EDITORIAL ADVISORY BOARD
Special Edition n Cleaning Validation III
Gamal Amer, Ph.D. Validation and Process Associates, Inc.
Louis A. Angelucci, III Foster Wheeler Corporation George N. Brower Analex Corporation
Kenneth G. Chapman Drumbeat Dimensions, Inc. Dennis Christensen Consultant
Robert C. Coleman US Food & Drug Administration Shahid Dara Independent Consultant
PCI, Pharmachem International William E. Hall, Ph.D. Hall & Associates Eldon Henson Boehringer Ingelheim Animal Health
JAY H. KING LifeScan, a Johnson & Johnson Company JOHN G. LANESE, Ph.D. The Lanese Group, Inc.
Barbara Mullendore AstraZeneca ROBERT A. NASH, Ph.D. St. John’s University Charlie Neal, Jr. BE&K
David R. Dills Medtronic Xomed
TOD E. RANSDELL Bio-Rad Laboratories
Michael Ferrante Catalytica Pharmaceuticals Patricia Stewart Flaherty Bayer Corporation
Roberta D. Goode Consultant
CYNTHIA GREEN Northwest Regulatory Support Daniel Harpaz, Ph.D.
MELVIN R. SMITH Independent Consultant
ROBERT W. STOTZ, Ph.D. Validation Technologies, Corporation ERIC D. VEIT Johnson & Johnson
David W. Vincent Validation Technologies, Inc.
Editor and Publisher Glenn Melvin Vice President Terri Kulesa Production Director Edward Eick Associate Publisher Brandon Melvin
Disclaimer: Any reproduction of the contents of this publication in whole or part is strictly prohibited without permission. Views and conclusions expressed in articles herein are those of the authors. The publisher accepts no responsibility for the accuracy of information supplied herein or for any opinion expressed. No liability can be accepted in anyway. The information provided does not constitute legal advice. Change of Address: Notices should be sent promptly. Provide new address, including zip code or postal code. Submissions: Manuscripts are welcomed. Please call for editorial guidelines. Reprints: Reprints of all articles in this issue are available. Call 561-790-2025 for more information.
JOURNAL MISSION The Journal of Validation Technology is a peer-reviewed publication that provides an objective forum for the dissemination of information to professionals in FDA-regulated industries. The Journal’s Editorial Advisory Board reviews all submissions to ensure that they have been researched thoroughly, reflect current industry standards, and are not promotional in nature. The Journal will not publish articles which have not been approved by the Board.
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CONTENTS TABLE
OF
Special Edition n Cleaning Validation III
Equipment Cleaning Validation: Microbial Control Issues . . . . . . . . . . . . . . . . . . . . . . . 6
Cleaning Validation: Maximum Allowable Residue: Question and Answer . . . . . . . 13
by
by
Destin A. LeBlanc, M.A.
William E. Hall, Ph.D.
Development of Total Organic Carbon (TOC) Analysis for Detergent Residue Verification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
by
James G. Jin and Cheryl Woodward
Total Organic Carbon Analysis for Cleaning Validation in Pharmaceutical Manufacturing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22 Karen A. Clark
by
Detergent Selection – A First Critical Step in Developing a Validated Cleaning Program . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28
by
Mark Altier
Analysis Cleaning Validation Samples: What Method? . . . . . . . . . . . . . . . . . . . . . . . . . . 35
by
Herbert J. Kaiser, Ph.D., Maria Minowitz, M.L.S.
Control and Monitoring of Bioburden in Biotech/Pharmaceutical Cleanrooms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46 by Raj Jaisinghani, Greg Smith and Gerald Macedo
A Cleaning Validation Program for the ELIFA System . . . . . . . . . . . . . . . . . . . . . . . . . . . 56 by
LeeAnne Macaulay, Jeff Morier, Patti Hosler and Danuta Kierek-Jaszczuk, Ph.D.
