PHARMACEUTICAL
`MANUFACTURING
`HANDBOOK
`
`Production and
`Processes
`
`SHAYNE COX GAD, PH.D., D.A.B.T.
`Gad Consulting Services
`Cary, North Carolina
`
`A JOHN WILEY & SONS, INC., PUBLICATION
`
`Novartis Exhibit 2336.001
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`PHARMACEUTICAL
`MANUFACTURING
`HANDBOOK
`
`Production and
`Processes
`
`Novartis Exhibit 2336.002
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`PHARMACEUTICAL
`MANUFACTURING
`HANDBOOK
`
`Production and
`Processes
`
`SHAYNE COX GAD, PH.D., D.A.B.T.
`Gad Consulting Services
`Cary, North Carolina
`
`A JOHN WILEY & SONS, INC., PUBLICATION
`
`Novartis Exhibit 2336.003
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`Copyright © 2008 by John Wiley & Sons, Inc. All rights reserved
`
`Published by John Wiley & Sons, Inc., Hoboken, New Jersey
`Published simultaneously in Canada
`
`No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any
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`
`Limit of Liability/Disclaimer of Warranty: While the publisher and author have used their best efforts
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`Printed in the United States of America
`
`10 9 8 7 6 5 4 3 2 1
`
`Novartis Exhibit 2336.004
`Regeneron v. Novartis, IPR2021-00816
`
`

`

` CONTRIBUTORS
`
`
`
`
`
` Susanna Abrahms é n - Alami, AstraZeneca R & D Lund, Lund, Sweden,
`Extended - Release Formulations
`
` Oral
`
` James Agalloco, Agalloco & Associates, Belle Mead, New Jersey, Sterile Product
`Manufacturing
`
` Fakhrul Ahsan, Texas Tech University, Amarillo, Texas, Nasal Delivery of Peptide
`and Nonpeptide Drugs
`
` James Akers, Akers Kennedy & Associates, Kansas City, Missouri, Sterile Product
`Manufacturing
`
` Raid G. Alany, The University of Auckland, Auckland, New Zealand, Ocular Drug
`Delivery; Microemulsions as Drug Delivery Systems
`
` Monique Alric, Universit é d ’ Auvergne, Clermont - Ferrand, France, Recombinant
`Saccharomyces Cerevisiae as New Drug Delivery System to Gut: In Vitro Valida-
`tion and Oral Formulation
`
` Sacide Alsoy Altinkaya, Izmir Institute of Technology, Urla - Izmir, Turkey, Con-
`trolled Release of Drugs from Tablet Coatings
`
` Maria Helena Amaral, University of Porto, Porto, Portugal,
`Delivery
`
` Vaginal Drug
`
` Anil Kumar Anal, Living Cell Technologies (Global) Limited, Auckland, New
`Zealand, Controlled - Release Dosage Forms
`
` Gavin Andrews, Queen ’ s University Belfast, Belfast, Northern Ireland, Effects of
`Grinding in Pharmaceutical Tablet Production
`
` Sophia G. Antimisiaris, School of Pharmacy, University of Patras, Rio, Greece,
` Liposomes and Drug Delivery
`
`Novartis Exhibit 2336.005
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`vi
`
` CONTRIBUT ORS
`
` Robert D. Arnold, The University of Georgia, Athens, Georgia, Biotechnology -
` Derived Drug Product Development
`
` C. Scott Asbill, Samford University, Birmingham, Alabama, Transdermal Drug
`Delivery
`
` Maria Fernanda Bahia, University of Porto, Porto, Portugal,
`Delivery
`
` Vaginal Drug
`
` Bernard Bataille, University of Montpelier 1, Montpellier, France, Tablet Design
`
` Gerald W. Becker, SSCI, West Lafayette, Indiana, Biotechnology - Derived Drug
`Product Development; Regulatory Considerations in Approval of Follow - On
`Protein Drug Products
`
` B. Wayne Bequette, Rensselaer Polytechnic Institute, Troy, New York, From Pilot
`Plant to Manufacturing: Effect of Scale - Up on Operation of Jacketed Reactors
`
` Erem Bilensoy, Hacettepe University Faculty of Pharmacy, Ankara, Turkey, Cyclo-
