How to build up a GMP Quality Manual

How to build up a GMP Quality Manual ? A quality manual is a document that a company writes to explain which portions of which regulations are applicable to the company (i.e. which regulations will be followed by the company.) The regulations that are to be followed are based on the process(es) that are performed at the company. Not all portions of a regulation may be applicable to all companies. Sometimes portions of various regulations are applicable (e.g. a medical device company that also performs aseptic processing may follow portions of 21 CRF Part 820, Part 210, and Part 211).

The company’s Quality Manual should outline which parts of which regulations are going to be followed, how they are going to be followed, who is responsible for ensuring that the regulations are followed, and which of the companies approved procedures address the regulations to be followed. If all parts of a regulation are not going to be followed a company may want to include a brief explanation as to why a part of a regulation is not applicable to the company and therefore will not be outlined in the Quality Manual. The Quality Manual should be written in general terms with minimal specifics. The format of a Quality Manual is usually different than the format used for the company’s other approved documents. The format should still include such things as a company’s logo and name, version control, approval signatures, and confidential markings. The following are examples of sections that a Quality Manual should contain: 1. 2. 3. 4. 5. 6. 7.

Table of Contents Introduction Quality Policies and Objectives Organization and Structure of Documentation Company’s Products References Quality Policies for Specific Regulation Elements

Table of Contents: A list of the sections contained within the Quality Manuel and the page each section begins on. Introduction: A brief description of the company, the company’s purpose for writing a Quality Manual, and a brief description of the scope of the Quality Manual.

Company Background: List the name of the company, if it is publicly or privately owned, where the company is located, the size of the facility, how the facility is used, the type of work that the company does, what products are produced at the company, and what the products will be used for. Purpose: Provide general statements explaining why and how the Quality Manual will be used. Example: “This manual will serve as a guide to company X quality policies and key procedures, as well as to describe how these policies will be implemented.” Example: “This Quality Manuel describes the quality management system that has been established by Company X in order to meet regulatory requirements for the commercial sale of products in the United States and in International Markets.” Scope: List the regulations that will be followed by the company as well as any portions of the regulations that will not be followed. Provide a justification for why those portions of the regulations are not going to be followed. Example: “The system described in this manual is intended to meet general requirements set forth in the United States Food and Drug Administration (FDA) Regulation according to 21CFR Part 210 and 21CFR Part 211 as well as the relevant section of 21CFR Part 820.” Example: “As a contract manufacturer of phase II materials Company X is not governed by section Y of 21 CRF Part 211 however the company does look to 21 CRF Part 211 for guidance in establishing and maintaining the quality system.” Quality Policies and Objectives: Include a brief statement about the approach that the company is taking in regards to quality, (i.e. a Quality Mission Statement) and list the quality objectives of the company. The quality objectives should not be numerous (five to seven is a typical number) and should be briefly stated. Example: Customer issues are addressed in a timely, professional, and thorough manner. Example: Personnel are adequately trained in the job they perform Example: Products and Services provided by our company are designed, manufactured, and delivered to our customers and meet or exceed our customer requirements.

Organization and Structure of Documentation: Provide an explanation as to how the documentation structure at your company is organized and managed in relation to the applicable regulations. Example: Documents related to the quality system are organized in a four level hierarchy structure, are maintained in accordance with applicable regulatory requirements and our company record retention policy, and are managed through a document change control system. Company’s Products: This section should include a brief description of the products that are made and distributed by the company including what the intended use of the products is to be. This description should be similar to a marketing type summary in that it does not list proprietary or explicit product information that would be detrimental to the company if persons outside the company read the description. This section should provide enough detail to justify the sections of the regulations that are and are not going to be followed. References: A list of all the different regulations that were sited within the Quality Manual. Example: FDA Title 21, Code of Federal Regulations Part 210 & 211, Current Good Manufacturing Practice in Manufacturing, Processing, Packing, or Holding of Drugs and Finished Pharmaceuticals. Quality Policies for Specific Regulation Elements: This section will encompass the majority of the manual. It will include each regulation that will be followed by the company, a brief description of how the company intends to follow the regulation, and a list of the approved documents (by document name and number) that the company has in place which specifically address/discuss the company’s policies and objectives as stated in this section of the Quality Manual. Example: Purchasing Controls; Procedures are established and maintained to ensure that materials, supplies, and services impacting the Quality System and procured by Company X purchasing department, conform to specified requirements. 1. 2. 3. 4.

