microbial control and identification - Bookstore - Parenteral Drug

MICROBIAL CONTROL AND

IDENTIFICATION

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Microbial Control and Identification Strategies Methods Applications

Dona Reber and Mary Griffin Editors To order this book, please visit: go.pda.org/MCID

PDA Bethesda, MD, USA

DHI Publishing, LLC River Grove, IL, USA


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10 9 8 7 6 5 4 3 2 1 ISBN: 978-1-942911-27-2 Copyright © 2018 Dona Reber and Mary Griffin All rights reserved. All rights reserved. This book is protected by copyright. No part of it may be reproduced, stored in a retrieval system or transmitted in any means, electronic, mechanical, photocopying, recording, or otherwise, without written permission from the publisher. Printed in the United States of America. Where a product trademark, registration mark, or other protected mark is made in the text, ownership of the mark remains with the lawful owner of the mark. No claim, intentional or otherwise, is made by reference to any such marks in the book. Websites cited are current at the time of publication. The authors have made every effort to provide accurate citations. If there are any omissions, please contact the publisher. While every effort has been made by the publisher and the authors to ensure the accuracy of the information expressed in this book, the organization accepts no responsibility for errors or omissions. The views expressed in this book are those of the authors and may not represent those of either Davis Healthcare International or the PDA, its officers, or directors.

This book is printed on sustainable resource paper approved by the Forest Stewardship Council. The printer, Gasch Printing, is a member of the Green Press Initiative and all paper used is from SFI (Sustainable Forest Initiative) certified mills. PDA Global Headquarters Bethesda Towers, Suite 600 4350 East-West Highway Bethesda, MD 20814 United States www.pda.org/bookstore 001-301-986-0293

Davis Healthcare International Publishing, LLC 2636 West Street River Grove IL 60171 United States www.DHIBooks.com


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We dedicate this book to Cynthia Sarnoski, Ph.D., our long-time mentor and advisor who offered invaluable encouragement and support throughout the writing and editing of this book.


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CONTENTS

Foreword Preface About the Editors

xiii xv xvii

SECTION 1 – STRATEGIES 1

REGULATORY AND COMPENDIAL GUIDANCE ON MICROBIAL IDENTIFICATION Tony Cundell Introduction Regulatory Guidelines Compendial Guidelines Detecting and Identifying Fungal Isolates from Manufacturing Facilities Human Microbiome Panel-based Molecular Diganostics Strain Typing Whole Genomic Analysis for the Detection and Identification of Microbial Pathogens Conclusions References About the Author

3 3 5 7 10 14 16 17 18 18 18 22

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Microbial Control and Identification MICROORGANISM IDENTIFICATION AND ITS ROLE IN CONTAMINATION CONTROL Jeanne Moldenhauer Introduction Background Identification Methods How Does the Organism Identification Aid in Finding a Root Cause for Contamination? Conclusion References About the Author

3

4

23 23 24 25 28 39 39 41

MEANINGFUL CONTAMINATION CONTROL TRENDING IN BIOLOGICAL MANUFACTURING

43

Ren-Yo Forng and Jeanne Mateffy Purpose Trending Process Monitoring Conclusion Case Study References About the Authors

43 45 58 65 66 68 70

ASSESSMENT OF MICROBIAL IMPACT FROM A LOW BIOBURDEN PERSPECTIVE

73

Hilary Chan and Lynn Johnson Introduction Microbial Impact and Significance for Patient Safety and Product Quality Microbial Impact Assessment Considerations Microbial Impact Assessment Tools Lifecycle Management and Quality by Design Summary References About the Authors

73 78 81 91 106 108 109 115



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Contents 5

QUALITY RISK MANAGEMENT IN THE CONTEXT OF VIRAL CONTAMINATION Consortium on Adventitious Agent Contamination in Biomanufacturing (CAACB) Introduction Use of QRM Tools Initiation of Risk Management Process Risk Assessment Risk Control Result of Risk Management Process Risk Review References About the CAACB