`dextrin - Based Nanomaterials in Pharmaceutical Field
`
` St é phanie Blanquet, Universit é d ’ Auvergne, Clermont - Ferrand, France, Recombi-
`nant Saccharomyces Cerevisiae as New Drug Delivery System to Gut: In Vitro
`Validation and Oral Formulation
`
` Gary W. Bumgarner, Samford University, Birmingham, Alabama, Transdermal
`Drug Delivery
`
` Isidoro Caraballo, University of Sevilla, Seville, Spain, Tablet Design
`
` Stephen M. Carl, Purdue University, West Lafayette, Indiana, Biotechnology -
` Derived Drug Product Development; Regulatory Considerations in Approval of
`Follow - On Protein Drug Products
`
` Sudhir S. Chakravarthi, University of Nebraska Medical Center, College of Phar-
`macy, Omaha, Nebraska, Biodegradable Nanoparticles
`
` D.F. Chowdhury, University of Oxford, Oxford, United Kingdom, Pharmaceutical
`Nanosystems: Manufacture, Characterization, and Safety
`
` Barbara R. Conway, Aston University, Birmingham, United Kingdom, Solid Dosage
`Forms
`
` Jos é das Neves, University of Porto, Porto, Portugal, Vaginal Drug Delivery
`
` Osama Abu Diak, Queen ’ s University Belfast, Belfast, Northern Ireland, Effects
`of Grinding in Pharmaceutical Tablet Production
`
` Brit S. Farstad, Instititue for Energy Technology, Isotope Laboratories, Kjeller,
`Norway, Radiopharmaceutical Manufacturing
`
` Dimitrios G. Fatouros, School of Pharmacy and Biomedical Sciences, Portsmouth,
`England, Liposomes and Drug Delivery
`č č
` Jelena Filipovi ç - Gr i , Faculty of Pharmacy and Biochemistry, University of
`Zagreb, Zagreb, Croatia, Nasal Powder Drug Delivery
`
`Novartis Exhibit 2336.006
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`CONTRIBUTORS
`
` vii
`
` Eddy Castellanos Gil, Center of Pharmaceutical Chemistry and University of
`Havana, Havana, Cuba; University of Sevilla, Seville, Spain; University of Mont-
`pelier 1, Montpellier, France, Tablet Design
` Anita Hafner, Faculty of Pharmacy and Biochemistry, University of Zagreb,
`Zagreb, Croatia, Nasal Powder Drug Delivery
` A. Atilla Hincal, Hacettepe University Faculty of Pharmacy, Ankara, Turkey,
` Cyclodextrin - Based Nanomaterials in Pharmaceutical Field
` Michael Hindle, Virginia Commonwealth University, Richmond, Virginia, Aerosol
`Drug Delviery
` Bhaskara R. Jasti, University of the Pacifi c, Stockton, California, Semisolid Dosages:
`Ointments, Creams, and Gels
` Yiguang Jin, Beijing Institute of Radiation Medicine, Beijing, China, Nanotechnol-
`ogy in Pharmaceutical Manufacturing
` David Jones, Queen ’ s University Belfast, Belfast, Northern Ireland, Effects of
`Grinding in Pharmaceutical Tablet Production
` Anne Juppo, University of Helsinki, Helsinki, Finland, Oral Extended - Release
`Formulations
` Paraskevi Kallinteri, Medway School of Pharmacy, Universities of Greenwich and
`Kent, England, Liposomes and Drug Delivery
` Gregory T. Knipp, Purdue University, West Lafayette, Indiana, Biotechnology -
` Derived Drug Product Development; Regulatory Considerations in Approval of
`Follow - On Protein Drug Products
` Anette Larsson, Chalmers University of Technology, G ö teborg, Sweden, Oral
`Extended - Release Formulations
` Beom - Jin Lee, Kangwon National University, Chuncheon, Korea, Pharmaceutical
`Preformulation: Physiochemical Properties of Excipients and Powders and Tablet
`Characterization
` Xiaoling Li, University of the Pacifi c, Stockton, California, Semisolid Dosages:
`Ointments, Creams, and Gels
` David J. Lindley, Purdue University, West Lafayette, Indiana, Biotechnology -
