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Relying on practical examples from the authors' experience, this book provides a thorough and modern approach to controlling and monitoring microbial contaminations during the manufacturing of non-sterile pharmaceuticals. Offers a comprehensive guidance for non-sterile pharmaceuticals microbiological QA/QC Presents the latest developments in both regulatory expectations and technical advancements Provides guidance on statistical tools for risk assessment and trending of microbiological data Describes strategy and practical examples from the authors' experience in globalized pharmaceutical companies and expert networks * Offers a comprehensive guidance for non-sterile pharmaceuticals microbiological QA/QC * Presents the latest developments in both regulatory expectations and technical advancements * Provides guidance on statistical tools for risk assessment and trending of microbiological data * Describes strategy and practical examples from the authors' experience in globalized pharmaceutical companies and expert networks

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Pharmaceutical Microbiological Quality Assurance and Control

Practical Guide for Non‐Sterile Manufacturing

 

Edited by

 

David Roesti

Novartis Pharma Stein AG, Switzerland

Marcel Goverde

MGP Consulting GmbH, Switzerland

 

 

 

 

 

 

This edition first published 2020© 2020 John Wiley & Sons, Inc.

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The right of David Roesti and Marcel Goverde to be identified as the authors of the editorial material in this work has been asserted in accordance with law.

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Hardback ISBN: 9781119356073

Cover Design: WileyCover Images: Courtesy of Christine Farrance, Senior Director of R&D Charles River Laboratories, Newark, Delaware; Courtesy of Sabrina Kuoni; Courtesy of Thomas Meindl, Labor LS

Editors

David Roesti, PhDNovartis Pharma Stein AG, Stein, [email protected]

Dr. David Roesti holds a PhD in microbial ecology from the University of Neuchâtel, Switzerland, and has more than 20 years of experience in the field of microbiology within various domains (drug product manufacturing, food microbiology, biogas production, and microbial interactions in the rhizosphere). Currently, he works at Novartis Pharma AG in Stein, Switzerland, in the Manufacturing Science & Technology department and is responsible to define the microbial control strategy at the site and is a global subject matter expert in microbiology for the Novartis group. Prior to this assignment, he led the Rapid Microbiological Methods team at Novartis Pharma AG and was the laboratory supervisor for the microbiological testing of non‐sterile drug products at Novartis Pharma Stein AG. David Roesti is an elected member of the General Chapters Microbiology Expert Committee of the Unites States Pharmacopoeia 2015–2020 revision cycle and is a member of the advisory board of the European Compliance Academy Microbiology Group. Finally, David Roesti is main author or coauthor of many different publications in either peer‐reviewed journals or book chapters and has regularly held presentations in scientific congresses or expert groups.

Marcel Goverde, PhDMGP Consulting GmbH, Binningen, [email protected]

Dr. Marcel Goverde studied biology at the University of Basel, where he gained his PhD in 2001. He gathered first work experience as a scientific collaborator in the agro‐biological section of Novartis. He is now associated with a development project in Costa Rica and teaching at different school levels. From 2002 to 2010 he led several QC labs for microbiology at F. Hoffmann‐La Roche Ltd. From 2010 to 2011 he worked as a QC expert for microbiology at Novartis Pharma Ltd. Since 2011 he has been running his own business for consulting, training, project, and deviation management named MGP Consulting GmbH. Marcel Goverde is a regular speaker at different institutions and has written several scientific papers. He has been the Swiss expert in the EDQM group for Modern Microbiological Methods since 2003, which was then integrated into Group 1 (Microbiological Methods and Statistical Analysis) in 2015. Marcel Goverde is deputy chair of the ECA Pharmaceutical Microbiology Working Group and holds a green belt in Lean Six Sigma.