6

TRENDING OF MICROBIOLOGICAL ISOLATES IN THE BIOPHARMACEUTICAL ENVIRONMENT Dona Reber Regulations and Guidelines Uses for EM Trending EM Sample Types of Monitoring Trended Trending Frequency Microbial Identification Strategy Steps in Isolate Trending Conclusion References About the Author

7

BURKHOLDERIA CEPACIA COMPLEX: CHARACTERISTICS, PRODUCT RISK, AND TESTING ASSESSMENTS Tim Sandle Introduction Organism Characteristics Origins in Pharmaceutical and Healthcare Potential Risk to Patients FDA Alert and the Testing Debate Testing Scope

vii 117 117 124 146 149 153 156 161 161 163

165 166 168 172 172 174 176 191 191 194

197 197 199 200 203 204 212



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Microbial Control and Identification Tests for BCC Assessment of Test Data Summary References About the Author

212 216 219 220 228

SECTION 2 – METHODOLOGIES 8

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OVERVIEW OF CONVENTIONAL AND EMERGING MICROBIAL IDENTIFICATION METHODS

231

Frank E. Matos and Jennifer R. Reyes Introduction Microbial Identification: What Method to Use Isolation of Microorganisms in Pure Culture Methods for Characterization and Preliminary Screening Phenotypic Methods for Microbial Identification Fatty Acid Analysis Using the Midi Sherlock® MALDI-TOF Genotypic Methods for Bacterial Identification Ribotyping Identification of Fungi Molecular Methods for Fungal Identification Use of Contract Laboratories for Microbial Identification Conclusion References About the Authors

231 232 234 235 241 246 248 249 254 258 265 268 269 269 273

QUALIFICATION AND IMPLEMENTATION OF MALDI-TOF TECHNOLOGY FOR USE IN A QUALITY CONTROL LABORATORY

275

Jennifer R. Reyes, Frank E. Matos and Gary Kruppa Introduction: Microbial Identification Using MALDI-TOF Mass Spectrometry In-House Evaluation Qualification Activities Improvements Routine Use Activities References About the Authors

276 285 287 293 295 298 301



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Contents 10

TESTING FOR MYCOPLASMA IN BIOTHERAPEUTICS Houman Dehghani and Martina Kopp Introduction General Biology of Mycoplasma Regulatory Guidelines Traditional Testing Methods for Mycoplasmas Emerging Rapid Testing Methods for Detection of Mycoplasma Conclusion References About the Authors

11

VIRUS DETECTION AND TESTING METHODS Cassandra L. Braxton and Maria M. Bednar Introduction Key Elements Adventitious Virus Detection New Rapid Molecular Methods Advanced Virus Detection Using NGS Challenges of NGS in a Biopharmaceutical Setting NGS Regulatory Guidance Conclusion References About the Authors

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ix 303 303 304 306 307 309 315 315 317

319 319 320 323 328 330 346 349 351 352 360

DATA INTEGRITY IN THE LABORATORY

361

Jeanne Moldenhauer Introduction What are Data? Requirements for Data Integrity Data Pedigree Regulatory Expectations for Data Integrity Difficulties in Having Complete Data Evaluating Data Integrity in the Laboratory Triggers for Checking Data Integrity in the Laboratory The Effect of Personnel Behavior on Data Integrity Conclusion References About the Author

362 363 363 364 365 366 367 369 375 376 376 377



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Microbial Control and Identification

SECTION 3 – APPLICATIONS 13

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DISINFECTANT PERFORMANCE AGAINST FUNGI,VIRUSES AND BACTERIA

381

James Polarine, Jr., David Shields, and Jennifer Loughman Introduction Disinfectant and Sporicide Activity against Fungal Spores Disinfectant and Sporicide Activity against Viruses Disinfectant and Sporicide Activity against Bacteria Conclusion References About the Authors

381 382 391 393 400 401 403

ENVIRONMENTAL ISOLATES IN PHARMACEUTICAL MANUFACTURING Angel L. Salamán-Byron Introduction Regulatory and Compendia Guidance Evaluation and Selection of EIs Application EIs in Pharmaceutical Test Methods Conclusion References About the Author