` Derived Drug Product Development
` Roberto Londono, Washington State University, Pullman, Washington, Liquid
`Dosage Forms
` Ravichandran Mahalingam, University of the Pacifi c, Stockton, California, Semi-
`solid Dosages: Ointments, Creams, and Gels
` Kenneth R. Morris, Purdue University, West Lafayette, Indiana, Biotechnology -
` Derived Drug Product Development; Regulatory Considerations in Approval of
`Follow - On Protein Drug Products
` Erin Oliver, Rutgers, The State University of New Jersey, Piscataway, New Jersey,
` Biotechnology - Derived Drug Product Development; Regulatory Considerations
`in Approval of Follow - On Protein Drug Products
`
`Novartis Exhibit 2336.007
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`viii
`
` CONTRIB UTORS
`
` Iv á n Pe ñ uelas, University of Navarra, Pamplona, Spain, Radiopharmaceutical
`Manufacturing
`
` Omanthanu P. Perumal, South Dakota State University, Brookings, South Dakota,
` Role of Preformulation in Development of Solid Dosage Forms
`
` Katharina M. Picker - Freyer, Martin - Luther - University Halle - Wittenberg, Institute
`of Pharmaceutics and Biopharmaceutics, Halle/Saale, Germany, Tablet Produc-
`tion Systems
`
` Satheesh K. Podaralla, South Dakota State University, Brookings, South Dakota,
` Role of Preformulation in Development of Solid Dosage Forms
`
` Dennis H. Robinson, University of Nebraska Medical Center, College of Phar-
`macy, Omaha, Nebraska, Biodegradable Nanoparticles
`
` Arcesio Rubio, Caracas, Venezuela, Liquid Dosage Forms
`
` Maria V. Rubio - Bonilla, Research Associate, College of Pharmacy, Washington
`State University, Pullman, Washington, Liquid Dosage Forms
`
` Ilva D. Rupenthal, The University of Auckland, Auckland, New Zealand, Ocular
`Drug Delivery
`
` Maria In ê s Rocha Miritello Santoro, Department of Pharmacy, Faculty of Pharma-
`ceutical Sciences, University of S ã o Paulo, S ã o Paulo, Brazil, Packaging and
`Labeling
`
` Helton M.M. Santos, University of Coimbra, Coimbra, Portugal,
`Compression
`
` Tablet
`
` Raymond K. Schneider, Clemson University, Clemson, South Carolina, Clean -
` Facility Design, Construction, and Maintenance Issues
`
` Anil Kumar Singh, Department of Pharmacy, Faculty of Pharmaceutical Sciences,
`University of S ã o Paulo, S ã o Paulo, Brazil, Packaging and Labeling
`
` Jo ã o J.M.S. Sousa, University of Coimbra, Coimbra, Portugal,
`Compression
`
` Tablet
`
` Shunmugaperumal Tamilvanan, University of Antwerp, Antwerp, Belgium, Prog-
`ress in Design of Biodegradable Polymer - Based Microspheres for Parenteral
`Controlled Delivery of Therapeutic Peptide/Protein; Oil - in - Water Nanosized
`Emulsions: Medical Applications
`
` Chandan Thomas, Texas Tech University, Amarillo, Texas, Nasal Delivery of
`Peptide and Nonpeptide Drugs
`
` Gavin Walker, Queen ’ s University Belfast, Belfast, Northern Ireland, Effects of
`Grinding in Pharmaceutical Tablet Production
`
` Jingyuan Wen, The University of Auckland, Auckland, New Zealand, Microemul-
`sions as Drug Delivery Systems
`
` Hui Zhai, Queen ’ s University Belfast, Belfast, Northern Ireland, Effects of Grind-
`ing in Pharmaceutical Tablet Production
`
`
`
`Novartis Exhibit 2336.008
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`CONTENTS
`
`PREFACE
`
`SECTION 1 MANUFACTURING SPECIALTIES
`
`1.1 Biotechnology-Derived Drug Product Development
`
`Stephen M. Carl, David J. Lindley, Gregory T. Knipp, Kenneth R. Morris,
`Erin Oliver, Gerald W. Becker, and Robert D. Arnold
`
`1.2 Regulatory Considerations in Approval on Follow-On Protein
