) 349.18(a) 310.545(a)(6)(ii)(B)

Nasal decongestant (topical/inhalant)

I

I

341.20(b)(3)

Cough/cold (bronchodilator) Cough/cold (nasal decongestant) Anorectal Anorectal Cough/cold (nasal decongestant)

Bronchodilator Nasal decongestant (topical/inhalant) Vasoconstrictor (intrarectal) Vasoconstrictor (external) Nasal decongestant (oral)

I I

I I

341.16(c) 341.20(b)(4)

I I IIIE

I I IIIE

346.12(a) 346.10(a) 310.545(a)(6)(ii)(B)

Cough/cold (bronchodilator) Anorectal Anorectal

Bronchodilator (inhalation) Vasoconstrictor (external) Vasoconstrictor (intrarectal)

I IIISE IIISE

I I IIISE

341.16(d) 346.10(b) 346.10(b)

Cough/cold (bronchodilator)

Bronchodilator (inhalation)

I

I

341.16(e)

Anorectal Anorectal

Vasoconstrictor (external) Vasoconstrictor (intrarectal)

I IIE

I IIE

346.10(c) 346.10(c)

====

====

====

====

====

Anorectal Anorectal

Vasoconstrictor (external) Vasoconstrictor (intrarectal)

IIISE IIE

IIISE IIE

310.545(a)(26)(ix) 310.545(a)(26)(ix)

Vaginal

Minor irritations

IIIE

Withdraw n/a

Current Regulatory Status of Over-the-Counter Products

95

Review Panel

Report

Drug Category

ANPR

PR

FR

Miscellaneous external Miscellaneous external Miscellaneous external Miscellaneous external Miscellaneous internal Ergot fluidextract Miscellaneous external Miscellaneous external Miscellaneous external Escalol 506 [see padimate A] Essential oils Miscellaneous external Estradiol Miscellaneous external Estrogens Miscellaneous external Miscellaneous internal Estrone Antimicrobial II Ether Miscellaneous internal Ethohexadiol Miscellaneous external

Antifungal Antimicrobial External analgesic Skin protectant Weight control

Diaper rash Diaper rash Diaper rash Diaper rash Anorectic

Defer Defer Defer Defer IISE

n/a n/a n/a n/a IISE

310.545(a)(22)(i) Pending 310.545(a)(10)(iv) Pending 310.545(a)(20)

Boil treatment External analgesic Skin protectant

Boil treatment Insect bite/sting Insect bite/sting

IISE IISE IISE

IISE IISE IISE

310.531(a) 310.545(a)(10)(vi) 310.545(a)(18)(v)(A)

Hair growth/loss

Hair grower

IISE

n/a

310.527(a)

Hair growth/loss

Hair grower

IIE

IIE

310.527(a)

Hormone Aphrodisiac

Hormone Aphrodisiac

IIE IIS

IIE IIS

310.530(a) 310.528(a)

Acne

Acne

IISE

IISE

310.545(a)(1)

Digestive aid

Digestive aid (ippuad)

n/a

n/a

310.545(a)(18)(ii)

Dandruff/seborrheic dermatitis/psoriasis

Dandruff

IIIE

IIIE

310.545(a)(7)

External analgesic Skin protectant

Insect bite/sting Insect bite/sting

IISE IISE

IISE IISE

310.545(a)(10)(vi) 310.545(a)(18)(v)

Sunscreen

Sunscreen

I

I

310.545(a)(29)

====

====

====

====

====

Menstrual/diuretic

Diuretic

n/a

IISE

310.545(a)(24)(i)

====

====

====

====

====

cold Cough/cold (antitussive)

Antitussive

IIIE

IIIE

[52 FR 30054]

Cough/cold (antitussive)

Antitussive (topical/inhalant) Antitussive (mouthwash) Antitussive (lozenge) Expectorant (lozenge) Expectorant (topical/inhalant) Nasal decongestant (topical/inhalant) Nasal decongestant (mouthwash) Nasal decongestant (lozenge) Nasal decongestant (lozenge) Diaper rash Diaper rash Dandruff

IIIE

IIIE

[52 FR 30055]

IIIE

IIIE

[52 FR 30055]

IIIE IIIE IIIE

IIIE IIIE IIIE

[52 FR 30054] 310.545(a)(6)(iii) 310.545(a)(6)(iii)

IIIE

IIIE

310.545(a)(6)(ii)(A)

IIIE

IIIE

310.545(a)(6)(ii)(A)

IIIE

IIIE

310.545(a)(6)(ii)(A)

IIIE

IIIE

310.545(a)(6)(ii)(A)

Defer Defer IIIE

n/a n/a IIIE

310.545(a)(22)(i) pending 310.545(a)(7)

Diaper rash Diaper rash Antimicrobial Analgesic/anesthetic

Defer Defer IIIE IIIE

IISE n/a IIIE IIIE

310.545(a)(10)(iv) pending pending 310.545(a)(14)

Antiplaque/gingivitis

I

====

pending

Ethoxylated alkyl alcohol Miscellaneous external Miscellaneous external Ethyl 4-[bis(hydroxypropyl)] aminobenzoate Topical analgesic Ethyl alcohol [see alcohol] ==== Ethyl nitrate Miscellaneous internal Ethylhexyl p-methoxycinnamate [see white pine extract, compound] ==== Ethylmorphine hydrochloride Cough/ Eucalyptol Cough/cold Cough/cold

Cough/cold (antitussive)

Cough/cold Cough/cold Cough/cold

Cough/cold (antitussive) Cough/cold (expectorant) Cough/cold (expectorant)

Cough/cold

Cough/cold (nasal decongestant)

Cough/cold

Cough/cold (nasal decongestant)

Cough/cold

Cough/cold (nasal decongestant)

Cough/cold

Cough/cold (nasal decongestant)

Miscellaneous external Miscellaneous external Miscellaneous external

Antifungal Antimicrobial Dandruff/seborrheic dermatitis/psoriasis External analgesic Skin protectant Oral health care Oral health care

Miscellaneous external Miscellaneous external Oral cavity Oral cavity Eucalyptol, menthol, methyl salicylate, and thymol ====

Gingivitis/plaque

96

Handbook of Pharmaceutical Manufacturing Formulations: Over-the-Counter Products

Review Panel Eucalyptus oil ==== Cough/cold Cough/cold Cough/cold Cough/cold Cough/cold Cough/cold Cough/cold Cough/cold Miscellaneous external Miscellaneous external Miscellaneous external Miscellaneous external Miscellaneous external Miscellaneous external Miscellaneous external Miscellaneous external Miscellaneous external Miscellaneous internal Topical analgesic Eugenol ==== Dental Miscellaneous external Miscellaneous external Miscellaneous external Topical analgesic Euphorbia pilulifera Cough/cold Extract white pine compound [see white pine extract, compound] ==== Fatty acids Miscellaneous external Fennel acid Miscellaneous internal Ferric ammonium citrate Miscellaneous internal Ferric chloride Miscellaneous external Miscellaneous external Miscellaneous external Miscellaneous internal Oral cavity Ferric pyrophosphate Miscellaneous internal Ferric subsulfate Miscellaneous external Miscellaneous external Ferrous furnarate Miscellaneous internal Ferrous gluconate Miscellaneous internal Ferrous sulfate Miscellaneous internal Miscellaneous internal Flax seed Miscellaneous internal Fluid extract ergot [see ergot, fluidextract] ==== Fluorosalan Antimicrobial I

Report

Drug Category

ANPR

PR

FR

External analgesic Cough/cold (antitussive) Cough/cold (antitussive) Cough/cold (antitussive) Cough/cold (expectorant) Cough/cold (expectorant) Cough/cold (nasal decongestant) Cough/cold (nasal decongestant) Cough/cold (nasal decongestant) Antifungal Antimicrobial External analgesic External analgesic External analgesic Hair growth/loss Skin protectant Skin protectant Skin protectant Smoking deterrent External analgesic

Fever blister (topical) Antitussive (mouthwash) Antitussive (lozenge) Antitussive (topical/inhalant) Expectorant (lozenge) Expectorant (topical/inhalant) Nasal decongestant (mouthwash) Nasal decongestant (inhalant room spray) Nasal decongestant (lozenge)

n/a IIIE IIIE IIIE IIIE IIIE IIIE

IIIE IIIE IIIE IIIE IIIE IIIE IIIE

310.545(a)(10)(v) [52 FR 30055] [52 FR 30054] [52 FR 30055] 310.545(a)(6)(iii) 310.545(a)(6)(iii) 310.545(a)(6)(ii)(A)

IIIE

IIIE

[59 FR 43408]

IIIE

IIIE

310.545(a)(6)(ii)(A)

Diaper rash Diaper rash Astringent Diaper rash Poison ivy/oak/sumac Hair grower Astringent Diaper rash Poison ivy/oak/sumac Smoking deterrent Counterirritant

Defer Defer IISE Defer Defer IISE IISE Defer Defer IIE IIIE

n/a n/a n/a n/a IISE n/a IISE n/a IISE IIE IIIE

310.545(a)(22)(i) Pending Pending 310.545(a)(10)(iv) 310.545(a)(10)(vii) 310.527(a) 310.545(a)(18)(ii) Pending 310.545(a)(18)(vi) 310.544(d) 310.545(a)(10)(ii)

External analgesic Relief of oral discomfort External analgesic External analgesic Skin protectant External analgesic

Poison ivy/oak/sumac Toothache relief Astringent Fever blister (topical) Astringent Analgesic/anesthetic

n/a I IISE Defer IISE IIIE

IIIE IIISE n/a IIIE IISE IIIE

310.545(a)(10)(vii) Pending Pending 310.545(a)(10)(v) 310.545(a)(18)(ii) 310.545(a)(10)(i)

