(Test Bank) Sterile Product Development Formulation, Process, Quality And Regulatory Considerations

Kolhe,Shah,Rathore, 2

Biology

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Author(s): Kolhe, Shah, Rathore

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AAPS Advances in the Pharmaceutical Sciences Series 6 Sterile Product DevelopmentParag Kolhe Mrinal Shah Nitin Rathore Editors Formulation, Process, Quality and Regulatory Considerations AAPS Advances in the Pharmaceutical Sciences Series The AAPS Advances in the Pharmaceutical Sciences Series, published in partnership with the American Association of Pharmaceutical Scientists, is designed to deliver well written volumes authored by opinion leaders and authoritarians from around the globe, addressing innovations in drug research and development, and best practice for scientists and industry professionals in the pharma and biotech industries. For more details and to see a list of titles in the Series please visit http://www.springer.com/series/8825 Series Editors Daan J.A. Crommelin Robert A. Lipper Parag Kolhe  Mrinal Shah  Nitin Rathore Editors Sterile Product Development Formulation, Process, Quality and Regulatory Considerations ISSN 2210-7371 ISSN 2210-738X (electronic) ISBN 978-1-4614-7977-2 ISBN 978-1-4614-7978-9 (eBook) DOI 10.1007/978-1-4614-7978-9 Springer New York Heidelberg Dordrecht London Library of Congress Control Number: 2013948456 © American Association of Pharmaceutical Scientists 2013 This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifi cally the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfi lms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. Exempted from this legal reservation are brief excerpts in connection with reviews or scholarly analysis or material supplied specifi cally for the purpose of being entered and executed on a computer system, for exclusive use by the purchaser of the work. Duplication of this publication or parts thereof is permitted only under the provisions of the Copyright Law of the Publisher’s location, in its current version, and permission for use must always be obtained from Springer. Permissions for use may be obtained through RightsLink at the Copyright Clearance Center. Violations are liable to prosecution under the respective Copyright Law. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specifi c statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. While the advice and information in this book are believed to be true and accurate at the date of publication, neither the authors nor the editors nor the publisher can accept any legal responsibility for any errors or omissions that may be made. The publisher makes no warranty, express or implied, with respect to the material contained herein. Printed on acid-free paper Springer is part of Springer Science+Business Media ( www.springer.com ) Editors Parag Kolhe Pharmaceutical R&D-BioTx Pharmaceutical Sciences P fi zer, Chesterfi eld , MO , USA Nitin Rathore Drug Product Technology Amgen, Thousand Oaks CA , USA Mrinal Shah LifeCell Corporation Bridgewater , NJ , USA v Pref ace Sterile products represent a signifi cant fraction of parenteral products and encompass a variety of challenging dosage forms. Development of sterile products poses mul- tifaceted challenges which can be broadly categorized into three areas: formulation dosage form development, processing and manufacturing and assurance of purity, safety and effi cacy of the manufactured product. The chapters in this book are struc- tured along this theme and offer a useful guide for scientists and personnel working on commercialization of sterile drug products. The fi rst part of the book covers the formulation aspects of sterile product devel- opment including basic principles of formulation development, formulation selec-tion via molecule and manufacturability assessments, and formulation approaches for polymer, lipid-based systems, PEGylated biotherapeutics, nasal delivery, vac-cines and adjuvant systems. The second part focuses on manufacturing process, container closure, and delivery considerations. This section covers freeze-thaw pro-cessing, technology transfer of sterile products, transfer across barrier systems, in addition, it focuses on recent innovations in aseptic fi lling, and approaches for developing lyophilized parenterals. The part also emphasizes on recent innovations in pen and autoinjector drug delivery devices and the methods available to establish container closure integrity (CCI). The last part of this book expands on quality and regulatory aspects of sterile products including particulate issues and appearance defects in sterile products, sterile fi ltration, and intravenous admixture compatibility. As sterilization process is an essential component of aseptic processing, the last four chapters cover the basic principles behind commonly used sterilization techniques, associated validation strategies along with an overview of microbial measurement methods. The book commences with an introduction to basic principles of sterile product formulation development. This chapter presents cogent approaches on development of injectable products and discusses formulation development considerations such as solubility, challenges for lipophilic formulations, nanoparticles, suspensions and dry formulations. Furthermore