15

405 405 406 409 421 426 427 438

MANAGING STOCK CULTURES

439

Vanessa Vasadi-Figueroa Introduction Applications and Use Top Six Lineup Culture Libraries Handling Storage Methods Cryopreservation Lyophilization Culture Recovery Market Availabilities Documentation and Inventory Management Conclusion References About the Author

439 440 441 442 443 444 446 448 449 452 454 454 455 456



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Contents 16

COMPETENCY-BASED TRAINING APPROACH FOR MICROBIAL IDENTIFICATIONS Edward S. Balkovic and Gary C. du Moulin Scope of Microbiology Based Training Expectations for Establishing the Training Program Expectations for Those Participating in the Training Program Training Material Development Training Phase – Process Training Phase – Task Specific Considerations Assessment Phase Summary References About the Authors

17

MOLD CONTAMINATION IN THE PHARMACEUTICAL INDUSTRY Brian G. Hubka and Jeanne Moldenhauer What is Mold? Why do I Care About Mold? Criteria for Mold Growth Mold Detection and Identification Setting Limits for Mold Contamination Mold Remediation Methods Mold Prevention Methods References About the Authors

18

KEY FEATURES OF A BIOSAFETY PROGRAM FOR THE BIOPHARMACEUTICAL INDUSTRY Jessica Avizinis Relevance of Biosafety to Drug Development, Manufacturing and Testing Operations The Importance of Biosafety: Impacts of Exposure Key Features of a Biosafety Program Future Biopharmaceutical Biosafety – Special Challenges Conclusion References About the Author

Index

xi 457 461 462 466 469 474 478 484 486 487 491

493 493 494 499 501 509 511 514 517 520

523 524 527 530 560 561 562 567 569


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FOREWORD

Many years have gone by since I first dabbled in microbiology, specifically as it relates to the manufacture of medical products and the impact microbiology has upon the pharmaceutical industry worldwide. I would have greatly appreciated being better versed back in those days with Strategies, Methods, Applications, all topics that remain to be within our focus and scientific realm of interest. The book’s stable of authors are subject matter experts, world renowned and highly respected microbiologists in their respective field of science. That said, you will appreciate reading their depth and breadth of experience regarding current microbiological challenges. For example, Cundell, Moldenhauer, Mateffy and Sandle provide their perspectives on strategies that you will find worthy of your consideration. The microbiological control and identification as well as microbiological assessment are areas that we all, and quite rightly so, continue to focus our energies and resources. Part and parcel with microbial identification includes trending of the microbial data and corrective measures that may need to be implemented to preclude and/or reduce the presence of microbial and bacterial endotoxin contamination. We all appreciate an inability to escape xiii


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from having a scientific discussion without including some form of risk assessment and risk management, which is no less important with regards to viral inactivation. I dare say you will find the chapter worthy of your read. The rapid microbiological methods (e.g., MicroSEQ®, MALDITOF) are more common place in todays’ laboratories and a far cry from someone who used to prepare a sea of the biochemicals, micro-bial test reagents, poured a river of agar plates and yes, indeed I washed my share of test tubes. The chapter includes laboratory equipment qualification considerations that historically may have not been performed by the laboratory staff. The reader will find it rewarding as they come to better understand and better appreciate how the equipment qualification can impact the microbiological results. There is a subject that has captured much of our time and to a notable extent has stretched precious resources. Jeanne Moldenhauer provides welcomed guidance and perspectives on this subject, Data Integrity, which you will find worthy of consideration to address and implement the necessary measures to preclude the accidental or unintentional deletion or omission of microbiological data. I continue to assess how well a company understands the microbiological impacts upon the manufacturing processes. Irrespective of whether the commodity is sterile or non-sterile, a comprehensive microbiological assessment is value added to any manufacturing operation. Equally important, which all have heard me say throughout the years, did the comprehensive assessments include a Microbiologist at the discussion table during the evaluation and implementation process. The individual topics within the text are of welcomed value to any organization. That said, when considering the Strategy, Methods and Applications, collectively, I would point out that is not unlike how I might possibly assess a medical products manufacturer. Thomas J. Arista June 14, 2018