Cough/cold (bronchodilator)

Bronchodilator

IIIE

IIIE

310.545(a)(6)(iv)(A)

====

====

====

====

====

Hair growth/loss

Hair grower

IISE

n/a

310.527(a)

Digestive aid

Digestive aid (intestinal distress)

n/a

n/a

310.545(a)(18)(ii)

Weight control

Anorectic

IISE

IISE

310.545(a)(20)

External analgesic Skin protectant Skin protectant Menstrual/diuretic Oral health care

Insect bite/sting Insect bite/sting Poison ivy/oak/sumac Diuretic Antimicrobial

IISE IISE IISE n/a IISE

IISE IISE IISE IISE IISE

310.545(a)(10)(vi) 310.545(a)(18)(v)(A) 310.545(a)(18)(vi)(A) 310.545(a)(24)(i) Pending

Weight control

Anorectic

IISE

IISE

310.545(a)(20)

External analgesic Skin protectant

Astringent Astringent

IISE IISE

n/a IISE

Pending 310.545(a)(18)(ii)

Weight control

Anorectic

IISE

IISE

310.545(a)(20)

Weight control

Anorectic

IISE

IISE

310.545(a)(20)

Menstrual/diuretic Weight control

Premenstrual/menstrual period Anorectic

n/a IISE

IISE IISE

310.545(a)(24)(i) 310.545(a)(20)

Weight control

Anorectic

IISE

IISE

310.545(a)(20)

====

====

====

====

====

Antimicrobial

Antimicrobial

IIS

IIS

Pending

Current Regulatory Status of Over-the-Counter Products

Review Panel Folic acid Miscellaneous internal Formaldehyde solution Dental Formic acid Miscellaneous external Frangula Laxative Fructose Miscellaneous internal Miscellaneous internal Galega Miscellaneous internal Gamboge Laxative Garlic, dehydrated Miscellaneous internal Miscellaneous internal Gastric mucin Antacid Gelatin Oral cavity Ophthalmic Gentian violet Miscellaneous internal Oral cavity Gentiana lutea (gentian) Miscellaneous internal Ginger Miscellaneous internal Ginger, ground [see ginger, Jamaica] ==== Ginger, Jamaica Miscellaneous internal Ginseng Miscellaneous internal Sedative Ginseng, korean Miscellaneous internal Glutamic acid Miscellaneous internal Glutamic acid hydrochloride Miscellaneous internal Miscellaneous internal Miscellaneous internal Glycerin Hemorrhoidal Hemorrhoidal Hemorrhoidal Hemorrhoidal Laxative Miscellaneous external Miscellaneous external Miscellaneous external Miscellaneous external Miscellaneous external Miscellaneous external Miscellaneous external Oral cavity Ophthalmic Topical analgesic Topical analgesic Glycerin, anhydrous ==== ====

97

Report

Drug Category

ANPR

PR

FR

Weight control

Anorectic

IISE

IISE

310.545(a)(20)

Relief of oral discomfort

Tooth desensitizer

IIIE

IIIE

Pending

Pediculicide

Pediculicide

n/a

n/a

310.545(a)(25)(i)

Laxative

Stimulant laxative

IIISE

IIISE

310.545(a)(12)(iv)(A)

Overindulgence in alcohol/food Weight control

Minimize inebriation

IIIE

IIIE

[48 FR 32873]

Anorectic

IISE

IISE

310.545(a)(20)

Digestive aid

Digestive aid (ippuad)

n/a

n/a

310.545(a)(18)(ii)

Laxative

Stimulant laxative

IIS

IIS

310.545(a)(12)(iv)(A)

Digestive aid Digestive aid

Digestive aid (intestinal distress) Digestive aid (ippuad)

IIE IIE

IIE IIE

310.545(a)(8)(i) 310.545(a)(8)(i)

Antacid

Antacid

IIIE

IIIE

[39 FR 19873]

Oral health care Ophthalmic

Demulcent Demulcent

I I

I I

Pending 349.12(c)

Anthelmintic Oral health care

Anthelmintic Antimicrobial

I IIIE

IIS IIE

[51 FR 27758] Pending

Menstrual/diuretic

Premenstrual/menstrual period

n/a

IISE

310.545(a)(24)(i)

Digestive aid

Digestive aid (ippuad)

n/a

n/a

310.545(a)(18)(ii)

====

====

====

====

====

Smoking deterrent

Smoking deterrent

IIE

IIE

310.544(d)

Aphrodisiac Stimulant

Aphrodisiac Stimulant

IISE IIE

IISE IIE

310.528(a) [39 FR 6104]

Aphrodisiac

Aphrodisiac

IISE

IISE

310.528(a)

Benign prostatic hypertrophy

Benign prostatic hypertrophy

IIE

IIISE

310.532((a)

Digestive aid Digestive aid Stomach acidifier

Digestive aid (ippuad) Digestive aid (intestinal distress) Stomach acidifier

IIE IIE IIE

IIE IIE IIE

310.545(a)(8)(i) 310.545(a)(8)(i) 310.540(a)

Anorectal Anorectal Anorectal Anorectal Laxative Antifungal Antimicrobial External analgesic External analgesic Skin protectant Skin protectant Skin protectant Oral health care Ophthalmic Otic Skin protectant

Antiseptic (intrarectal) Antiseptic (external) Protectant (external) Protectant (intrarectal) Hyperosmotic laxative Diaper rash Diaper rash Diaper rash Poison ivy/oak/sumac Diaper rash Fever blister (topical) Poison ivy/oak/sumac Demulcent Demulcent Ear wax softening agent Skin protectant

IISE IISE I I I Defer Defer Defer Defer Defer Defer Defer I I I I

IISE IISE I I I n/a n/a DEF IISE IIISE I IISE I I IIIE I

310.545(a)(26)(ii) 310.545(a)(26)(ii) 346.14(3) 346.14(3) Pending 310.545(a)(22)(i) Pending 310.545(a)(10)(iv) 310.545(a)(10)(vii) 310.545(a)(18)(iii) Pending 310.545(a)(18)(vi)(A) Pending 349.12(d)(1) [51 FR 28660] 347.10(h)

Otic Otic

Drying water/water clogged ears Swimmer’s ear prevention

n/a n/a

IIIE IIIE

310.545(a)(15)(ii) 310.545(a)(15)(ii)

98

Handbook of Pharmaceutical Manufacturing Formulations: Over-the-Counter Products

Review Panel Glycerin, anhydrous [see glycerin] ==== Glyceryl aminobenzoate Topical analgesic Glycine Antacid Internal analgesic Laxative Laxative Miscellaneous internal Miscellaneous internal Glycol salicylate ==== Miscellaneous external Topical analgesic Glycyrrhiza Miscellaneous internal Miscellaneous internal Golden seal Miscellaneous internal Golden seal [see hydratis] ==== Gotu kola Miscellaneous internal Gramicidin Antimicrobial II Antimicrobial II Antimicrobial II Guaifenesin Cough/cold Guar gum Laxative Miscellaneous internal Haloprogin Antimicrobial II Antimicrobial II Hamamelis water of xi [see witch hazel] ==== Hard fat ==== Hemorrhoidal Hemorrhoidal Hectorite Miscellaneous external Miscellaneous external Miscellaneous internal Hemicellulase Miscellaneous internal Miscellaneous internal Hexachlorophene Antimicrobial I Contraceptive/vaginal Miscellaneous external Miscellaneous external Miscellaneous external Miscellaneous external Miscellaneous external Hexylresorcinol ==== Antimicrobial I Antimicrobial I

Report

Drug Category

ANPR

PR

FR

====

====

====

====

====

Sunscreen

Sunscreen

I

I

310.545(a)(29)

Antacid Internal analgesic Antidiarrheal Antiemetic Benign prostatic hypertrophy Digestive aid

Antacid Corrective Antidiarrheal Antiemetic Benign prostatic hypertrophy

I I IIE IIE IIE

I n/a IIE IIE IIISE

331.11(f) Pending 310.545(a)(3)(i) [52 FR 15891] 310.532(a)

Digestive aid (ippuad)

n/a

n/a

310.545(a)(18)(ii)

External analgesic External analgesic External analgesic

Poison ivy/oak/sumac Fever blister (topical) Analgesic/anesthetic

n/a Defer IIIE

IIIE IIIE IIIE

310.545(a)(10)(vii) 310.545(a)(10)(v) Pending

Aphrodisiac Menstrual/diuretic

Aphrodisiac Premenstrual/menstrual period

IIE n/a

IISE IISE

310.528(a) 310.545(a)(24)(i)

Aphrodisiac

Aphrodisiac

IISE

IISE

310.528(a)

====

====

====

====

====

Aphrodisiac

Aphrodisiac

IISE

IISE

310.528(a)

Antibiotic Antibiotic Antibiotic

First aid antibiotic Skin wound protectant Skin wound antibiotic

n/a IIS IIISE

IIISE Defer Defer

[52 FR 47322] [52 FR 47322] [52 FR 47322]

Cough/cold (expectorant)

Expectorant

IIIE

IIIE

341.18

Laxative Weight control

Bulk laxative Anorectic

IIIE IIIE

IIIE IISE

310.545(a)(12)(i) 310.545(a)(20)

Antifungal Antifungal

Anticandidal Antifungal

I I

n/a I

n/a 333.210(b)