Receiving Procedure SOP # XX. 01 Vendor Qualification Procedure SOP # XX. 01 Release of In-coming Goods Procedure SOP # XX. 01 ......

Example: Corrective and Preventive Action; At Company X, Corrective and Preventive Actions are integral in a variety of programs. Whenever possible, these programs make an effort to determine the root cause of the incident and to implement appropriate actions to prevent the reoccurrence of the incident. Quality Assurance approves all Corrective and Preventive plans and tracks their completion and effectiveness.

1. 2. 3. 4.

CAPA Procedure SOP # XX. 01 Material Review Board SOP # XX. 01 Failure Investigation Procedure SOP # XX. 01 .......

GMP Document Management System - a brief Guide A key aspect of a GMP facility is well written procedures. Procedures should be clear, concise, unambiguous, and easy for employees to follow. Well written procedures should not leave any room for misinterpretation. They should be written in such a manner that anyone who is properly trained and knowledgeable in the field can follow them as they are written.

There are various types of procedures that a GMP facility can have. The following is a list and brief description of the most common types of documents. Quality Manual A global company document that describes, in paragraph form, the regulations and/or parts of the regulations that the company is required to follow. Policies Documents that describe, in general terms and not with step-by-step instructions, how overall guidelines for how specific GMP aspects (such as security, documentation, health, and responsibilities) will be implemented. Standard Operating Procedures (SOPs) Step-by-step instructions for how to perform operational tasks or activities. Batch Records These documents are typically used and completed by the manufacturing department. Batch records provide step-by-step instructions for production related tasks and activities as well as include areas on the batch record itself for documenting such tasks. Test Methods These documents are typically used and completed by the Quality Control Department. Test Methods provide step-by-step instructions for testing supplies, materials, products and other production related tasks and activities such as environmental monitoring of the GMP facility.

Test Methods typically contain forms at the end of the procedure which are used for documenting the testing and the results of the testing. Specifications Documents that list the requirements that a supply, material, or product must meet before being released for use or sale. The Quality Control Department will compare their test results to specifications to determine if the testing passes. Logbooks Bound collection of forms used to document activities. Typically logbooks are used for documenting the operation, maintenance, and calibration of a piece of equipment Logbooks are also used for such things are recording the monitoring of clean room activities, solution preparations, deviation and corrective action assignment. • • • • •

Controlled Document Management System

A controlled document template should be created for each document type. This template can then be used by all personnel who are writing documents. The following are examples of a document template:

A document number system also needs to be established for the various types of documents that are created. Document # Examples: GEN-001 (General SOPs), TM-001 (Test Methods), BR-001 (Batch Records), QP-001 (Quality Policy), Standard Operating Procedure Template Creation Any knowledgeable employee should be able to write or revise documents as needed. When revising a document the redline changes along with detailed justification of the changes should be routed.