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PREFACE

It has been six years since we edited our initial volume on Microbial Identifications: The Keys to a Successful Program for the PDA and DHI Publishing, LLC. Microbial identification continues to evolve with new technologies and expectations, yet remains so fundamental to microbial control of quality biopharmaceutical products. We decided it was the perfect time to once again bring together a group of expert microbiologists and biopharmaceutical industry leaders to discuss microbial identifications in a new light, that of how microbial identification knowledge is a cornerstone in the concept of microbial and contamination control programs. The chapters show how microbial control programs for our facilities, equipment and personnel result in a positive impact on our products and ultimately our patients. Some of these authors were included in our initial volume and we welcome them back for their continued support and excellent and informative chapters: Drs. Anthony M. Cundell, Jeanne Moldenhauer, Martina Kopp and Houman Dehghani. The remaining authors are new for us, but not to our industry by any means – all are xv


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well known for their expertise, and we are very pleased that they have joined us here. Please open the book and you will most likely recognize some of these authors, others are newcomers to writing chapters, and we are delighted they all rose to the challenge. This book has three sections: Strategies, Methods and Applications. Strategies cover regulations and regulatory expectations as well as strategies for trending, risk assessments, and risk management. Methods include current best practice microorganism identification methods, both conventional and emerging rapid methods for bacteria, viruses, mycoplasma and fungi. Applications include microbiology laboratory training for identifications, use of environmental and control microorganisms, disinfectant effectiveness and best practices, and an up and coming chapter subject, biosafety for laboratories, manufacturing facilities and personnel. It is recognized that each author has taken time from his or her very busy schedules and free time because of a passion for microbiology and microbial control, and with it the desire to share knowledge with others in our industry. This is very much appreciated by us. We also share this passion and dedication as evidenced by our many years of working and presenting on microbiological issues. This text will provide valuable information for the new microbiologist as well as a reference for well-seasoned professionals. We sincerely hope you enjoy the book. Dona Reber and Mary Griffin June 2018


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ABOUT THE EDITORS

Dona Reber has more than 25 years of academic and industrial microbiology experience, including developing and implementing contamination control strategies for aseptic/non aseptic manufacturing, microbiology testing/development, and managing/ networking microbiology laboratories. She is Senior Manager of Microbiology and Aseptic Support, Global Quality Operations for Pfizer, responsible for assessing aseptic processing facilities, investigations, troubleshooting, and developing policy documents for microbiology. Dona holds B.S. and M.S. degrees in related sciences, is (SM) NCRM certified, has been a PDA member for 20+ years, and a longtime chair of the Pharmaceutical Micro Expert Discussion Group. She has numerous publications on microbial identifications systems, environmental monitoring and microbiology risk assessments. She has co-authored three PDA Technical Reports: TR#13, Fundamentals of an Environmental Monitoring Program; TR#67, Exclusion of Objectionable Microorganisms from Non Sterile Pharmaceutical, Medical Devices and Cosmetics; and TR#70, xvii


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Fundamentals of Cleaning and Disinfection. She is on a PDA Task Force for Low Bioburden Environmental Monitoring. She has participated in instructing new FDA inspectors, and is an instructor for the PDA on TR#13, Fundamentals of an EM Program. She presented at the most recent PDA Micro Conference on environmental monitoring for low bioburden processes.

Mary Griffin, Principal, MG Quality Microbiology Consulting, LLC, is a subject matter expert in microbiology with more than 35 years of academic (University of Michigan; University of Massachusetts) and global biopharmaceutical experience. She initiated and directed the Quality Control Microbial Science and Technology department at Pfizer (previously Wyeth, Andover, MA) during a period of significant growth. She adapted her extensive knowledge of microorganisms and classical identification techniques to successfully implement both identification and rapid automated detection systems to keep the facility on the cutting edge of novel technologies. She continues to support the industry as a consultant through the application of her microbiological identification and rapid technologies expertise for microbial control. She holds a M.S. degree in Microbiology and is certified as a Specialist Microbiologist SM (NRCM). She is an active member of the Parenteral Drug Association (New England Chapter) and is published in the pharmaceutical industry.