====

====

====

====

====

Skin protectant Anorectal Anorectal

Skin protectant Protectant (external) Protectant (intrarectal)

n/a n/a n/a

n/a n/a n/a

347.10(i) 346.14(4) 346.14(4)

External analgesic Skin protectant Digestive aid

Poison ivy/oak/sumac Poison ivy/oak/sumac Digestive aid (intestinal distress)

Defer Defer n/a

IISE IISE n/a

310.545(a)(10)(vii) 310.545(a)(18)(vi)(A) 310.545(a)(18)(ii)

Digestive aid Exocrine pancreatic insufficiency

Digestive aid (intestinal distress) Exocrine pancreatic insufficiency

IIIE IIE

IIIE IIE

310.545(a)(8)(i) 310.543(a)

Antimicrobial Vaginal Antifungal Antimicrobial Boil treatment External analgesic Skin protectant

Antimicrobial Minor irritations Diaper rash Diaper rash Boil treatment Diaper rash Diaper rash

IIS IISE Defer Defer IISE Defer Defer

n/a Withdraw n/a IISE IISE n/a n/a

[37 FR 20163] n/a 310.545(a)(22)(i) Pending 310.531(a) 310.545(a)(10)(iv) Pending

External analgesic Antimicrobial Antimicrobial

Poison ivy/oak/sumac Antimicrobial soap First aid antiseptic

n/a n/a n/a

IIIE IIE I

310.545(a)(10)(vii) Pending Pending

Current Regulatory Status of Over-the-Counter Products

Review Panel

Report

Drug Category

ANPR

PR

FR

Antimicrobial I

Antimicrobial

IIIE

IIIE

Pending

Antimicrobial I Antimicrobial I Antimicrobial I Antimicrobial I

Antimicrobial Antimicrobial Antimicrobial Antimicrobial

IIIE IIIE I IIIE

IIIE IIIE I IIIE

Pending Pending Pending Pending

Antimicrobial I Miscellaneous external Oral cavity Topical analgesic Histamine dihydrochloride Miscellaneous external Topical analgesic Histidine Miscellaneous internal Homatropine methylbromide Laxative Miscellaneous internal

Antimicrobial External analgesic Oral health care External analgesic

Health care personnel handwash Preoperative skin prep Skin antiseptic Skin wound cleanser Skin wound protectant Surgical hand scrub Fever blister (topical) Analgesic/anesthetic Analgesic/anesthetic

IIIE Defer I IIIE

IIIE IIIE I IIIE

Pending 310.545(a)(10)(v) Pending 310.545(a)(10)(i)

External analgesic External analgesic

Fever blister (topical) Counterirritant

Defer I

IISE I

310.545(a)(10)(v) Pending

Weight control

Anorectic

IISE

IISE

310.545(a)(20)

Antidiarrheal Digestive aid

Antidiarrheal Digestive aid (intestinal distress) Digestive aid (ippuad) Smooth muscle relaxant

IIISE IIIE

IIISE IIIE

310.545(a)(3) 310.545(a)(8)(i)

IIE IIE

IIE IIIE

310.545(a)(8)(i) 310.545(a)(24)(i)

External analgesic n/a

Fever blister (topical) Sunscreen

Defer n/a

Defer I

Pending 352.10(f)

External analgesic Skin protectant

Astringent Astringent

IISE IISE

n/a IISE

Pending 310.545(a)(18)(ii)

Cough/cold (antitussive) Oral health care

Antitussive

IIIE

IIIE

[52 FR 30054]

Expectorant

IIIE

IIIE

310.545(a)(6)(iii)

Hair growth/loss

Hair grower

IISE

IIE

310.527(a)

Digestive aid

Digestive aid (ippuad)

n/a

n/a

310.545(a)(18)(ii)

Digestive aid

Digestive aid (ippuad)

n/a

n/a

310.545(a)(18)(ii)

Menstrual/diuretic

Diuretic

n/a

IISE

310.545(a)(24)(i)

Menstrual/diuretic

Diuretic

n/a

IISE

310.545(a)(24)(i)

Anorectal

Counterirritant (intrarectal) Antiseptic (external) Counterirritant (external) Antiseptic (intrarectal) Aphrodisiac

IISE

IISE

310.545(a)(26)(iv)

IISE IISE

IISE IISE

310.545(a)(26)(iv) 310.545(a)(26)(iv)

IISE

IISE

310.545(a)(26)(ii)

IISE

IISE

310.528(a)

n/a

n/a

310.545(a)(18)(ii)

n/a IISE

IISE IISE

310.545(a)(24)(i) 310.545(a)(20)

Miscellaneous internal Miscellaneous internal Homosalate Miscellaneous external Topical analgesic Honey Miscellaneous external Miscellaneous external Horehound Cough/cold Oral cavity Hormone constituents Miscellaneous external Horsetail Miscellaneous internal Huckleberry Miscellaneous internal Hyascyamine sulfate Miscellaneous internal Hydrangea, powdered extract (extract of hydrangea) Miscellaneous internal Hydrastis Hemorrhoidal

Digestive aid Menstrual/diuretic

Hemorrhoidal Hemorrhoidal

Anorectal Anorectal

Hemorrhoidal

Anorectal

Miscellaneous internal Hydrastis canadensis (golden seal) Miscellaneous internal

Aphrodisiac

Miscellaneous internal Miscellaneous internal Hydrastis fluid extract Miscellaneous internal Hydrate magnesium aluminate activated sulfate Antacid Hydriodic acid syrup Cough/cold

Menstrual/diuretic Weight control

Digestive aid (intestinal distress) Menstrual Anorectic

Digestive aid

Digestive aid (ippuad)

n/a

n/a

310.545(a)(18)(ii)

Antacid

Antacid

n/a

n/a

331.11(g)(1)

Cough/cold (expectorant)

Expectorant

IISE

IISE

310.545(a)(6)(iii)

Digestive aid

Digestive aid (ippuad)

n/a

n/a

310.545(a)(18)(ii)

Hydrochloric acid Miscellaneous internal

Digestive aid

99

100

Handbook of Pharmaceutical Manufacturing Formulations: Over-the-Counter Products

Review Panel Hydrochloric acid diluted [see hydrochloric acid, diluted] ==== Hydrochloric acid, diluted Miscellaneous internal Hydrocodone bitartrate Cough/cold Hydrocortisone Antimicrobial II Miscellaneous external Topical analgesic Hydrocortisone (0.25–5%) Miscellaneous external Hydrocortisone (0.5–1%) Miscellaneous external Hydrocortisone acetate ==== Antimicrobial II Miscellaneous external Miscellaneous external Miscellaneous external Miscellaneous external Miscellaneous external Topical analgesic Hydrocortisone acetate (0.25–5.0%) Miscellaneous external Hydrocortisone acetate (0.25–0.5%) Miscellaneous external Hydrocortisone alcohol [see hydrocortisone] ==== Hydrogen fluoride Dental Hydrogen peroxide Antimicrobial I Dental Dental Miscellaneous external Miscellaneous external Oral cavity Oral cavity Hydrogen peroxide and povidone iodine ==== Hydrogen peroxide and sodium bicarbonate ==== Hydrogen peroxide, sodium citrate, sodium lauryl sulfate, and zinc chloride ==== Hydroquinone Miscellaneous external Hydroxyethyl cellulose Ophthalmic Hydroxyethylcellulose [see hydroxyethyl cellulose] ==== Hydroxypropyl methylcellulose [see hypromellose] ==== Hyoscyamine sulfate Laxative Miscellaneous internal Hypromellose Ophthalmic

Report

Drug Category

ANPR

PR

FR

====

====

====

====

====

Stomach acidifier

Stomach acidifier

IIE

IIE

310.540(a)

Cough/cold (antitussive)

Antitussive

IIS

IIS

[52 FR 30054]

Antifungal Dandruff/seborrheic dermatitis/psoriasis External analgesic

Anti-inflammatory Dandruff/seborrheic dermatitis/psoriasis Antipruritic

I combo IIISE

n/a Defer

n/a n/a

I

I

Pending

External analgesic

Dandruff/seborrheic dermatitis/psoriasis

n/a

I

Pending

External analgesic

Dandruff

n/a

IIISE

Pending

External analgesic Antifungal Antifungal Antimicrobial Dandruff/seborrheic dermatitis/psoriasis External analgesic Skin protectant External analgesic

Poison ivy/oak/sumac Anti-inflammatory (dissent) Diaper rash Diaper rash Dandruff/seborrheic dermatitis/psoriasis Diaper rash Diaper rash Antipruritic

n/a I combo Defer Defer IIISE

I n/a n/a n/a Defer

Pending n/a 310.545(a)(22)(i) Pending n/a

Defer Defer I

n/a n/a I

310.545(a)(10)(iv) Pending Pending

External analgesic

Dandruff/seborrheic Dermatitis/psoriasis

n/a

I

Pending

External analgesic

Dandruff/seborrheic dermatitis /psoriasis

n/a

I

Pending

====

====

====

====

====

Anticaries

Anticavity dental rinse

n/a

IIISE

310.545(a)(2)(i)

Antimicrobial Oral mucosal injury Oral mucosal injury External analgesic Skin protectant Oral health care Oral health care

First aid antiseptic Wound cleanser Wound healing agent Poison ivy/oak/sumac Poison ivy/oak/sumac Antimicrobial Debriding agent

n/a I IIIE Defer Defer IIIE III

I I IIIE IISE IISE IIIE III

Pending Pending 310.534(a) 310.545(a)(10)(vii) 310.545(a)(18)(vi)(A) Pending Pending