List of Contributors

Ina Bach, PhDGlobal Compliance Assistance, St. Gallen, [email protected]‐bach.ch

Dr. Ina Bach is an independent consultant specializing in the areas of quality assurance, compliance, and auditing, with particular application to the pharmaceutical and biotech industry. Ina Bach has worked over 15 years as a senior compliance auditor in a Global Auditing and Compliance group of one of the top 10 international pharmaceutical companies and as an inspector for the Swiss regulator authority. When she was working for the authorities, she also worked closely with international health organization as a nominated inspector in several of prequalification projects. Additionally, she can look back on many years of experience in the pharmaceutical industry in which she was in responsible positions involved in the development, manufacture of various dosage forms, in project management, as well as in quality assurance and quality control.

Tony Cundell, PhDMicrobiological Consulting, LLC, Scarsdale, NY, [email protected]

Dr. Tony Cundell consults with a number of pharmaceutical, consumer health, and dietary supplement companies; microbiology instrument manufacturers; contract testing laboratories; and sterile compounding pharmacies in the areas of microbial risk assessment, regulatory affairs, and microbiological testing. Prior to November 2013, he worked for Merck Research Laboratories in Summit, New Jersey, as the Senior Principal Scientist in early phase drug development. Earlier in his career, Tony Cundell worked at a director level in Quality Control and Product Development organizations at the New York Blood Center, Lederle Laboratories, Wyeth Pharmaceuticals, and Schering‐Plough. He is a member of the 2015–2020 USP Microbiology Committee of Experts where he takes a leadership role in the area of modern microbiology methods, cochairing the USP Expert Panel that published a stimuli article in the September–October 2017 Pharmacopeial Forum entitled The Development of Compendial Rapid Sterility Tests. Tony Cundell chaired the PDA task force responsible for the ground‐breaking 2000 Technical Report No. 33 The Development, Validation, and Implementation of New (Rapid) Microbiological Methods. In June 2009, he coedited with Anthony Fontana a book entitled Water Activity Applications in the Pharmaceutical Industry and contributed two chapters to the book. He was cochair of the PDA task force responsible for 2014 Technical Report No. 67 Exclusion of Objectionable Microorganisms from Non‐Sterile Drug Products. He received the 2016 PDA Martin Van Trieste Pharmaceutical Science Award for outstanding contributions to the advancement of pharmaceutical science. He has a PhD in microbiology from Lincoln University, Canterbury, New Zealand.

Christine E. Farrance, PhDSenior Director of R&D and Scientific Affairs, Charles River Laboratories, Inc., Newark, DE, [email protected]

Dr. Christine E. Farrance received a Ph.D. in Cellular and Molecular Biology from the University of Pennsylvania, a B.S. in Biochemistry from Cornell University, and has more than 20 years of experience conducting both applied and basic research using molecular, microbial, genetic, and biochemical techniques. Currently, Senior Director of R&D and Scientific Affairs at Charles River Laboratories, Inc., she manages the scientific development projects and priorities across a cross‐functional team. She is also involved in coordinating research studies, and developing technical content for publications, presentations, and training. In addition, she provides her expertise to other business units within Charles River for technical trouble shooting and evaluation of new technologies. Before joining Accugenix/Charles River, she was a scientist at a nonprofit institute developing a plant‐based production system for recombinant vaccines and protein therapeutics. Her work has also included research in the food safety industry, and in plant‐based production systems for monoclonal antibodies as a Research Assistant Professor. Christine Farrance brings unique scientific and technical experiences to Charles River.

Oliver Gordon, PhDThe Francis Crick Institute, London, United [email protected]

Dr. Oliver Gordon studied Molecular Biology (main focus in Microbiology and Infection Biology) at the Biocenter and the University Hospital in Basel, Switzerland. From 2010 to 2014, he was working at Novartis Pharma AG in Switzerland in the QA/QC‐Microbiology department in the Launch Center for Rapid Microbiological Methods. As Rapid Microbiology Specialist, he played a leading role in evaluation and validation of Rapid Microbiological Methods and the subsequent replacement of Traditional Microbiological Methods, including method transfers to interested Novartis sites worldwide. In 2014, he started a PhD in the lab of Caetano Reis e Sousa at the Francis Crick Institute in London, where his research focuses on understanding how molecules released from dead cells modulate immune and tissue repair responses.