general considerations for compatibility with pri-mary packaging and manufacturing are provided. vi Chapter 2 discusses an approach for selection of molecules based on manufac- turability assessment so that robust commercial formulation can be developed for protein products. This chapter covers aspects of protein sequence analysis from product quality standpoint and identifying “hot spots” for degradation and approaches for initial formulation screening through assessment of physical and chemical stability. This chapter dives deeper into considerations for manufactur- ability assessment through various process studies by subjecting molecule to stresses experienced during manufacturing process. Chapter 3 provides a snapshot of polymer- and lipid-based drug delivery tech- nologies. Drug delivery technologies, especially controlled drug release technolo- gies have come a long way and their use in commercial drugs highlights the utility of such technologies. This chapter reviews the matured technologies that are being used in parenteral drug delivery and focuses on in situ forming gel depot formula- tions and lipid-based drug delivery technologies. Authors have also provided insights into the considerations for the development of newer technologies. Chapter 4 touches upon an important area of PEGylated biotherapeutics where a comprehensive review of commercial products and clinical products in develop- ment has been provided for readers. Authors initiate the discussion with chemistry of PEGylation and go into the details of manufacturing and formulation aspects such as issues during reaction, process considerations and characterization for drug substance, and stability aspects to consider during formulation development fol- lowed by delivery challenges for PEGylated products due to viscosity issues. Chapter 5 shifts the attention to nasal delivery aspects for sterile products. This chapter navigates readers through nasal physiology and mechanism of delivery, provides good review of local and systemic acting nasal products, discusses various challenges encountered during nasal drug delivery, and provides a comprehensive approach for formulation development and characterization. One of the important aspects in nasal delivery is the consideration for delivery devices. This chapter also provides an in-depth discussion on delivery devices, analytical testing, regulatory expectations, and manufacturing aspects through relevant case studies. Chapter 6 focuses on considerations for vaccine formulation development which include antigen and adjuvant formulation development. This chapter differentiates between the protein formulation vs. vaccine formulations and guides readers to the important aspect of immune response and how it is achieved in vaccines. The chap- ter reviews formulation considerations and available adjuvants for vaccines. In addi- tion, authors discuss the impact of route of delivery and challenges in stability and analytical characterization of vaccines. Part II begins with a chapter on freeze-thaw processing of bulk protein solutions. This chapter provides excellent insight into mechanistic aspects of freezing process for protein solutions, impact of freezing on proteins through cold denaturation, ice– liquid interface, and implications of cryoconcentration effects through solute crys- tallization and phase separation. Furthermore considerations for formulation and protection against freezing induced stress, design of freeze-thaw process parame- ters, scale down studies, and container closure aspects are discussed. Prefacevii Chapter 8 is a comprehensive collection of case studies by the author on best practices for technology transfer of sterile products. This chapter provides outstand- ing overview of requirements for material release testing for API and excipients with underlying case studies. The author discusses production aspect preparations, compounding operation, lyophilization, and sterilization elucidated with case stud- ies. Product release testing approach is explained through visual inspection, particu- late matter testing, and sterility testing. Chapter 9 discusses transfer of material across barrier systems in aseptic fi ll fi n- ish operations. It outlines topics such as requirements based on type of material being transferred, methods of transfer for solids, liquids, and suspensions. A compre- hensive discussion on selection of appropriate transfer process is presented with illustrating case studies with isolator for potent compounds, biotech products in prefi lled syringes, and for sterile suspensions for vaccines. Challenges and recent innovations in aseptic fi lling technology are covered in Chap. 10 . Aseptic fi lling requirements for clean room classifi cations, environmental monitoring, operator training, and gowning requirements are explained. An in- depth discussion on barrier system such as restricted access barriers (RABS) and isolators has been provided. Various fi lling containers and available fi lling processes are dis- cussed which include ampoules, vials, prefi lled syringes, cartridges, and Blow Fill Seal (BFS). This chapter concludes with case study on closed vial technology. Because not all products have adequate stability in solution state, manufacturers rely on the lyophilization process to manufacture formulations, both