Gingivitis/plaque

Antiplaque/gingivitis

n/a

IIISE

Pending

Gingivitis/plaque

Antiplaque/gingivitis

n/a

IIISE

Pending

Gingivitis/plaque

Antiplaque/gingivitis

n/a

IIISE

Pending

Skin bleach

Skin bleaching

I

I

Pending

Ophthalmic

Demulcent

I

I

349.12(a)(2)

====

====

====

====

====

====

====

====

====

====

Antidiarrheal Menstrual/diuretic

Antidiarrheal Diuretic

IIISE n/a

IIISE IISE

310.545(a)(3) 310.545(a)(24)(i)

Ophthalmic

Demulcent

I

I

349.12(a)(3)

Current Regulatory Status of Over-the-Counter Products

101

Review Panel

Report

Drug Category

ANPR

PR

FR

Ibuprofen ==== ==== Ichthammol Miscellaneous external Miscellaneous external Impatiens biflora tincture Miscellaneous external Miscellaneous external Infusion of rose petal [see rose petal, infusion of] ==== Inositol Miscellaneous internal Iodine Miscellaneous external Miscellaneous external Miscellaneous internal Miscellaneous internal Oral cavity Iodine complex/phosphate ester of alkylaryloxy polyethylene Antimicrobial I Antimicrobial I Antimicrobial I Antimicrobial I

Internal analgesic Internal analgesic

Analgesic Antipyretic

n/a n/a

I I

[67 FR 54139] [67 FR 54139]

Boil treatment Corn/callus remover

Boil treatment Corn/callus remover

IISE IISE

IIISE IISE

310.531(a) [55 FR 33261]

Skin protectant External analgesic

Poison ivy/oak/sumac Poison ivy/oak/sumac

Defer Defer

IISE IISE

310.545(a)(18)(vi)(A) 310.545(a)(10)(vii)

====

====

====

====

====

Weight control

Anorectic

IISE

IISE

310.545(a)(20)

Wart remover Corn/callus remover Digestive aid Weight control Oral health care

Wart remover Corn/callus remover Digestive aid (ippuad) Anorectic Antimicrobial

IISE IISE n/a IISE IIISE

IISE IISE n/a IISE IIISE

[55 FR 33254] [55 FR 33261] 310.545(a)(18)(ii) 310.545(a)(20) Pending

Antimicrobial Antimicrobial Antimicrobial Antimicrobial

IIISE IIISE IIISE IIISE

IIISE IIISE IIISE IIISE

Pending Pending Pending Pending

Antimicrobial I Antimicrobial I Antimicrobial I Iodine tincture Antimicrobial I Antimicrobial I Antimicrobial I Antimicrobial I Antimicrobial I Antimicrobial I Antimicrobial I Antimicrobial I

Antimicrobial Antimicrobial Antimicrobial

Surgical hand scrub Skin wound cleanser Skin wound protectant Health care personnel handwash Preoperative skin preparation Antimicrobial soap Skin antiseptic

IIISE n/a IIISE

IIISE IISE IIISE

Pending Pending Pending

Antimicrobial Antimicrobial Antimicrobial Antimicrobial Antimicrobial Antimicrobial Antimicrobial Antimicrobial

First aid antiseptic Preoperative skin prep Surgical hand scrub Antimicrobial soap Skin wound protectant Skin wound cleanser Skin antiseptic Health care personnel handwash

n/a I IIS n/a IISE IIS IIS IISE

I I IIS IISE IIISE IIIS IIIS IISE

Pending Pending Pending Pending Pending Pending Pending Pending

Antimicrobial

First aid antiseptic

n/a

I

Pending

Cough/cold (expectorant)

Expectorant

IISE

IISE

310.545(a)(6)(iii)

Internal analgesic Internal analgesic Internal analgesic

Analgesic Antipyretic Antirheumatic

IISE IISE IISE

IISE IISE Not OTC

310.545(a)(23)(i) 310.545(a)(23)(i) 310.545(a)(23)(i)

====

====

====

====

====

Cough/cold (expectorant)

Expectorant

IIE

IIE

310.545(a)(6)(iii)

Cough/cold (expectorant) Poison treatment

Expectorant

IIE

IIE

310.545(a)(6)(iii)

Emetic

n/a

IIS

310.545(a)(16)

Cough/cold (expectorant) Emetic Poison treatment

Expectorant

IIIE

IIIE

310.545(a)(6)(iii)

Emetic Emetic

I n/a

I I

Pending Pending

Poison treatment

Emetic

n/a

IIS

310.545(a)(16)

Laxative

Stimulant laxative

IIS

IIS

310.545(a)(12)(iv)(A)

Iodine topical solution Antimicrobial I Iodized lime Cough/cold Iodoantipyrine Internal analgesic Internal analgesic Internal analgesic Iodochlorhydroxyquin [see clioquinol] ==== Ipecac Cough/cold Ipecac fluidextract Cough/cold Miscellaneous internal Ipecac syrup Cough/cold Miscellaneous internal Miscellaneous internal Ipecac tincture Miscellaneous internal Ipomea Laxative

102

Handbook of Pharmaceutical Manufacturing Formulations: Over-the-Counter Products

Review Panel Iron ox bile Miscellaneous internal Iron oxide Miscellaneous external Miscellaneous external Miscellaneous external Miscellaneous external Miscellaneous external Miscellaneous external Isobornyl thiocyanoacetate Miscellaneous external Isobutamben Miscellaneous external Isobutyl p-aminobenzoate [see isobutaben] ==== Isoleucine Miscellaneous internal Isopropyl alcohol Miscellaneous external Miscellaneous external Miscellaneous external Miscellaneous external Miscellaneous external Miscellaneous external Isopropyl palmitate ==== ==== ==== Jalap Laxative John’s wort Miscellaneous internal Jojoba oil Miscellaneous external Juniper Miscellaneous internal Juniper oil (oil of juniper) Miscellaneous internal Juniper tar ==== ==== ==== ==== ==== ==== Hemorrhoidal Hemorrhoidal Hemorrhoidal Miscellaneous external Miscellaneous external Topical analgesic Juniper, extract Miscellaneous internal Kaolin ==== Antacid Hemorrhoidal Hemorrhoidal Laxative Miscellaneous external Topical analgesic Kaolin, colloidal Miscellaneous internal Karaya [see karaya gum] ====

Report

Drug Category

ANPR

PR

FR

Digestive aid

Digestive aid (intestinal distress)

n/a

n/a

310.545(a)(18)(ii)

Antifungal Antimicrobial External analgesic External analgesic Skin protectant Skin protectant

Diaper rash Diaper rash Diaper rash Poison ivy/oak/sumac Diaper rash Poison ivy/oak/sumac

Defer Defer Defer Defer Defer Defer

n/a n/a n/a IISE n/a IISE

310.545(a)(22)(i) Pending 310.545(a)(10)(iv) 310.545(a)(10)(vii) Pending 310.545(a)(18)(vi)(A)

Pediculicide

Pediculicide

IISE

IISE

310.545(a)(25)(i)

Boil treatment

Boil treatment

IISE

IISE

310.531(a)

====

====

====

====

====

Weight control

Anorectic

IISE

IISE

310.545(a)(20)

Alcohols (topical) Mercury Analgesic External analgesic Skin protectant Skin protectant

Antiseptic First aid antiseptic Astringent Poison ivy/oak/sumac Astringent Poison ivy/oak/sumac

I n/a IISE Defer IISE Defer

I I n/a IISE IISE IISE

Pending Pending Pending 310.545(a)(10)(vii) 310.545(a)(18)(ii) 310.545(a)(18)(vi)(A)

Insect bite/sting Poison ivy/oak/sumac Skin protectant

Insect bite/sting Poison ivy/oak/sumac Skin protectant

n/a n/a n/a

n/a n/a n/a

310.545(a)(18)(v)(B) 310.545(a)(18)(vi)(B) 310.545(a)(18)(i)(B)

Laxative

Stimulant laxative

IIS

IIS

310.545(a)(12)(iv)(A)

Digestive aid

Digestive aid (ippuad)

n/a

n/a

310.545(a)(18)(ii)

Hair growth/loss

Hair grower

n/a

IIE

310.527(a)

Digestive aid

Digestive aid (intestinal distress)

n/a

n/a

310.545(a)(18)(ii)

Menstrual/diuretic

Diuretic

n/a

IISE

310.545(a)(24)(i)

Antifungal Antimicrobial External analgesic External analgesic External analgesic Skin protectant Anorectal Anorectal Anorectal Boil treatment Dandruff/seborrheic dermatitis/psoriasis External analgesic

Diaper rash Diaper rash Diaper rash Fever blister (topical) Poison ivy/oak/sumac Diaper rash Counterirritant (external) Analgesic (external) Counterirritant (intrarectal) Boil treatment Dandruff/seborrheic dermatitis/psoriasis Analgesic/anesthetic

n/a n/a n/a n/a n/a n/a IIISE n/a IIISE IISE IIIE

n/a n/a IISE I I n/a n/a I n/a IIISE IIIE

310.545(a)(22)(i) Pending 310.545(a)(10)(iv) Pending Pending Pending n/a 346.16(b) n/a 310.531(a) 310.545(a)(7)

I

I

Pending

Weight control

Anorectic

IISE

IISE

310.545(a)(20)

Skin protectant Antacid Anorectal Anorectal Antidiarrheal Skin protectant Skin protectant

Poison ivy/oak/sumac Antacid Protectant (intrarectal) Protectant (external) Antidiarrheal Diaper rash Skin protectant

n/a IIIE I I IIIE n/a I

I IIIE I I IIIE I I

347.10(j) [39 FR 19873] 346.14(5) 346.14(5) 347.10(b) Pending 347.10(j)