Ingo GrimmDirector Sales & Services, Labor LS, Bad Bocklet, [email protected]‐ls.de

Ingo Grimm is an experienced specialist in sales and business development activities in the field of microbiological and analytical testing of pharmaceutical products (small molecules and biotech) and medical devices. Within the last 15 years he became an expert in the needs of these industries, especially in the DACH‐region. Currently, Ingo Grimm works as Head of Sales & Services at Labor LS SE & Co. KG which is one of the leading cGMP‐laboratories in Europe. He graduated at the University of Applied Sciences Würzburg‐Schweinfurt and holds a Master of Business Administration.

David Hussong, PhDChief Technical Officer, Eagle Analytical Services, Houston, TX, [email protected]

Dr. David Hussong is currently the Chief Technical Officer at Eagle Analytical Services (Houston, TX). He has previously served as a regulatory microbiology consultant (2015–2017). In 2014, David Hussong retired from the Commissioned Corps of the US Public Health Service after 30 years with the Food and Drug Administration (FDA), where he had served in many positions, culminating as the Associate Director for New Drug Microbiology in the Office of Pharmaceutical Science. In addition, he is currently the chair of the USP Microbiology Expert Committee for the 2015–2020 cycle. David Hussong earned his PhD in microbiology from the University of Maryland at College Park (UMCP), and he previously served as a research microbiologist at UMCP, the US Department of Agriculture, and the US Naval Medical Research Institute.

Laurent LeblancR&D Manager Health and Personal Care Business, bioMé[email protected]

Laurent Leblanc is the R&D Manager of bioMérieux' Health and Personal Care business. He holds a Master's degree in Biotechnology from the University of Limoges, France. For the last 15 years, he worked in several biotechnology companies and before joining bioMérieux in 2008, he worked in microbiological control in the pharmaceutical industry. He is now involved in designing and bringing to the market the new innovative and efficient solutions dedicated to the pharmaceutical and cosmetic industries.

Marion LouisGlobal Solution Manager for Pharmaceutical Culture Media of the Healthcare Business, bioMé[email protected]

Marion Louis is a Global Solution Manager for Pharmaceutical Culture Media in the HealthCare Business of bioMérieux. Graduated with an Engineering degree in Biotechnologies from Polytech, graduate schools of engineering in France, Marion Louis holds as well a Master degree in Management from University of Clermont‐Ferrand. With 10 years' experience in microbiology as a Senior Application Engineer in pharmaceutical industries, she is now responsible to provide performant solutions to pharmaceutical industries.

Thomas Meindl, PhDSenior Consultant, Labor LS, Bad Bocklet, [email protected]‐ls.de

Dr. Thomas Meindl studied biology in Mainz and Tübingen, Germany, and received a PhD from the University of Basel. He started his career at Novartis, Basel, working on receptor–ligand interaction studies. Then, he moved to Sympore GmbH, a start‐up company in Tübingen, where he helped to develop new drugs in the field of immune suppression and inflammation. From there he moved to SKM oncology, Fürth, Germany, a company active in clinical trials. Finally, he moved to Labor LS SE, formally known as Labor L + S AG, in Bad Bocklet, Germany. There he worked as head of department and division manager for several departments (assays, endotoxin testing, molecular biology, disinfectant testing, research and development, validation of computerized systems, and implementation of LIMS); until today he works as a senior consultant for release testing of pharmaceuticals.