Routing The document control function of QA is responsible for routing documents for review and approval. It is suggested that a pre-route be done to ensure that all affected parties are in agreement with the document before it is submitted to QA. There should be a documented process detailing how documents are submitted for review and approval. A controlled form listing all the changes made to the document, justification for the changes, and a list of personnel who need to review the document needs to be routed along with the document. At a minimum the author’s manager, all affected department heads, and QA need to review the document. Other Subject Matter Experts can be included. Approval Once all affected parties have agreed to the changes, document control will prepare the document for approval. All changes will be incorporated into the document. For new documents the version # will be 00. For each revision of a document the version number will increase (01, 02, 03, etc). A master document will be routed for approval signatures. Typically the approval signatures are the Author, the Department Head, and QA. QA must be the last signature on all documents. The approval signatures on Batch Records are typically the Head of Manufacturing and the Head of QA. Usually the approval signatures only appear on the first page of the document. Once the master document has been signed, and effective date is stamped onto each page of the document. The effective date must be far enough in advance to allow for the document to be trained on before it becomes effective (typically this is 5 days). Distributing On the effective day copies of the signed master document are routed to the affected departments. The departments will remove the old version and replace it the new version (for revised documents). If the document is new, there will be no replacement document to remove. The old versions must be returned to document control. On a periodic basis document control personnel should audit the binders to determine if they contain the correct versions. Each document binder should contain a table of contents and only those documents that the department is responsible for. A full set of all approved documents should be in the QA department as well as in a central company location.

Archiving Old revisions of documents will be stamped as superseded. No document revisions will be discarded or altered. A file will be maintained within QA that contains all the Superseded documents and the signature approvals of personnel who agreed to the revisions. Obsolete If a document will no longer be used by any department in the company it can become obsolete. The document must be stamped as Obsolete and all copies removed from all document binders. It is a good idea to place a notice in the document stating that the document has been Obsolete. The role of QA , in regards to the document system, is one of management and overview. QA ensures that all documents are maintained in a controlled fashion. That all procedures being used within a company are approved by the appropriate subject matter experts, are consistent with other documents, and are the most current version. One way that QA ensures this is by being the last signature on all approved documents. All documents; current, obsolete, superseded, as well as all the history on the creation and revision of the document are kept with in Quality Assurance.

Document Hierarchy A company’s controlled GMP document system should be established in a hierarchical manner starting with the general regulations and working downward to more specific documents such as batch records. Refer to Diagram below for an example of a hierarchical document system. The regulations that a company is responsible for following (e.g. 21CFR210, 21CFR211, 21CFR820, etc) should be at the top of the document pyramid and should govern the directives of the sub levels. The level underneath the regulations, Level 1 documents (e.g. Quality Manual), should break the regulations into parts specific to those that the company is required to follow. These documents should establish overall principles and guidelines for how the company plans on developing, documenting, and implementing a CGMP compliant quality system. Top level documents apply to all departments within a CGMP compliant company and are not specific in nature.

The next level, Level 2, of documents on the hierarchy document pyramid should further break down the parts of the regulations into specific subjects or topics. These documents (e.g. Company Polices) should establish guidelines to which all subordinate level procedures must comply with to ensure consistency across departments. Level 2 documents should not provide specific how to directive instructions or forms for documenting data on but rather provide overall intentions and guidelines governing critical programs or systems as well as explanations for the rationale and program designs. These documents will apply to all departments within a GMP compliant company. (Example: Company X Quality Policy: GMP Personnel Responsibility. “To describe the responsibility that personnel have in achieving and maintaining compliance to Current Good Manufacturing Practices (GMP) and to the Quality System that has been established at Company XXX.”) Standard Operating Procedures (SOP) should be the next level in the document hierarchy after Company Policy documents. These types of documents should provide specific step-by-step instructions for how to perform the operational tasks or activities that were generally talked about in the previous levels. (Example: SOP titled “Writing, Revising, Numbering, and Distributing Controlled Documents”) Level 3 documents (e.g., SOPs) should be department specific or function specific. The last level of documents in a document hierarchical structure is the Level 4 documents. These documents are the most specific in nature, (e.g. Batch Record, Test Methods, Validation Procedures) they would apply to a specific department, product, equipment, or process. Level 4 document provide step-by-step instructions for production related tasks and activities as well as providing a means for documenting such tasks such as data sheets, forms, or batch records. The details outlined in these documents may override directions given in other level documents. (Example: The Company’s documentation SOP states to round numbers to 3 significant figures but the batch record states to record all numbers calculated in scientific notation. The requirements listed in the batch record are what are followed.) The document hierarchy pyramid is an example of one way to organize your company’s documents. More or less levels may be added/subtracted to meet your company’s specific needs. Document Hierarchy Diagram