Digestive aid

Digestive aid (ippuad)

n/a

n/a

310.545(a)(18)(ii)

====

====

====

====

====

Current Regulatory Status of Over-the-Counter Products

Review Panel Karaya gum Laxative Miscellaneous internal Kelp Miscellaneous internal Knotgrass Miscellaneous internal Lactic acid Contraceptive/vaginal

Report

Drug Category

ANPR

PR

FR

Laxative Weight control

Bulk laxative Anorectic

I IIIE

I IISE

Pending 310.545(a)(20)

Weight control

Anorectic

IIIE

IISE

310.545(a)(20)

Digestive aid

Digestive aid (intestinal distress)

n/a

n/a

310.545(a)(18)(ii)

Vaginal

IIIE

Withdraw

n/a

IIIE IIIE n/a

Withdraw IIIE n/a

n/a [55 FR 33254] 310.545(a)(18)(ii)

Contraceptive/vaginal Miscellaneous external Miscellaneous internal Lactobacillus acidophilus Laxative Miscellaneous internal Lactobacillus bulgaricus Laxative Miscellaneous internal Lactose Miscellaneous internal

Vaginal Wart remover Digestive aid

Lowers surface tension mucolytic effects Alters vaginal pH Wart remover Digestive aid (ippuad)

Antidiarrheal Fever blister (oral)

Antidiarrheal Fever blister/oral

IIIE IIIE

IIIE IIIE

310.545(a)(3)(i) 310.537(a)

Antidiarrheal Fever blister (oral)

Antidiarrheal Fever blister/oral

IIIE IIIE

IIIE IIIE

310.545(a)(3)(i) 310.537(a)

Digestive aid

n/a

n/a

310.545(a)(18)(ii)

Miscellaneous internal Lanolin ==== Hemorrhoidal Hemorrhoidal

Weight control

Digestive aid (intestinal distress) Anorectic

IISE

IISE

310.545(a)(20)

n/a I I

n/a I I

347.10(k) 346.14(6) 346.14(6)

Miscellaneous external Miscellaneous external Miscellaneous external Miscellaneous external Miscellaneous external Miscellaneous external

Antifungal Antimicrobial Boil treatment External analgesic External analgesic External analgesic

Defer Defer IISE Defer Defer Defer

n/a n/a IISE n/a n/a IISE

310.545(a)(22)(i) Pending 310.531(a) 310.545(a)(10)(iv) n/a 310.545(a)(10)(vii)

Miscellaneous external Miscellaneous external Miscellaneous external Miscellaneous external

Hair growth/loss Skin protectant Skin protectant Skin protectant

Skin protectant Protectant (external) Protectant (intrarectal) Diaper rash Diaper rash Boil treatment Diaper rash Fever blister (topical) Poison ivy/oak/ sumac Hair grower Diaper rash Fever blister (topical) Poison ivy/oak/ sumac

IIE Defer Defer Defer

IIE I n/a IISE

310.527(a) Pending n/a 310.545(a)(18)(vi)

Lanolin (in combination) Ophthalmic Lanolin alcohol [see lanolin alcohols] ==== Lanolin alcohols Hemorrhoidal Hemorrhoidal Miscellaneous external Miscellaneous external Lanolin anhydrous [see lanolin, anhydrous] ==== Lanolin nonionic derivatives Ophthalmic Lanolin, anhydrous (in combination) Ophthalmic lappa extract Hemorrhoidal Hemorrhoidal Laureth 10s Contraceptive/vaginal Lauric diethanolamide Miscellaneous external Lauryl isoquinolinium bromide Miscellaneous external

Skin protectant Anorectal Anorectal

103

Ophthalmic

Emollient

I

I

349.14(a)(2)

====

====

====

====

====

Anorectal Anorectal

I I

IIISE IIISE

310.545(a)(26)(viii) 310.545(a)(26)(viii)

External analgesic Skin protectant

Protectant (external) Protectant (intrarectal) Fever blister (topical) Fever blister (topical)

Defer Defer

n/a n/a

Pending Pending

====

====

====

====

====

Ophthalmic

Emollient

I

I

349.14

Ophthalmic

Emollient

I

I

349.14(a)(1)

Anorectal Anorectal

Anorectal (external) Anorectal (intrarectal)

IISE IISE

IISE IISE

310.545(a)(26)(vii) 310.545(a)(26)(vii)

Contraceptive (vaginal)

Contraceptive

IIIE

Withdraw)

310.545(a)(28

Hair growth/loss

Hair grower

IISE

n/a

310.527(a)

Dandruff/seborrheic dermatitis/psoriasis

Dandruff

IIIE

IIIE

310.545(a)(7)

104

Handbook of Pharmaceutical Manufacturing Formulations: Over-the-Counter Products

Review Panel Lavender compound, tincture of Miscellaneous internal Lavender oil Miscellaneous external Miscellaneous external Miscellaneous external Lawsone with dihydroxyacetone Topical analgesic L-Desoxyephedrine [see desoxyephedrine, L-] ==== Lead acetate Miscellaneous external Miscellaneous external Lecithin Miscellaneous internal Lemon oil (terpeneless) Miscellaneous internal Leptandra extract Hemorrhoidal Hemorrhoidal Leucine Miscellaneous internal Levmetamfetamine Cough/cold Levomethamphetamine [see desoxyephedrine, L-] ==== Licorice Miscellaneous internal Licorice root extract Miscellaneous internal Lidocaine Hemorrhoidal Hemorrhoidal Miscellaneous external Miscellaneous external

Report

Drug Category

ANPR

PR

FR

Digestive aid

Digestive aid (ippuad)

n/a

n/a

310.545(a)(18)(ii)

Antifungal External analgesic Skin protectant

Diaper rash Diaper rash Diaper rash

Defer Defer Defer

n/a n/a n/a

310.545(a)(22)(i) 310.545(a)(10)(iv) Pending

Sunscreen

Sunscreen

I

I

310.545(a)(29)

====

====

====

====

====

External analgesic

Poison ivy/oak/ sumac Poison ivy/oak/ sumac

Defer

IISE

310.545(a)(10)(vii)

Defer

IISE

310.545(a)(18)(vi)(A)

Weight control

Anorectic

IISE

IISE

310.545(a)(20)

Smoking deterrent

Smoking deterrent

IIE

IIE

310.544(d)

Anorectal Anorectal

Anorectal (external) Anorectal (intrarectal)

IISE IISE

IISE IISE

310.545(a)(26)(vii) 310.545(a)(26)(vii)

Weight control

Anorectic

IISE

IISE

310.545(a)(20)

Cough/cold (nasal decongestant)

Nasal decongestant (topical/inhalant))

IIIE

I

341.20(b)(1)

====

====

====

====

====

Aphrodisiac

Aphrodisiac

IISE

IISE

310.528(a)

Smoking deterrent

Smoking deterrent

IIE

IIE

310.544(d)

Anorectal Anorectal

Anesthetic (external) Anesthetic (intrarectal) Fever blister (topical) Male genital desensitizer Poison ivy/oak/ sumac Poison ivy/oak/ sumac Analgesic/anesthetic Analgesic/anesthetic

IIIE IIIE

I IIIE

346.10(f) [55 FR 1779]

Defer I

I I

Pending 348.10(a)(2)

Defer

I

Pending

Defer

IISE

310.545(a)(18)(vi)(A)

IIS I

IIS I

310.545(a)(14) Pending

n/a

I

Pending

External analgesic Oral health care External analgesic

Poison ivy/oak/ sumac Fever blister (topical) Analgesic/anesthetic Analgesic/anesthetic

Defer IIS I

I IIS I

Pending 310.545(a)(14) Pending

Digestive aid

Digestive aid (ippuad)

n/a

n/a

310.545(a)(18)(ii)

Digestive aid

Digestive aid (intestinal distress)

n/a

n/a

310.545(a)(18)(ii)

Insect bite/sting Poison ivy/oak/sumac

n/a n/a

n/a n/a

310.545(a)(18)(v)(B) 310.545(a)(18)(vi)(B)

Skin protectant

Insect bite/sting Poison ivy/oak/ sumac Skin protectant

IIIE

IIIE

310.545(a)(18)(i)(B)

Weight control

Anorectic

IISE

IISE

310.545(a)(20)

Smoking deterrent

Smoking deterrent

IIIE

IIIE

310.544(d)

Skin protectant

Miscellaneous external

External analgesic Male genital desensitizer External analgesic

Miscellaneous external

Skin protectant

Oral cavity Topical analgesic Lidocaine hydrochloride ====

Oral health care External analgesic

Miscellaneous external Oral cavity Topical analgesic Linden Miscellaneous internal Lipase Miscellaneous internal Live yeast cell derivative ==== ==== Topical analgesic Liver concentrate Miscellaneous internal Lobeline Miscellaneous internal

External analgesic

Current Regulatory Status of Over-the-Counter Products

Review Panel Lysine Miscellaneous internal Lysine aspirin Internal analgesic Lysine hydrochloride Miscellaneous internal Miscellaneous internal Miscellaneous internal Magaldrate Antacid Magnesium Miscellaneous internal Magnesium aluminum silicate Antimicrobial II Antacid Magnesium aluminumsilicate [see magnesium aluminum silicate] ==== Magnesium carbonate Antacid Internal analgesic Miscellaneous external Miscellaneous external Miscellaneous external Miscellaneous external Miscellaneous internal