Michael J. Miller, PhDPresident, Microbiology Consultants, LLC, Lutz, [email protected]

Dr. Michael J. Miller is an internationally recognized microbiologist and subject matter expert in pharmaceutical microbiology, contamination control, aseptic processing, sterilization, laboratory design, and the validation and implementation of rapid microbiological methods (RMMs). He is currently the President of Microbiology Consultants, LLC (microbiologyconsultants.com) and owner of rapidmicromethods.com, a website dedicated to the advancement of rapid methods within healthcare‐related industries. For 30 years, he has held numerous R&D, manufacturing, quality, business development, and executive leadership roles at multinational firms such as Johnson & Johnson, Eli Lilly and Company, and Bausch & Lomb. In his current role, Michael Miller consults with multinational companies in providing technical, quality, regulatory, and training solutions in support of RMMs; sterile and non‐sterile pharmaceutical manufacturing; contamination control; isolator technology; environmental monitoring; sterilization; and antimicrobial effectiveness. Michael Miller has authored more than 100 technical publications and presentations and is the editor of PDA's Encyclopedia of Rapid Microbiological Methods. He currently serves on the editorial and scientific review boards for American Pharmaceutical Review, European Pharmaceutical Review, and the PDA Journal of Science and Technology. Michael Miller also was the chairperson during the revision of PDA Technical Report #33: Evaluation, Validation and Implementation of New Microbiological Testing Methods. He currently serves as an advisor to the USP Microbiology Expert Committee in the area of rapid sterility testing. Michael Miller holds a PhD in Microbiology and Biochemistry from Georgia State University (GSU), a BA in Anthropology, and Sociology from Hobart College.

Félix A. Montero Julian, PhDScientific Director of the Healthcare Business, bioMé[email protected]

Dr. Félix Montero is a Scientific Director of the Healthcare Business of bioMérieux. He has over 25 years of experience in industrial and clinical diagnostics and previously served as the Chemunex R&D Director in bioMérieux. Félix Montero graduated from the Autonomous Metropolitan University in Mexico as Industrial Biochemistry Engineer and obtained a PhD in Immunology from the Aix Marseille II University in France. He is a member of different scientific organizations (PDA, ISAC) and served as an expert in a panel for the Development of Compendial Rapid Sterility Tests for the USP. Félix Montero has been and continues to be extensively involved in the implementation and acceptance of rapid and alternative microbiological methods. He is a prominent speaker at congresses and conferences and a regular contributor to bioMérieux whitepapers.

Tim Sandle, PhDHead of Microbiology, Bio Products Laboratory, Hertfordshire, United [email protected]

Dr. Tim Sandle is a pharmaceutical microbiologist, with experience in microbiological testing, research and development, risk assessment, and investigation. Tim Sandle is Head of Microbiology at Bio Products Laboratory, United Kingdom and a visiting tutor at University College London and the School of Pharmacy and Pharmaceutical Sciences, University of Manchester. In addition, he serves on several national and international committees, including the microbiology society Pharmig. Tim Sandle has written over 600 book chapters, peer‐reviewed papers, and technical articles, largely relating to microbiology and pharmaceutical sciences.

Robert SchwarzUniversity Lecturer, University of Applied Sciences, Wien, [email protected]‐campuswien.ac.at

Robert Schwarz worked after his education as a medical‐technical analyst and as a biomedical analyst at a medical laboratory in Vienna with his core responsibilities in clinical chemistry, hematology, and hemostaseology. From 2001 to 2005, he led the environmental monitoring team at Baxter Bioscience in Vienna with the core tasks microbiological and physical clean room monitoring and qualification. Meanwhile, he completed his studies at the University of Applied Sciences FH Campus Wien in parallel with his professional career and successfully graduated hereby with the double degree “Bioprocess Engineering” and “Biotechnological Quality Management.” From 2005 to 2018, he was a validation specialist and was besides equipment qualification responsible for sterilization, decontamination, and cleaning validation as well. Since 2010, he has also been working as a university lecturer at FH Campus Wien in the field of biotechnology with a focus on validation/qualification, aseptic process methods, and clean room technology. He is now starting his business as a freelancing consultant and trainer for pharmaceutical industry.