`Drug Products
`Erin Oliver, Stephen M. Carl, Kenneth R. Morris, Gerald W. Becker, and
`Gregory T. Knipp
`
`
`
`1.3 Radiopharmaceutical Manufacturing
`
`Brit S. Farstad and Iván Peñuelas
`
`SECTION 2 ASEPTIC PROCESSING
`
`2.1
`
`
`Sterile Product Manufacturing
`James Agalloco and James Akers
`
`SECTION 3 FACILITY
`
`3.1
`
`
`
`From Pilot Plant to Manufacturing: Effect of Scale-Up on
`Operation of Jacketed Reactors
`B. Wayne Bequette
`
`xiii
`
`1
`
`3
`
`33
`
`59
`
`97
`
`99
`
`137
`
`139
`
`ix
`
`Novartis Exhibit 2336.009
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`x
`
` CONTENTS
`
`3.2 Packaging and Labeling
`
`Maria Inês Rocha Miritello Santoro and Anil Kumar Singh
`
`3.3 Clean-Facility Design, Construction, and Maintenance Issues
`
`Raymond K. Schneider
`
`SECTION 4 NORMAL DOSAGE FORMS
`
`4.1
`
`
`4.2
`
`
`Solid Dosage Forms
`Barbara R. Conway
`
`Semisolid Dosages: Ointments, Creams, and Gels
`Ravichandran Mahalingam, Xiaoling Li, and Bhaskara R. Jasti
`
`4.3 Liquid Dosage Forms
`
`Maria V. Rubio-Bonilla, Roberto Londono, and Arcesio Rubio
`
`SECTION 5 NEW DOSAGE FORMS
`
`5.1 Controlled-Release Dosage Forms
`
`Anil Kumar Anal
`
`5.2 Progress in the Design of Biodegradable Polymer-Based
`Microspheres for Parenteral Controlled Delivery of Therapeutic
`Peptide/Protein
`Shunmugaperumal Tamilvanan
`
`
`
`5.3 Liposomes and Drug Delivery
`
`Sophia G. Antimisiaris, Paraskevi Kallinteri, and Dimitrios G. Fatouros
`
`5.4 Biodegradable Nanoparticles
`
`Sudhir S. Chakravarthi and Dennis H. Robinson
`
`5.5 Recombinant Saccharomyces cerevisiae as New Drug Delivery
`System to Gut: In Vitro Validation and Oral Formulation
`Stéphanie Blanquet and Monique Alric
`
`
`
`5.6 Nasal Delivery of Peptide and Nonpeptide Drugs
`
`Chandan Thomas and Fakhrul Ahsan
`
`5.7 Nasal Powder Drug Delivery
`ć
`č ć
`
`Jelena Filipovi -Gr i and Anita Hafner
`
`5.8 Aerosol Drug Delivery
`
`Michael Hindle
`
`5.9 Ocular Drug Delivery
`
`Ilva D. Rupenthal and Raid G. Alany
`
`5.10 Microemulsions as Drug Delivery Systems
`
`Raid G. Alany and Jingyuan Wen
`
`159
`
`201
`
`233
`
`235
`
`267
`
`313
`
`345
`
`347
`
`393
`
`443
`
`535
`
`565
`
`591
`
`651
`
`683
`
`729
`
`769
`
`Novartis Exhibit 2336.0010
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`CONTENTS
`
` xi
`
`5.11 Transdermal Drug Delivery
`
`C. Scott Asbill and Gary W. Bumgarner
`
`5.12 Vaginal Drug Delivery
`
`José das Neves, Maria Helena Amaral, and Maria Fernanda Bahia
`
`SECTION 6 TABLET PRODUCTION
`
`6.1 Pharmaceutical Preformulation: Physicochemical Properties of
`Excipients and Powers and Tablet Characterization
`Beom-Jin Lee
`
`
`
`6.2 Role of Preformulation in Development of Solid Dosage Forms
`
`Omathanu P. Perumal and Satheesh K. Podaralla
`
`6.3 Tablet Design
`
`Eddy Castellanos Gil, Isidoro Caraballo, and Bernard Bataille
`
`6.4 Tablet Production Systems
`
`Katharina M. Picker-Freyer
`
`6.5 Controlled Release of Drugs from Tablet Coatings
`
`Sacide Alsoy Altinkaya
`
`6.6 Tablet Compression
`
`Helton M. M. Santos and João J. M. S. Sousa
`
`6.7 Effects of Grinding in Pharmaceutical Tablet Production
`
`Gavin Andrews, David Jones, Hui Zhai, Osama Abu Diak, and
`Gavin Walker
`
`6.8 Oral Extended-Release Formulations
`
`Anette Larsson, Susanna Abrahmsén-Alami, and Anne Juppo
`
`SECTION 7 ROLE OF NANOTECHNOLOGY
`
`7.1 Cyclodextrin-Based Nanomaterials in Pharmaceutical Field
`
`Erem Bilensoy and A. Attila Hincal
`
`7.2 Nanotechnology in Pharmaceutical Manufacturing
`
`Yiguang Jin
`