Magnesium citrate Laxative Magnesium glycinate Antacid Magnesium hydroxide Antacid Internal analgesic Laxative Miscellaneous internal Miscellaneous internal Magnesium oxide Antacid Miscellaneous internal Magnesium salicylate Internal analgesic Internal analgesic Internal analgesic Miscellaneous internal Magnesium sulfate Antimicrobial II Laxative Miscellaneous external Miscellaneous internal Magnesium trisilicate Antacid Miscellaneous internal Miscellaneous internal

Malt Miscellaneous internal Malt soup extract Laxative Maltodextrin Miscellaneous internal

Report

Drug Category

ANPR

PR

FR

Weight control

Anorectic

IISE

IISE

310.545(a)(20)

Internal analgesic

Analgesic

n/a

IISE

310.545(a)(23)(i)

Digestive aid

n/a

n/a

310.545(a)(18)(ii)

Fever blister (oral) Weight control

Digestive aid (intestinal distress) Fever blister/oral Anorectic

IIIE IISE

IIIE IISE

310.537(a) 310.545(a)(20)

Antacid

Antacid

I

I

331.11(g)(2)

Weight control

Anorectic

IISE

IISE

310.545(a)(20)

Acne Antacid

Acne Antacid

IIE I

IIE I

310.545(a)(1) 331.11(g)(3) 331.11(k)(2)(1)

====

====

====

====

====

Antacid Internal analgesic Antifungal Antimicrobial External analgesic Skin protectant Overindulgence in alcohol/food

Antacid Corrective Diaper rash Diaper rash Diaper rash Diaper rash Overindulgence remedies (hangover)

I I Defer Defer Defer Defer I

I n/a n/a n/a n/a n/a I

331.11(g)(4) n/a 310.545(a)(22)(i) Pending 310.545(a)(10)(iv) Pending Pending

Laxative

Saline laxative (oral solution)

I

I

Pending

Antacid

Antacid

I

I

331.11(g)(5)

Antacid Internal analgesic Laxative Digestive aid Digestive aid

Antacid Corrective Saline laxative Digestive aid (ippuad) Digestive aid (intestinal distress)

I I I IIIE IIIE

I n/a I IIIE IIIE

331.11(g)(6) Pending Pending 310.545(a)(8)(i) 310.545(a)(8)(i)

Antacid Weight control

Antacid Anorectic

I IISE

I IISE

331.11(g)(7) 310.545(a)(20)

Internal analgesic Internal analgesic Internal analgesic Menstrual/diuretic

Analgesic Antipyretic Antirheumatic Analgesic

I I I I

I I Not I

Pending Pending OTC n/a Pending

Acne Laxative Boil treatment Menstrual/diuretic

Acne Saline laxative Boil treatment Diuretic

IIE I IISE n/a

IIE I IIISE IISE

310.545(a)(1) Pending 310.531(a) 310.545(a)(24)(i)

Antacid

Antacid

I

I

Digestive aid Overindulgence in alcohol/food

Digestive aid (ippuad) Overindulgence remedies (hangover)

IIIE I

IIIE I

331.11(g)(8) 331 11(k)(3)(1) 310.545(a)(8)(i) Pending

Weight control

Anorectic

IISE

IISE

310.545(a)(20)

Laxative

Bulk laxative

I

I

Pending

Weight control

Anorectic

IISE

IISE

310.545(a)(20)

105

106

Handbook of Pharmaceutical Manufacturing Formulations: Over-the-Counter Products

Review Panel Mandrake Miscellaneous internal Manganese citrate Miscellaneous internal Mannitol Miscellaneous internal Miscellaneous internal Meclizine hydrochloride Laxative Menfegol Contraceptive/vaginal Menthol Antimicrobial II Cough/cold Cough/cold Cough/cold Cough/cold Cough/cold Cough/cold

Report

Drug Category

ANPR

PR

FR

Aphrodisiac

Aphrodisiac

n/a

n/a

310.528(a)

Weight control

Anorectic

IISE

IISE

310.545(a)(20)

Digestive aid Weight control

Digestive aid (ippuad) Anorectic

n/a IISE

n/a IISE

310.545(a)(18)(ii) 310.545(a)(20)

Antiemetic

Antiemetic

I

I

336.10(d)

Contraceptive (vaginal)

Contraceptive (dissent)

I

Withdraw

n/a

Antifungal Cough/cold (antitussive) Cough/cold (antitussive) Cough/cold (antitussive) Cough/cold (expectorant) Cough/cold (expectorant) Cough/cold (nasal decongestant) Cough/cold (nasal decongestant) Relief of oral discomfort Anorectal Antifungal Boil treatment Dandruff/seborrheic dermatitis/psoriasis

Antifungal Antitussive (mouthwash) Antitussive (topical/inhalant) Antitussive (lozenge)

IIE IIIE

IIE IIIE

310.545(a)(22)(ii) [52 FR 30055]

IIIE

I

341.14(b)(2)

IIIE

I

341.14(b)(2)

Expectorant (topical/inhalant) Expectorant (lozenge)

IIIE

IIIE

310.545(a)(6)(iii)

IIIE

IIIE

310.545(a)(6)(iii)

IIIE

IIIE

[59 FR 43408]

IIIE

IIIE

310.545(a)(6)(ii)(A)

IIS n/a Defer IISE IIIE

IIS I IISE IISE IIIE

Pending 346.16(c) 310.545(a)(22)(ii) 310.531(a) 310.545(a)(7)

IISE Defer IISE Defer

n/a IISE I I

Pending 310.545(a)(10)(iv) Pending Pending

IISE Defer Defer IISE Defer

IISE n/a Defer IISE IISE

310.545(a)(18)(ii) Pending Pending 310.545(a)(18)(v)(A) 310.545(a)(18)(vi)(A)

IISE Defer IIE IIIE I I I

IISE n/a IIE IIIE I I I

[55 FR 33254] Pending 310.544(d) Pending Pending Pending Pending

Miscellaneous external Miscellaneous external Miscellaneous external Miscellaneous external

External analgesic External analgesic External analgesic External analgesic

Miscellaneous external Miscellaneous external Miscellaneous external Miscellaneous external Miscellaneous external

Skin protectant Skin protectant Skin protectant Skin protectant Skin protectant

Miscellaneous external Miscellaneous external Miscellaneous internal Oral cavity Oral cavity Topical analgesic Topical analgesic Menthol (0.1–1.0%) Miscellaneous external Menthol (1.25–16%) Miscellaneous external Hemorrhoidal

Wart remover Antimicrobial Smoking deterrent Oral health care Oral health care External analgesic External analgesic

Nasal decongestant (lozenge) Nasal decongestant (mouthwash) Toothache relief Analgesic (external) Diaper rash Boil treatment Dandruff/seborrheic dermatitis/ psoriasis Astringent Diaper rash Insect bite/sting Poison ivy/oak/ sumac Astringent Diaper rash Fever blister (topical) Insect bite/sting Poison ivy/oak/ sumac Wart remover Diaper rash Smoking deterrent Antimicrobial Analgesic/anesthetic Counterirritant Analgesic/anesthetic

External analgesic

Fever blister (topical)

Defer

I

Pending

External analgesic Anorectal

Defer IIE

IIIE IIE

310.545(a)(10)(v) 310.545(a)(26)(iv)

Hemorrhoidal

Anorectal

Fever blister (topical) Counterirritant (intrarectal) Counterirritant (external)

I

IIE

310.545(a)(26)(iv)

====

====

====

====

====

Sunscreen

Sunscreen

I

I

352.10(h)

Oral health care

Antimicrobial

IISE

IISE

Pending

Cough/cold Dental Hemorrhoidal Miscellaneous external Miscellaneous external Miscellaneous external

Menthyl anthranilate [see meradimate] ==== Meradimate Topical analgesic Meralein sodium Oral cavity

Current Regulatory Status of Over-the-Counter Products

107

Review Panel

Report

Drug Category

ANPR

PR

FR

Merbromin Miscellaneous external

External analgesic

Defer

IISE

310.545(a)(10)(vii)

Miscellaneous external

Skin protectant

Defer

IISE

310.545(a)(18)(vi)

Miscellaneous external Merbromin (mercurochrome) Miscellaneous external Mercufenol chloride Miscellaneous external Miscellaneous external Miscellaneous external Miscellaneous external

Mercury

Poison ivy/oak/ sumac Poison ivy/oak/ sumac Antiseptic

IISE

IISE

310.545(a)(27)(i)

Mercury

First aid antiseptic

n/a

IIIE

310.545(a)(27)(i)

Mercury Mercury Antimicrobial External analgesic

n/a IISE n/a Defer

IIIE IISE IIS IISE

310.545(a)(27)(i) 310.545(a)(27)(i) 310.545(a)(27)(i) 310.545(a)(10)(vii)

Miscellaneous external

Skin protectant

First aid antiseptic Antiseptic First aid antiseptic Poison ivy/oak/ sumac Poison ivy/oak/ sumac

Defer

IISE

310.545(a)(18)(vi)(A)

====

====

====

====

====

Mercury Mercury Ophthalmic

First aid antiseptic Antiseptic Anti-infective

n/a IISE IIISE

IISE IISE IISE

310.545(a)(27)(i) 310.545(a)(27)(i) 310.545(a)(21)(ii)

Mercury Mercury

First aid antiseptic Antiseptic

n/a IISE

IISE IISE

310.545(a)(27)(i) 310.545(a)(27)(i)

Mercury Mercury

First aid antiseptic Antiseptic

n/a IISE

IISE IISE

310.545(a)(27)(i) 310.545(a)(27)(i)