Alexandra StärkMS&T Technical Steward Sterility Assurance, Novartis Pharma Stein AG, Stein, [email protected]

After studying Hygiene Technology at the Technical University of Albstadt‐Sigmaringen, Alexandra Stärk worked since 1995 at Novartis Pharma Stein AG in the microbiological QA/QC department, first as team leader and then 8 years as head of this department. Since 2016, she moved into a new role within Novartis Pharma Stein AG and is now responsible for a team of microbiological experts in the department of Manufacturing, Science & Technology which defined the microbiological control strategies for sterile, non‐sterile, and cell‐gene‐therapy production on a global and local level.

Preface

The present book is targeted at microbiologists and those in charge of microbiological quality primarily working in pharmaceutical companies of every size and specialty. The functions held by the readers are microbiology laboratory heads, QA/QC departments, outsourcing departments, regulatory departments, CEOs of small to midsize companies, and health authorities.

The aim of the book is to deliver very special knowledge for microbiological control and its strategy for non‐sterile products in a comprehensive way with practical examples. The focus of pharmaceutical microbiology is often on sterile products and aseptic processing. But especially in non‐sterile manufacturing, microbiological issues are often present but neglected. Furthermore, many more companies are producing non‐sterile than sterile products, and these companies often outsource their microbiological testing to third parties. Thus, they do not have the microbiological expertise in‐house and therefore have difficulties interpreting the results they receive from the third party.

Whereas often neglected and considered less critical than for sterile pharmaceuticals, microbial contamination in products not required to be sterile may also cause a health hazard for the patient or may degrade the product thus impacting its therapeutic activity. Even if these products are not required to be free of microorganisms, only a low bioburden is generally accepted and no objectionable microorganisms should be present. In drug products not required to be sterile, regulators therefore expect cGMPs controlling microbial contamination to be followed and implemented.

This book provides the reader a thorough and modern approach to controlling and monitoring microbial contamination during the manufacturing of non‐sterile pharmaceuticals. It covers state‐of‐the‐art microbiology quality control (QC) tests as well as risk mitigation strategies so that readers can implement these methodologies in their own facility or laboratory to meet microbiology cGMPs. The latest developments in technology for microbiological testing are also discussed.

The chapter authors, who are international leaders in the topics they have written about, share their long experience in practicing microbiological QA/QC in different types of pharmaceutical companies or by health authorities.

The Book Is Outlined as Follows

Chapter 1 summarizes the different strategies, outlined in detail in the rest of the book, to control and monitor microbiological contamination during the manufacturing of non‐sterile pharmaceuticals. The focus is on the six main factors facility, procedures, product ingredients, utilities, equipment, and formulation, which have an influence on the quality of the final drug product.

Chapter 2 presents the central importance of different approaches to microbial risk assessment and mitigation in non‐sterile drug product manufacturing. Risk assessment should take place during product development as well as routine manufacturing, QC, and product release. Involving microbiological expertise at an early stage of development can help to provide a robust process to control microbiological contaminations. Furthermore, production processes that are already running can be optimized or critical control points can be elaborated with risk‐based assessment tools. Different risk assessment tools such as impact matrix, failure mode and effects analysis (FMEA), and hazard analysis and critical control points (HACCP) are described, thereby considering the hierarchical risk of ingredients, dosage forms, and processing steps as well as the products' attributes. Finally, the potential of new emerging manufacturing technologies in terms of their microbial risks are addressed.

Chapter 3 introduces one of the most important aspects of receiving robust and reproducible results with microbiological product testing – the qualification of microbiological laboratory personnel and equipment. Since most testing is not yet automated, variability between analysts may affect the outcome of the test result. The chapter describes different approaches to laboratory personnel qualification and re‐qualification. While for equipment, a classification of the equipment is needed to address its qualification. Descriptive practical examples are given that show the importance of correct and maintained qualification of laboratory personnel as well as equipment or methods.

Chapter 4 dives into the world of culture media that are the most relevant to any growth‐based microbiological method. Therefore, the quality of these media is most important. In recent years more and more companies outsource the preparation of the growth media. In this chapter, challenges such as the development of a culture media, the quality of the raw materials, and the manufacturing process are described. There is a special focus on the QC and release of the manufactured or purchased culture media. Finally, several examples of issues and troubleshooting are given.