`7.3 Pharmaceutical Nanosystems: Manufacture, Characterization,
`and Safety
`D. F. Chowdhury
`
`
`
`7.4 Oil-in-Water Nanosized Emulsions: Medical Applications
`
`Shunmugaperumal Tamilvanan
`
`INDEX
`
`793
`
`809
`
`879
`
`881
`
`933
`
`977
`
`1053
`
`1099
`
`1133
`
`1165
`
`1191
`
`1223
`
`1225
`
`1249
`
`1289
`
`1327
`
`1367
`
`Novartis Exhibit 2336.0011
`Regeneron v. Novartis, IPR2021-00816
`
`

`

` PREFACE
`
`
`
` This Handbook of Manufacturing Techniques focuses on a new aspect of the drug
`development challenge: producing and administering the physical drug products
`that we hope are going to provide valuable new pharmacotherapeutic tools in medi-
`cine. These 34 chapters cover the full range of approaches to developing and pro-
`ducing new formulations and new approaches to drug delivery. Also addressed are
`approaches to the issues of producing and packaging these drug products (that is,
`formulations). The area where the most progress is possible in improving therapeu-
`tic success with new drugs is that of better delivery of active drug molecules to the
`therapeutic target tissue. In this volume, we explore current and new approaches to
`just this issue across the full range of routes (oral, parenteral, topical, anal, nasal,
`aerosol. ocular, vaginal, and transdermal) using all sorts of forms of formulation.
`The current metrics for success of new drugs in development once they enter the
`clinic (estimated at ranging from as low as 2% for oncology drugs to as high as 10%
`for oral drugs) can likely be leveraged in the desired direction most readily by
`improvements in this area of drug delivery.
` The Handbook of Manufacturing Techniques seeks to cover the entire range of
`available approaches to getting a pure drug (as opposed to a combination product)
`into the body and to its therapeutic tissue target. Thanks to the persistent efforts of
`Michael Leventhal, these 34 chapters, which are written by leading practitioners in
`each of these areas, provide coverage of the primary approaches to these funda-
`mental problems that stand in the way of so many potentially successful pharmaco-
`therapeutic interventions.
`
`xiii
`
`Novartis Exhibit 2336.0012
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`2.1
`
` STERILE PRODUCT
`MANUFACTURING
`
` James Agalloco 1 and James Akers 2
`1 Agalloco & Associates, Belle Mead, New Jersey
`2 Akers Kennedy & Associates, Kansas City, Missouri
`
` Contents
`
` 2.1.1
` 2.1.2
`
` 2.1.3
`
` 2.1.4
`
` 2.1.5
`
` Introduction
` Process Selection and Control
` 2.1.2.1
` Formulation and Compounding
` 2.1.2.2
` Primary Packaging
` 2.1.2.3
` Process Objectives
` Facility Design
` 2.1.3.1
` Warehousing
` 2.1.3.2
` Preparation Area
` 2.1.3.3
` Compounding Area
` 2.1.3.4
` Aseptic Compound Area (If Present)
` 2.1.3.5
` Aseptic Filling Rooms and Aseptic Processing Area
` 2.1.3.6
` Capping and Crimping Sealing Areas
` 2.1.3.7
` Sterilizer Unload (Cooldown) Rooms
` 2.1.3.8
` Corridors
` 2.1.3.9
` Aseptic Storage Rooms
` 2.1.3.10
` Lyophilizer Loading and Unloading Rooms
` 2.1.3.11
` Air Locks and Pass - Throughs
` 2.1.3.12
` Gowning Rooms
` 2.1.3.13
` Terminal Sterilization Area
` 2.1.3.14
` Inspection, Labeling, and Packaging
` Aseptic Processing Facility Alternatives
` 2.1.4.1
` Expandability
` Utility Requirements
` 2.1.5.1
` Water for Injection
` 2.1.5.2
` Clean (Pure) Steam
` 2.1.5.3
` Process Gases
` 2.1.5.4
` Other Utilities
`
`Pharmaceutical Manufacturing Handbook: Production and Processes, edited by Shayne Cox Gad
`Copyright © 2008 John Wiley & Sons, Inc.