====

====

====

====

====

Mercury Mercury

First aid antiseptic Antiseptic

n/a IISE

IISE IISE

310.545(a)(27)(i) 310.545(a)(27)(i)

Antimicrobial Contraceptive (vaginal)

Diaper rash Contraceptive

Defer n/a

n/a n/a

310.545(a)(27)(ii) 310.545(a)(28)

====

====

====

====

====

Mercury Dandruff/seborrheic dermatitis/psoriasis Mercury

First aid antiseptic Psoriasis

n/a IIE

IISE IIE

310.545(a)(27)(i) 310.545(a)(7)

Antiseptic

IISE

IISE

310.545(a)(27)(i)

Antimicrobial Skin bleach Mercury

First aid antiseptic Skin bleaching Antiseptic

n/a IISE IISE

IISE IISE IISE

310.545(a)(27)(i) 310.545(a)(17) 310.545(a)(27)(i)

Cough/cold (bronchodilator)

Bronchodilator

n/a

III

310.545(a)(6)(iv)(A)

Antifungal Antimicrobial External analgesic Skin protectant

Diaper rash Diaper rash Diaper rash Diaper rash

Defer Defer Defer Defer

n/a n/a n/a n/a

310.545(a)(22)(i) Pending 310.545(a)(10)(iv) Pending

Antihistamine

I

IIS

310.545(a)(6)(i)(A)&(B)

Internal analgesic Internal analgesic Internal analgesic Internal analgesic

Cough/cold (antihistamine) Internal analgesic Internal analgesic Internal analgesic Internal analgesic

IIIE IIE IIIE IIIE

IIS n/a IIS IIS

310.545(a)(23)(i) 310.545(a)(6)(A) 310.545(a)(23)(i) 310.545(a)(23)(i)

Sedative Sedative

Daytime sedative Nighttime sleep aid

Analgesic adjuvant Antihistamine Antipyretic adjuvant Antirheumatic adjuvant Sedative Sleep aid

IIISE IIISE

IISE IIS

310.519(a) [54 FR 6826]

Mercuric chloride [see calomel] ==== Mercuric oxide, yellow Miscellaneous external Miscellaneous external Ophthalmic Mercuric salicylate Miscellaneous external Miscellaneous external Mercuric sulfide, red Miscellaneous external Miscellaneous external Mercurous chloride [see calomel] ==== Mercury Miscellaneous external Miscellaneous external Mercury (any ingredient) ==== ==== Mercury chloride [see mercuric chloride] ==== Mercury oleate Miscellaneous external Miscellaneous external Miscellaneous external Mercury, ammoniated Miscellaneous external Miscellaneous external Miscellaneous external Metaproterenol sulfate Cough/cold Methapyrilene Miscellaneous external Miscellaneous external Miscellaneous external Miscellaneous external Methapyrilene fumarate Cough/cold

108

Handbook of Pharmaceutical Manufacturing Formulations: Over-the-Counter Products

Review Panel

Report

Drug Category

ANPR

PR

FR

Methapyrilene hydrochloride ====

External analgesic

n/a

IISE

310.545(a)(10)(vii)

Cough/cold (antihistamine) External analgesic Menstrual/diuretic Nighttime sleep aid Daytime sedative External analgesic

Poison ivy/oak/ sumac Antihistamine

I

IIS

310.545(a)(6)(i)(A)&(B)

Fever blister (topical) Menstrual Sleep aid Sedative Analgesic/anesthetic

Defer n/a IIISE IIISE I

IIE IISE IIS IIS IIS

310.545(a)(10)(v) 310.545(a)(24)(i) [54 FR 6826] 310.519(a) 310.545(a)(10)(i)

Menstrual/diuretic

Diuretic

n/a

IISE

310.545(a)(24)(i)

Antifungal Antimicrobial External analgesic Skin protectant Weight control

Diaper rash Diaper rash Diaper rash Diaper rash Anorectic

Defer Defer Defer Defer IISE

n/a n/a n/a n/a IISE

310.545(a)(22)(i) Pending 310.545(a)(10)(iv) Pending 310.545(a)(20)

Cough/cold (bronchodilator)

Bronchodilator

I

IIE

310.545(a)(6)(iv)(A)

Contraceptive (vaginal)

Contraceptive

IIIE

IIIE

310.545(a)(28)

External analgesic External analgesic

Fever blister (topical) Counterirritant

Defer I

IIIE I

310.545(a)(10)(v) Pending

Relief of oral discomfort Relief of oral discomfort

Toothache relief Oral mucosal analgesic Boil treatment Dandruff

IISE IISE

IISE IISE

Pending Pending

IISE IIIE

IISE IIIE

310.531(a) 310.545(a)(7)

Astringent Fever blister (topical) Astringent Corn/callus remover Smoking deterrent Antimicrobial Analgesic/anesthetic Counterirritant

n/a Defer IISE IISE IIE IIIE IIIE I

n/a IIIE IISE IISE IIE IIIE IIIE I

Pending 310.545(a)(10)(v) 310.545(a)(18)(ii) [55 FR 33261] 310.544(d) Pending 310.545(a)(14) Pending

n/a n/a IIISE IIISE IIISE I IIISE IIIE

I IISE IIISE IIISE IIISE I IIISE IIIE

Pending Pending Pending Pending Pending Pending Pending Pending

Antifungal Antimicrobial Dandruff/seborrheic dermatitis/psoriasis External analgesic Skin protectant Corn/callus remover

First aid antiseptic Antimicrobial soap Skin antiseptic Skin protectant Preoperative skin prep Skin wound cleanser Surgical hand scrub Health care personnel handwash Diaper rash Diaper rash Cradle cap

Defer Defer IIIE

n/a IIISE IIIE

310.545(a)(22)(i) Pending 310.545(a)(7)

Diaper rash Diaper rash Corn/callus remover

Defer Defer IISE

n/a n/a IISE

310.545(a)(10)(iv) Pending [55 FR 33261]

Antacid Laxative Weight control Ophthalmic

Antacid Bulk laxative Anorectic Demulcent

IIIE I IIIE I

IIIE I IISE I

[39 FR 19873] Pending 310.545(a)(20) 349.12(a)(4)

Menstrual/diuretic

Diuretic

n/a

IISE

310.545(a)(24)(i)

Cough/cold Miscellaneous external Miscellaneous internal Sedative Sedative Topical analgesic Methenamine Miscellaneous internal Methionine Miscellaneous external Miscellaneous external Miscellaneous external Miscellaneous external Miscellaneous internal Methoxyphenamine hydrochloride Cough/cold Methoxypolyoxyethylene glycol 550 laurate Contraceptive/vaginal Methyl nicotinate Miscellaneous external Topical analgesic Methyl salicylate Dental Dental Miscellaneous external Miscellaneous external Miscellaneous external Miscellaneous external Miscellaneous external Miscellaneous external Miscellaneous internal Oral cavity Oral cavity Topical analgesic Methylbenzethonium chloride Antimicrobial I Antimicrobial I Antimicrobial I Antimicrobial I Antimicrobial I Antimicrobial I Antimicrobial I Antimicrobial I Miscellaneous external Miscellaneous external Miscellaneous external Miscellaneous external Miscellaneous external Miscellaneous external Methylcellulose Antacid Laxative Miscellaneous internal Ophthalmic Methylene blue Miscellaneous internal

Boil treatment Dandruff/seborrheic dermatitis/psoriasis External analgesic External analgesic Skin protectant Corn/callus remover Smoking deterrent Oral health care Oral health care External analgesic Antimicrobial Antimicrobial Antimicrobial Antimicrobial Antimicrobial Antimicrobial Antimicrobial Antimicrobial

Current Regulatory Status of Over-the-Counter Products

Review Panel Methylparaben Antimicrobial II Methyltestosterone Miscellaneous internal Miconazole nitrate Antimicrobial II Antimicrobial II Microporous cellulose [see cellulose, microporous] ==== Milk solids, dried Antacid Mineral oil Hemorrhoidal Hemorrhoidal Laxative Miscellaneous external Miscellaneous external Miscellaneous external Miscellaneous external Miscellaneous external Miscellaneous external Ophthalmic Mineral oil, emulsified [see mineral oil] ==== Mineral oil, light Ophthalmic Minerals Miscellaneous internal Mono- and di-glycerides Miscellaneous internal Mullein Hemorrhoidal Hemorrhoidal Mustard oil [see allyl isothiocyanate] ==== Mycozyme Miscellaneous internal Myrrh Dental Myrrh tincture Oral cavity Oral cavity Myrrh tincture of [see myrrh tincture] ==== Myrrh, fluid extract of Miscellaneous internal Naphazoline hydrochloride Cough/cold Ophthalmic Natural estrogenic hormone Miscellaneous internal Neomycin sulfate Antimicrobial II Neomycin sulfate (cream) Antimicrobial II Neomycin sulfate (ointment) Antimicrobial II Nettle Miscellaneous internal

Report

Drug Category

ANPR

PR

FR

Antifungal

Antifungal

IIISE

IIISE

310.545(a)(22)(ii)

Aphrodisiac

Aphrodisiac

IIS

IIS

310.528(a)

Antifungal Antifungal

Anticandidal Antifungal

I I

n/a I

n/a 333.210(c)

====

====

====

====

====

Antacid

Antacid

I

I

331.11(h)

Anorectal Anorectal

I I

I I

346.14(7) 346.14(7)

Laxative Antifungal Antimicrobial External analgesic External analgesic Skin protectant Skin protectant Ophthalmic

Protectant (external) Protectant (intrarectal) Lubricant laxative Diaper rash Diaper rash Diaper rash Fever blister (topical) Diaper rash Fever blister (topical) Emollient