Chapter 5 outlines the microbiological test methods used to test non‐sterile dosage forms, drug substances, and excipients. It provides the reader with a detailed understanding of procedures including practical tips as well as the rationale for setting acceptance criteria, internal out of expectation (OOE) levels, and testing frequencies. One of the most important aspects of testing is the verification of the suitability of the method used, which is addressed in detail. The whole chapter is supported with practical examples.

Chapter 6 addresses the microbiological testing of primary packaging. Primary packaging is in direct contact with the drug product or API. Therefore, its microbial status must be controlled or monitored. However, there are no regulations for microbial requirements in regard to primary packaging for non‐sterile products, which must be developed internally by each company. This chapter gives guidance on the acceptance criteria and testing frequencies that may be used depending on the type of primary packaging. Furthermore, guidance to the testing of primary packaging material including the verification of suitability of the test method applied and handling of out of specification (OOS) and OOE results is provided with practical examples.

Chapter 7 looks at all different types of utilities and discusses how they are designed, qualified, and controlled. Instructions are given when utilities need to be upgraded, reconstructed, or renovated. Utilities such as compressed air, gas, water systems, clean steam, and cleanrooms are reviewed in terms of their performance from the microbiological contamination perspective. Aspects of regulatory requirements, monitoring, sampling, instruments, and methods used for sampling and testing are highlighted. Finally, cleaning of equipment, sanitization, and cleaning validation are also described.

Chapter 8 describes microbiological environmental monitoring in non‐sterile manufacturing, which is executed to verify that the environment remains under acceptable microbiological control. Compared to sterile manufacturing, no clear regulatory requirements exist for monitoring levels and sampling frequency, thus user examples are given including the definition of sampling points. Different methods used for testing are presented with different approaches for proving their validation or suitability such as recovery rates, incubation conditions, culture media, or sample hold time. Furthermore, strategies for initial validation as well as revalidation for cleanrooms are elaborated and a clear strategy for deviations is described with some practical examples of an investigation.

Chapter 9 reviews microbiological identification systems used in the GMP environment and discusses their advantages and disadvantages depending on their usage. Precise identification of microorganisms has also gained high relevance for non‐sterile product testing. Since non‐sterile products must be shown to be free of objectionable microorganisms, the identification of each isolate down to the correct species level is needed. Finally, some examples of isolate identification and their challenges are provided.

Chapter 10 defines microbiological monitoring levels based on historical data and how to trend microbiological data. In general, microbiological counts are not regularly distributed which means that statistical methods assuming a regular distribution of data cannot be used to determine microbiological acceptance levels based on historical data. Alternative statistical methods using other distribution models should be used and are described in this chapter. In addition, microbiological data should be reviewed routinely and trended to assess the capability of the measures to control contamination and verify that no adverse trend is occurring. An adverse trend can be defined as repeating, higher‐than‐usual counts, or an increasing number of microorganisms or contamination occurrences over a certain time period. Different methods to trend microbiological data using either statistical or graphical approaches are described.

Chapter 11 gives guidance on the handling of objectionable microorganisms. In non‐sterile manufacturing, low microbial counts are tolerated, and the final product does not necessarily need to be devoid of microorganisms. Nonetheless, some microorganisms are considered objectionable in the sense that they can adversely affect the appearance, physicochemical attributes, or therapeutic effects of a non‐sterile product, or, due to their numbers and/or pathogenicity, may cause infection, allergic response, or toxemia in patients receiving the product. Findings with objectionable microorganisms represent the majority of microbiologically related FDA recalls of non‐sterile products. This chapter focuses on microbiological risk assessments that evaluate whether a recovered microorganism is objectionable. Different strategies are given where the objectionability of the isolate found is regarded in relation to the criticality of the product (low‐risk to high‐risk products) and its patient population. Different sources of objectionable microorganisms are described. Finally, the chapter contains working examples of real cases with which readers would also be confronted.