biologics and small molecules, in freeze-dried state. Chapter 11 provides a detail overview of the scientifi c and technological advancements in the fi eld of lyophilization. The chapter is an ideal resource for scientists involved with process design and qualifi cation of freeze-dried products. Specifi c guidance on critical process parameters, critical qual- ity attributes, and design space principles are covered that will help one to design process characterization studies. The author has also provided pertinent discussion on application of recent FDA guidance on process validation for this unit operation. Assurance of CCI is critical to ensure safety of the fi nal drug product presenta- tion for the end user. Process development scientists should have a general under- standing of the CCI testing and associated technical challenges in order to develop a robust drug product presentation. Chapter 12 provides an overview of regulatory expectations and Industry trend in CCI testing. A variety of CCI test methods are discussed along with considerations for method selection, develop- ment, and validation. The ease and fl exibility associated with the self-injection of parenteral drugs has also led to the increase in use of pens and autoinjectors as delivery devices. Chapter 13 provides an overview of the different types of injection devices as well as what the development of such a device entails. Regulatory requirements applicable to device development are discussed and examples are included to describe various steps associated with the injection device development and commercialization. Part III brings the focus on regulatory and quality aspects of sterile product development. Chapter 14 reviews our understanding of the particulate matter as a critical quality attribute and the related concerns that impact product safety. The Prefaceviii origin of these particles as well as the available enumeration techniques are dis- cussed in detail. The chapter also provides an overview of the pharmacopeial requirements and guidance on addressing regulatory queries related to subvisible particles in biopharmaceuticals. The discussion on product appearance is continued in Chap. 15 . This chapter deals with the visual inspection of drug products with a focus on defects that are visible to eye—both cosmetic and functional. The chapter covers inspection attributes, regulatory expectations for manual and automated visual inspections, and related case studies. The next chapter focuses on sterile fi ltration, a critical step in the manufacturing process needed to ensure sterility of the fi nal product. The chapter covers the perfor- mance requirements for sterile fi ltration and membrane properties including pore size and material of construction that can affect the fi ltration process. Basic fi ltration concepts such as fi lter selection and fi lter sizing are included. Operational practices including installation, sterilization, fl ushing, and integrity testing are also covered, as well as the main components of fi lter validation including retention studies and fi lter integrity testing. Intravenous (IV) admixture studies are an integral part of developing a safe and effi cacious sterile drug product intended for IV administration. Chapter 17 dis- cusses requirements and challenges associated with conducting IV admixture stud- ies and the related regulatory guidance. A pharmaceutical admixture consists of a drug product mixed with an appropriate diluent in a suitable dosing/delivery device for the purpose of parenteral infusion to the patient. The discussion presented in the chapter will help researchers identify critical admixture issues for their products and gain insights into addressing those issues while meeting regulatory expectations. The last four chapters of the book focus on sterilization process, microbiological methods, and the associated validation challenges. Chapter 18 deals with basics of sterilization methods commonly employed for sterile products. This chapter dis- cusses requirements for sterilization methods that are subject to review by regula- tory agencies when a sterile product is fi led for approval. The author provides a summary of requirements for sterilization process, sterilization method details, and considerations for validation of sterilization methods including heat sterilization, radiation sterilization, and ethylene oxide sterilization. In addition the author discusses aseptic processing requirements which include fi lters, clean room consid- eration, personnel qualifi cation, and aseptic process validation. Chapter 19 discusses the common errors made during investigation of microbial contamination events. Several thought patterns and behavior that prevents one from fi nding the source of contamination and the associated root cause are cov- ered. Multiple case studies are provided to aid the reader in conducting the best possible root cause investigation for a sterility assurance failure. Microbiological testing used to assess product sterility as well as microbiological quality of compo- nents, ingredients, environment and utilities, is foundational to the operation of pharmaceutical facilities. Given the slow turnaround time associated with the con- ventional methods, there has been an increasing interest in the use of rapid micro- biological methods (RMMs). Chapter 20 discusses different types of available RMMs and provides guidance on the validation of such RMMs. A detailed Prefaceix discussion of the validation strategy is provided including the user requirements, vendor assessments, documentation, and other qualifi cation activities needed to meet regulatory expectations. Chapter 21 describes the current expectations for validation of dry and moist heat sterilization cycles. The chapter explains the basic concepts behind dry and moist heat sterilization including the mechanism of sterilization, determination of worst case conditions, and the relevant loading confi gurations. References to key literature from Parenteral Drug Association and the International Organization for Standardization are provided to the reader for further details. The chapter also cov- ers assessment of biological and physical aspects of sterilization process and pro- vides guidance on strategy for validation of sterilization cycles. Overall this book covers essential aspects of sterile product development with excellent contributions, including several case studies, made by key experts in the fi eld. We trust that this book serves as reference guide for researchers, process engi- neers, pharmaceutical and biotechnology scientists as well as academic students. Chesterfi eld , MO Parag Kolhe Bridgewater , NJ Mrinal Shah Thousand Oaks , CA Nitin Rathore Preface xi Acknowledgments We thank Dr. Daan Crommelin for giving us the opportunity to edit this book as part of the Advances in the Pharmaceutical Sciences Series. We are also thankful to all our coauthors who took the time to make such excellent contributions as well as to the scientists and experts whose work has been cited in this book. We express our appreciation towards Sterile Pharmaceutical Focus Group (SPFG), AAPS for this opportunity and its committee members including Dr. Scott Steffen for the help in identifying key contributors for this book. xiiiPart I Formulation Approaches for Sterile Products 1 Basic Principles of Sterile Product Formulation Development .......... 3 Martin A. Joyce and Leonore C. Witchey-Lakshmanan 2 Molecule and Manufacturability Assessment Leading to Robust Commercial Formulation for Therapeutic Proteins ........... 33 Ranjini Ramachander and Nitin Rathore 3 Polymer- and Lipid-Based Systems for Parenteral Drug Delivery ..... 47 David Chen and Sara Yazdi 4 Formulation Approaches and Strategies for PEGylated Biotherapeutics .............................................................. 61 Roger H. Pak and Rory F. Finn 5 Considerations for the Development of Nasal Dosage Forms ............. 99 Jason D. Ehrick, Samir A. Shah, Charles Shaw, Vitthal S. Kulkarni,Intira Coowanitwong, Samiran De, and Julie D. Suman 6 Formulation Approaches and Strategies for Vaccines and Adjuvants .................................................................... 145 Kimberly J. Hassett, Pradyot Nandi, and Theodore W. Randolph Part II Process, Container Closure and Delivery Considerations 7 Challenges in Freeze-Thaw Processing of Bulk Protein Solutions ..... 167 Hari R. Desu and Sunil T. Narishetty 8 Best Practices for Technology Transfer of Sterile Products: Case Studies ............................................................................................. 205 Leonore C. Witchey-Lakshmanan Contents xiv 9 Transfer Across Barrier Systems: A New Source of Simplifi cation in Aseptic Fill and Finish Operations .................................................... 227 Benoît Verjans 10 Challenges and Innovation in Aseptic Filling: Case Study with the Closed Vial Technology ........................................ 249 Benoît Verjans 11 Contemporary Approaches to Development and Manufacturing of Lyophilized Parenterals ...................................................................... 275 Edward H. Trappler 12 Advances in Container Closure Integrity Testing ................................ 315 Lei Li 13 Pen and Autoinjector Drug Delivery Devices ....................................... 331 Ian Thompson and Jakob Lange Part III Regulatory and Quality Aspects14 Particulate Matter in Sterile Parenteral Products ............................... 359 Satish K. Singh 15 Appearance Evaluation of Parenteral Pharmaceutical Products ....... 411 Erwin Freund 16 Sterile Filtration: Principles, Best Practices and New Developments ........................................................................... 431 Herb Lutz, Randy Wilkins, and Christina Carbrello 17 Intravenous Admixture Compatibility for Sterile Products: Challenges and Regulatory Guidance ................................................... 461 Manoj Sharma, Jason K. Cheung, Anita Dabbara, and Jonathan Petersen 18 Basics of Sterilization Methods .............................................................. 475 Gregory W. Hunter 19 Avoiding Common Errors During Viable Microbial Contamination Investigations ................................................................ 501 Kenneth H. Muhvich 20 Validation of Rapid Microbiological Methods (RMMs) ...................... 513 Jeanne Moldenhauer 21 Validation of Moist and Dry Heat Sterilization .................................... 535 Jeanne Moldenhauer Index ................................................................................................................. 575Contents