Regulations (CFR)

GMP Abbreviations AAMI Association for the Advancement of Medical Instrumentation AAPS American Association of Pharmaceutical Scientists AdvaMed Advanced Medical Technology Association AESGP Association Européenne des Specialités Grand Public ANDA Abbreviated New Drug Application ANSI American National Standards Institute APIC Active Pharmaceutical Ingredients Committee ASQ American Society for Quality BP British Pharmacopoeia BSE Bovine Spongiform Encephalopathy CDRH FDA Center for Devices and Radiological Health CEO Chief/Corporate Executive Officer CEFIC European Chemical Industry Council CPMP Committee of Proprietary Medicinal Products (EU) CVMP Committee of Proprietary Veterinary Products (EU) CRO Contract Research Organization CTD Common Technical Document

(Register ICH) DIA Drug Information Association (USA) DOE Department of Energy (USA) DSHEA Dietary Suplement Health and Education Act (USA) DSMA Division of Small Manufacturers EIR Establishment Inspection Report EMI Electro-Magnetic Interference ESD Electro-static Discharge EDQM European Directorate for the Quality of Medicines EGA European Generics Association EMEA European Medicines Evaluation Agency EFPIA European Federation of Pharmaceutical Industries Associations EUR PH European Pharmacopoeia (Commission) FDA Food and Drug Administration (USA) FDLI The Food and Drug Law FEDESA Federation Européenne de la Santé Animale GCP Good Clinical Practice GMO Genetically Modified Organisms GMP Good Manufacturing Practice

GLP Good Laboratory Practice (For Safety Evaluation) GPIA Generic Pharmaceutical Industry Association HIMA The Health Industry Manufacturers Association ICH International Conference of Harmonization IDE Investigational Device Exemption IEEE Institute of Electrical and Electronic Engineering IVD InVitro Diagnostic Devices IFPMA International Federation of Pharmaceutical Manufacturers Associations IGPA International Generic Pharmaceutical Association IPEC International Pharmaceutical Excipients Council ISPE International Society for Pharmaceutical Engineering MCA Medicines Control Agency (UK) MDMA Medical Device Manufacturers Association MDR Medical Device Reporting (21 CFR Part 803 ) NAFL Notice of Adverse Findings NAI No Action Indicated NEMA National Electrical Manufacturers

Association NIST National Institute for Standards and Technology NAFTA North American Free Trade Agreement NAPM National Association of Pharmaceutical Manufacturers NAS National Academy of Sciences (USA) NCE New Chemical Entity NDA New Drug Application NIST National Institute of Science and Technology (USA) NPA National Pharmaceutical Alliance NSE Not Substantially Equivalent OAI Official Action Indicated ODE FDA Office of Device Evaluation ORA FDA Office of Regulatory Affairs OC Oral Contraceptive OEM Original Equipment Manufacturer PCR Polymerase Chain Reaction PDUFA Prescription Drug User Fee Act (USA, 1992) PEFRAS Pan European Federation of Regulatory Affairs Society PhARMA Pharmaceutical Association of

Research-based Manufacturers (PMA, USA) PIC Pharmaceutical Inspection Convention (EFTA) PICS Pharmaceutical Inspection Cooperation Scheme PRP FDA's Problem Reporting Program PTO Patent and Trademark Office (USA) QSR Quality System Regulations (devices) SE Substantially Equivalent SMDA Safe Medical Devices SMO Site Management Organization SPC Summary of Product Characteristics or Statistical Process Control SRM Specified Risk Material (EU) TSE Transmissible Spongiform Encephalopathies (Veure BSE) USP United States Pharmacopoeia VAI Voluntary Action Indicated VFA Verband der Forschender Artzneitmittelherstellern VOC Volatile Organic Compound WHO World Health Organization (OMS) WTO World Trade Organization

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