Chapter 12 summarizes the complexity of the investigations of microbiological OOS cases or deviations that require high expertise. First, data integrity in microbiological laboratories is addressed including the implementation of the ALCOA+ principle for the laboratory. Second, definitions for OOS, OOE, out of trend (OOT), and exceedance of action or alert level are given. The two‐level approach (investigation in the lab and investigation of product quality) is described with practical examples. For all general microbiological tests (environmental monitoring, water testing, growth promotion test, and product testing), a detailed procedure for handling deviations is given.

Chapter 13 provides a current overview of rapid microbiological methods (RMMs) that can be used in non‐sterile product manufacturing. RMMs may significantly reduce the time‐to‐result of microbiological tests and therefore have the potential to shorten throughput time for drug product release. Other potential benefits of RMMs are, for instance, a reduction in inventory costs, faster stop or go decisions during manufacturing, decreased risk of stock‐outs and supply bottlenecks, improved data integrity, automation, and introduction of a paperless laboratory. The chapter gives guidance on the validation approaches for RMMs with a focus on the three relevant guiding documents, USP chapter <1223>, Ph. Eur. chapter 5.1.6, and PDA TR No. 33. Finally, it shows how a business case for RMMs can be developed if you want to implement such a method in your facility.

Chapter 14 is the validation protocol of an RMM that was established for the microbiological examination of non‐sterile and nonfilterable drug products, excipients, and APIs. The Celsis Advance system using ATP bioluminescence was used to do this and a thorough validation protocol covering robustness, ruggedness, repeatability, specificity, limit of detection, accuracy, and precision was developed. There was a special focus on the correct and sophisticated statistical evaluation approach for the validation data, which can be used as an example for the reader's own validation studies. Finally, equivalence in routine operation of the RMM with the compendial method is demonstrated as well as the suitability for product‐specific testing.

Chapter 15 is an ex‐regulator's view of the microbiological QA/QC functions in the pharmaceutical industry. The author starts with the beginning of pharmaceuticals in the fifteenth century and shows where and when the first legally authorized standards were published all the way up to modern GMP regulations. Microbes have the possibility to grow and survive in places that are often unique to a specific material or environment and therefore need special attention. Our testing of the product or environment should be seen as a snapshot of the contamination present and only continuous quality activities can give a reasonable control of microbiological product quality. Product quality is the responsibility of quality management made up of quality assurance (QA) and QC.

Chapter 16 provides an overview of the most important regulatory chapters and guidelines for non‐sterile product manufacturing and testing in the EU. The author gives a general overview of audit assessment tools for a microbiological laboratory. Several drop‐down lists for each subject (personnel, documentation, culture media, trends, methods, facility, equipment, and reference cultures) help the reader to prepare adequately for the next audit or inspection. The chapter closes with typical issues detected during the evaluation of microbiological laboratories.

Chapter 17 describes outsourcing strategies to contract laboratories. Outsourcing may result in other issues that could impact resources. The chapter provides some guidance on the most relevant points to verify if microbiological testing has been outsourced to a contractor. For example, which microbiological tests can better be performed in‐house and what can be easily outsourced? It addresses the advantages and disadvantages of outsourcing and the business case for outsourcing. Most important of all, when outsourcing a process, is the quality agreement to ensure that both parties are talking about the same thing.

David Roesti

Novartis Pharma Stein AG, Switzerland

Marcel Goverde

MGP Consulting GmbH, Switzerland

Foreword

“Another new textbook on Pharmaceutical Microbiology,” you, dear reader, may think. “There are already so many textbooks on pharmaceutical, microbiological laboratories on the market – why do I need THIS textbook?” could come to your mind in this context.

What makes this book so special that it is worth a second look? In my opinion, this book closes a gap that has existed until now: while there are some very good textbooks available for sterile products and their (aseptic) production, the focus of this textbook is on non‐sterile products and their production.