I Defer Defer Defer Defer Defer Defer I

I n/a n/a n/a n/a I n/a I

Pending 310.545(a)(22)(i) Pending 310.545(a)(10)(iv) n/a Pending Pending 349.14(b)(2)

====

====

====

====

====

Ophthalmic

Emollient

I

I

349.14(b)(1)

Aphrodisiac

Aphrodisiac

n/a

IISE

310.528(a)

Weight control

Anorectic

IISE

IISE

310.545(a)(20)

Anorectal Anorectal

Anorectal (external) Anorectal (intrarectal)

IISE IISE

IISE IISE

310.545(a)(26)(vii) 310.545(a)(26)(vii)

====

====

====

====

====

Digestive aid

Digestive aid (intestinal distress)

n/a

n/a

310.545(a)(18)(ii)

Relief of oral discomfort

Oral mucosal protectant

IIISE

IIISE

Pending

Oral health care Oral health care

Antimicrobial Astringent

IISE IISE

IISE IISE

310.545(a)(14) Pending

====

====

====

====

====

Digestive aid

Digestive aid (ippuad)

n/a

n/a

310.545(a)(18)(ii)

Cough/cold (nasal decongestant) Ophthalmic

Nasal decongestant (topical/inhalant)) Vasoconstrictor

I

I

341.20(b)(6)

I

I

349.18(b)

Menstrual/diuretic

Menstrual

n/a

IISE

310.545(a)(24)(i)

Antibiotic

Skin wound protectant

IIIS

Defer

n/a

Antibiotic

First aid antibiotic

n/a

I

333.110(e)

Antibiotic

First aid antibiotic

n/a

I

333.110(d)

Digestive aid

Digestive aid (ippuad)

n/a

n/a

310.545(a)(18)(ii)

109

110

Handbook of Pharmaceutical Manufacturing Formulations: Over-the-Counter Products

Review Panel Niacinamide Miscellaneous internal Miscellaneous internal Sedative Nickel-pectin Miscellaneous internal Nitromersol Miscellaneous external Miscellaneous external Oral cavity Nonoxynol 9 Contraceptive/vaginal

Contraceptive/vaginal Contraceptive/vaginal Nonylphenoxypoly (ethyleneoxy) ethanol iodine Antimicrobial I Antimicrobial I Antimicrobial I Antimicrobial I Antimicrobial I Antimicrobial I Noscapine Cough/cold Noscapine hydrochloride Cough/cold Nucleic acids Miscellaneous external Nutmeg oil (oil of nutmeg) Miscellaneous internal Nux vomica Miscellaneous internal Nux vomica extract Miscellaneous internal Nystatin Antimicrobial II Obtundia surgical dressing Miscellaneous external Miscellaneous external Octinoxate Topical analgesic Octisalate Topical analgesic Octocrylene Topical analgesic Octoxynol 9 Contraceptive/vaginal Contraceptive/vaginal

Contraceptive/vaginal Octyl salicylate [see octisalate] ==== Octyldodecanol Miscellaneous external Miscellaneous external Octylmethoxycinnamate [see octinoxate] ==== Octyl Triazone n/a

Report

Drug Category

ANPR

PR

FR

Menstrual/diuretic Weight control Daytime sedative

Menstrual Anorectic Sedative

n/a IISE IIE

IISE IISE IISE

310.545(a)(24)(i) 310.545(a)(20) 310.519(a)

Digestive aid

Digestive aid (intestinal distress)

n/a

n/a

310.545(a)(18)(ii)

Mercury Mercury Oral health care

First aid antiseptic Antiseptic Antimicrobial

n/a IISE IISE

IISE IISE IISE

310.545(a)(27)(i) 310.545(a)(27)(i) Pending

Vaginal

Lowers surface tension mucolytic effects Minor irritations Contraceptive

I

Withdraw

n/a

IIIE I

Withdraw Withdraw

n/a n/a

Surgical hand scrub Antimicrobial soap Health care personnel handwash Skin wound cleanser Preoperative skin prep Skin antiseptic

IIISE n/a IIISE

IIISE IISE IIISE

Pending Pending Pending

IIISE IIISE IIISE

IIISE IIISE IIISE

Pending Pending Pending

Cough/cold (antitussive)

Antitussive

IIIE

IIIE

[52 FR 30054]

Cough/cold (antitussive)

Antitussive

IIIE

IIIE

[52 FR 30054]

Hair growth/loss

Hair grower

n/a

n/a

310.527(a)

Menstrual/diuretic

Diuretic

n/a

IISE

310.545(a)(24)(i)

Aphrodisiac

Aphrodisiac

IISE

IISE

310.528(a)

Digestive aid

Digestive aid (ippuad)

n/a

n/a

310.545(a)(18)(ii)

Antifungal

Anticandidia

I

IIISE

310.545(a)(22)(iv)

External analgesic Skin protectant

Insect bite/sting Insect bite/sting

IISE IISE

IISE IISE

Pending Pending

Sunscreen

Sunscreen

I

I

352.10(j)

Sunscreen

Sunscreen

I

I

352.10(k)

Sunscreen

Sunscreen

I

I

352.10(i)

Vaginal Vaginal

IIIE I

Withdraw Withdraw

310.545(a)(28)(ii) 310.545(a)(28)(ii)

Contraceptive (vaginal)

Minor irritations Lowers surface tension mucolytic effects Contraceptive

I

Withdraw

310.545(a)(28)(ii)

====

====

====

====

====

External analgesic Skin protectant

Fever blister (topical) Fever blister (topical)

Defer Defer

n/a n/a

n/a Pending

====

====

====

====

====

TEA

Sunscreen

n/a

Vaginal Contraceptive (vaginal) Antimicrobial Antimicrobial Antimicrobial Antimicrobial Antimicrobial Antimicrobial

Current Regulatory Status of Over-the-Counter Products

Review Panel Oil of erigeron Miscellaneous internal Olive oil Miscellaneous external Opium powder [see opium, powdered] ==== Opium tincture Laxative Opium, tincture of [see opium tincture] ==== Opium, powdered Laxative Organic vegetables Miscellaneous internal Orthophosphoric acid Miscellaneous internal Orthophosphoric acid [see phosphoric acid] ==== Ox bile Laxative Ox bile extract Miscellaneous internal Miscellaneous internal Oxybenzone Topical analgecis Oxymetazoline hydrochloride Cough/cold Oxyquinoline Antimicrobial II Miscellaneous external Miscellaneous external Miscellaneous external Miscellaneous external Oral cavity Oxyquinoline citrate Contraceptive/vaginal Oxyquinoline sulfate Antimicrobial II Contraceptive/vaginal Miscellaneous external Miscellaneous external Miscellaneous external Oxyquinoline sulfate [see oxyquinoline] ==== Oxytetracycline hydrochloride Antimicrobial II Antimicrobial II Antimicrobial II Ozokerite Miscellaneous external Miscellaneous external Paba [see aminobenzoic acid] ==== Padimate A Miscellaneous external Miscellaneous external Topical analgesic Topical analgesic Padimate O Topical analgesic Pamabrom Miscellaneous internal

111

Report

Drug Category

ANPR

PR

FR

Menstrual/diuretic

Diuretic

n/a

IISE

310.545(a)(24)(i)

Hair growth/loss

Hair grower

IISE

n/a

310.527(a)

====

====

====

====

====

Antidiarrheal

Antidiarrheal

I

IIISE

310.545(a)(3)(i)

====

====

====

====

====

Antidiarrheal

Antidiarrheal

I

IIISE

310.545(a)(3)(i)

Weight control

Anorectic

IISE

IISE

310.545(a)(20)

Digestive aid

Digestive aid (ippuad)

n/a

n/a

310.545(a)(18)(ii)

====

====

====

====

====

Laxative

Stimulant laxative

IIISE

IIISE

310.545(a)(12)(iv)(A)

Digestive aid

IIE

IIE

310.545(a)(8)(i))

Digestive aid

Digestive aid (intestinal distress) Digestive aid (ippuad)

IIE

IIE

310.545(a)(8)(i)

Sunscreen

Sunscreen

I

I

352.10(1)

Cough/cold (nasal decongestant)

Nasal decongestant (topical/inhalant)

I

I

341.20(b)(7)

Antifungal Antifungal Antimicrobial External analgesic Skin protectant Oral health care

Antifungal Diaper rash Diaper rash Diaper rash Diaper rash Antimicrobial

IIISE Defer Defer Defer Defer IIISE

IIISE IISE IIISE n/a n/a IIISE

310.545(a)(22)(ii) 310.545(a)(22)(ii) Pending 310.545(a)(10)(iv) Pending Pending

Vaginal

Minor irritations

IIISE

Withdraw

n/a

Antifungal Vaginal Boil treatment External analgesic Skin protectant

Antifungal Minor irritations Boil treatment Astringent Astringent

IIISE IIISE IISE IISE IISE

IIISE Withdraw IISE n/a IISE

310.545(a)(22)(ii) n/a 310.531(a) n/a 310.545(a)(18)(ii)

====

====

====

====

====

Antibiotic Antibiotic Antibiotic

First aid antibiotic Skin wound antibiotic Skin wound protectant

n/a IIIE I

I Defer Defer

333.120 [combos] n/a n/a

External analgesic Skin protectant

Fever blister (topical) Fever blister (topical)

Defer Defer

n/a n/a

n/a n/a

====

====

====

====

====

External analgesic Skin protectant Sunscreen Sunscreen

Fever blister (topical) Fever blister (topical) Sunscreen (≥5%) Sunscreen (
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