BONUS
A Cleaning Validation Master Plan for Oral Solid Dose Pharmaceutical Manufacturing Equipment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61 by Julie A. Thomas
Proposed Validation standard — VS-3 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71
Special Edition: Cleaning Validation III
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Equipment Cleaning Validation: Microbial Control Issues By Destin A. LeBlanc, M.A. Cleaning Validation Technologies
v
T
he PDA spring conference taminants.” However, Section 6.7 of was held in Las Vegas, this document that covers “Microbio }…it is Nevada in March 20, 2001. Aspects” focuses exclusively becoming more logical The conference showcased clean on the same issue discussed in the common for ing validation, residue limits, bio FDA guidance document, namely burden, microbial limits, and sani the issue of preventing microbial pro regulatory tization. This paper is based on a liferation during storage. authorities presentation at that conference. As a practical matter, microbial The initial focus of regulatory residues on equipment surfaces are to cite documents relating to cleaning part of the contaminants that should manufacturers validation for process equipment be reduced to an acceptable level; in pharmaceutical manufacturing that acceptable level being what is for deficiencies involved measuring residues of the safe for the manufacture of the sub related to drug active and the cleaning agent. sequently manufactured product. For example, the introduction to Unfortunately, very little has been microbial the Food and Drug Administration written on what is a safe level for control in (FDA) guidance document on clean microorganisms following cleaning ing validation1 states: “This guide is and/or sanitation.3,4 Part of the reason cleaning intended to cover equipment clean for this is that microbial residues are validation ing for chemical residues only.” significantly different from chemi While admitting that microbial res cal residues. Chemical residues are programs.~ idues are beyond the scope of the “inert” in the sense that it is easy to guideline, that guidance document calculate (especially using scenarios further states, “microbiological aspects of equip of uniform contamination in the subsequently manu ment cleaning should be considered,” particularly factured product) the potential levels and effects of with reference to preventive measures so that micro those chemical residues in the subsequently manu bial proliferation does not occur during storage. The factured product should they be transferred to that European PIC/S document,2 that was issued several subsequently manufactured product. With microbial years later, does explicitly mention microbial resi residues left after the cleaning process, the situation dues. In Section 6.2.1, contaminants to be removed is somewhat different. Because microorganisms are include “the previous products, residues of cleaning living organisms, those left as residues on equipment agents as well as the control of potential microbial con may change in number after the cleaning process, but 6
Institute of Validation Technology
Destin A. LeBlanc, M.A.
before the manufacture of the subsequently manu the cleaned equipment. However, many times this factured product. Those microbes transferred to the does not include any assessment as to the effect of subsequently manufactured product may also change that unchanged bioburden level on the subsequently in number after they are incorporated into the subse manufactured product. quently manufactured product in the manufacturing This paper will address issues covering approaches step. This change may be a significant reduction in to control of microorganisms in process equipment, bioburden, either due to drying of the equipment or setting of acceptance limits, sampling techniques, and due to a preservative in the finished drug product, approaches to providing acceptable documentation. for example. This change may also involve rapid Microbial Control Measures proliferation, either due to suitable growth conditions in wet equipment during storage, or due to suitable Control measures to reduce the bioburden on growth conditions in the finished drug product. Or, they may result in no significant change in microbial cleaned process equipment include control of bio level, because the bioburden was due to bacterial burden of raw materials, the cleaning process itself, spores (that will survive readily in dried equipment), or because the }Some companies will measure the subsequently manufactured product was a dry product (with low water change in microbial levels on activity). Therefore, knowing the equipment surfaces during storage levels of microorganisms left on the equipment following cleaning does of the cleaned equipment. However, not necessarily give one the full many times this does not include any story of the potential hazards of those microbial residues. Additional infor assessment as to the effect mation is required to assess those of that unchanged bioburden potential hazards. Why has microbial evaluation level on the subsequently during cleaning of process equip manufactured product.~ ment been a little discussed topic? Part of the reason is that it is not a significant problem in process man ufacturing. Yes, it could conceivably be a problem if a separate sanitizing step, and drying of the equip cleaning and storage were inadequate. However, for ment following cleaning. Bioburden of raw materials the most part, cleaning and storage of process equip includes the active, excipients, water, and any process ing aids. In many cases, the manufacturer may have ment, in so far as it applies to microbial residues, probably is done relatively well in most pharmaceu little control over the bioburden of raw materials other tical manufacturing facilities. On the other hand, it is than to accept a specification by the raw material sup becoming more common for regulatory authorities to plier. The most critical raw materials probably will be cite manufacturers for deficiencies related to micro natural products, in which there may be considerable bial control in cleaning validation programs. One variation in the levels and types of microorganisms. A solid monitoring program to control incoming bio reason for this seeming anomaly is that while firms are adequately controlling microbial contamination of burden of raw material is necessary. If there could be process equipment, there may be little documentation significant variation in bioburden, then that should to support this. This lack of documentation includes be addressed in the cleaning validation Performance any measurement of microbial residues during the Qualification (PQ) trials. At least one PQ trial should cleaning validation and/or during routine monitoring. utilize the worst-case incoming bioburden of raw Some companies will measure the change in micro materials to demonstrate adequate cleaning and micro bial levels on equipment surfaces during storage of bial control under those conditions. Special Edition: Cleaning Validation III
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Destin A. LeBlanc, M.A.
A second means of microbial control is the cleaning process itself. The conditions of aqueous cleaning are often hostile to microbial survival. These conditions include high temperature (commonly 60-80ºC), pH extremes (>11 and