As the expert reader knows, the microbiological laboratory is one of the pillars of quality control in the pharmaceutical industry, alongside to the analyticalchemical laboratory. In contrast to the analytical‐chemical laboratory, the microbiological laboratory and the microbiological control concept for the production of non‐sterile products may not have received the attention that would have been required in recent years. An indicator that supports this assumption is the increasing number of “major” and “critical” observations and “warning letters” issued by Health Authorities in recent years concerning microbiological control concepts and the pharmaceutical microbiological laboratory. This is certainly also due to the fact that the microbiological control concept and the microbiological laboratory are increasingly becoming the focus of Health Authority inspections.

The pharmaceutical microbiological laboratory is involved in all phases of the product life cycle: from research and development to the manufacture of clinical trial batches as well as batches for the commercial market. All steps of the manufacturing process are controlled by microbiological analyses. This includes the evaluation of the microbial quality of raw or primary packaging material, the detection of microbial contamination during the manufacturing process, the control of the production environment (“Environmental Monitoring”), and last, but not least, assessment of the final product to release the produced batch. In addition, microbiological testing is also required for equipment qualification, process validation, and cleaning validation.

For all these parameters and activities, limits or, if applicable, specifications must be defined. These limits or specifications may be based on historical data using adequate statistical tools. If these limits are exceeded or even if the specification is failed, a deviation management must be defined.

In my opinion, the textbook comes at the right time. Pharmaceutical microbiology is currently in a transition phase: some growth‐based methods that have been used for several decades (but which still have their right to exist, are used in daily routine and are described in detail in this textbook) are currently being replaced by modern, automated methods that can generate the analytical result faster: the so‐called alternative or rapid microbiological methods. With the help of these alternative microbiological methods not only analytical lead time for batch release can be significantly shortened (up to now the classical, growth‐based microbiological tests were the time‐limiting analyses of the release process) but also the manufacturing processes can be controlled more tightly. In the best case the analysis results are available in real time. This allows an immediate reaction if deviations occur during the manufacturing process.

In summary, this textbook, written by leading authors familiar with practice in GMP‐processes, covers all of the above aspects of a modern microbiological control system for the manufacture of non‐sterile products. All measures required to establish and assess the microbiological control concept, and which should be reflected in a modern microbiological quality control laboratory for the manufacture of non‐sterile products, are described in detail in this textbook. Practical examples from “QC/QA everyday life” in large multinational pharmaceutical companies are included in this textbook. It is not only for readers with a microbiological background but also for “non‐microbiologists,” i.e. colleagues in other quality control units, the quality assurance departments, the regulatory departments, and other colleagues interested in the topic.

I wish you a few entertaining hours reading this comprehensive and informative textbook!

August 2019

Dr. Sven Deutschmann

Acknowledgments

The editors would like to express their sincere gratitude to all the chapter authors that have contributed to this endeavor on top of their numerous activities.

We are also grateful to Jonathan T. Rose, Senior Editor at Wiley for having approached us to write a book on pharmaceutical microbiology and his trust throughout this project as well as Aruna Pragasam, Project Editor, and Gayathree Sekar, Production Editor, at Wiley for their continuous support during the editing and production process.

We would also like to show our gratitude to Sabrina Kuoni for assisting in formatting all the chapters as well as Yvonne Böhler for the editing work on the images received.

Finally, our heartfelt thanks go to Anne Smiejan‐Roesti and Maja Christina Goverde for their continuous encouragement and support during this time‐consuming writing process.

The Editors

Messieurs, c'est les microbes qui auront le dernier mot.

(Gentlemen, it is the microbes who will have the last word.)

– Louis Pasteur

1Microbiological Control Strategy

David Roesti1 and Marcel Goverde2

1 Novartis Pharma Stein AG, Stein, Switzerland

2 MGP Consulting GmbH, Binningen, Switzerland

CONTENTS

1.1 Introduction

1.2 Overview of a Microbial Control Strategy Program