`
`99
`
`Novartis Exhibit 2336.0013
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`100
`
`STERILE PRODUCT MANUFACTURING
`
` 2.1.6
`
` 2.1.7
` 2.1.8
`
` 2.1.9
`
` 2.1.10
` 2.1.11
`
` 2.1.12
` 2.1.13
`
`
`
`
`
`
`
` Sterilization and Depyrogenation
` 2.1.6.1
` Steam Sterilization
` 2.1.6.2
` Dry - Heat Sterilization and Depyrogenation
` 2.1.6.3
` Gas and Vapor Sterilization
` 2.1.6.4
` Radiation Sterilization
` 2.1.6.5
` Sterilization by Filtration
` Facility and System: Qualifi cation and Validation
` Environmental Control and Monitoring
` 2.1.8.1
` Sanitization and Disinfection
` 2.1.8.2
` Monitoring
` Production Activities
` 2.1.9.1
` Material and Component Entry
` 2.1.9.2
` Cleaning and Preparation
` 2.1.9.3
` Compounding
` 2.1.9.4
` Filling
` 2.1.9.5
` Stoppering and Crimping
` 2.1.9.6
` Lyophilization
` Personnel
` Aseptic Processing Control and Evaluation
` 2.1.11.1
` In - Process Testing
` 2.1.11.2
` End - Product Testing
` 2.1.11.3
` Process Simulations
` Terminal Sterilization
` Conclusion
` Appendix
` References
` Additional Readings
`
` 2.1.1
`
` INTRODUCTION
`
` The manufacture of sterile products is universally acknowledged to be the most
`diffi cult of all pharmaceutical production activities to execute. When these products
`are manufactured using aseptic processing, poorly controlled processes can expose
`the patient to an unacceptable level of contamination. In rare instances contami-
`nated products can lead to microbial infection resulting from products intended to
`hasten the patient ’ s recovery. The production of sterile products requires fastidious
`design, operation, and maintenance of facilities and equipment. It also requires
`attention to detail in process development and validation to ensure success. This
`chapter will review the salient elements of sterile manufacturing necessary to
`provide acceptable levels of risk regarding sterility assurance.
` Commensurate with the criticality associated with sterile products, the global
`regulatory community has established a substantial number of the basic require-
`ments that fi rms are expected to adhere to in the manufacture of sterile products.
`The most extensive of these are those defi ned by the Food and Drug Administration
`
`Novartis Exhibit 2336.0014
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`PROCESS SELECTION AND DESIGN
`
`101
`
`(FDA) in its 2004 Guideline on Sterile Drug Products Produced by Aseptic Process-
`ing and the European Agency for the Evaluation of Medicinal Products (EMEA)
`Annex 1 on Sterile Medicinal Products [1, 2] . Substantial additional information is
`available from the International Organization for Standardization (ISO), the Par-
`enteral Drug Association (PDA), and the International Society for Pharmaceutical
`Engineering (ISPE) (see Appendix ) [3] . The organizations have provided a level of
`practical, experience - based detail not found in the regulatory documents, thereby
`better defi ning practices that are both compliant with regulatory expectations and
`based upon rational, evidence - based science and engineering.
` Consideration of patient risk associated with pharmaceutical production emerged
`largely from regulatory impetus, by which the regulatory community stated its
`intended goal to structure its inspectional process using patient safety as a major
`focus in determining where to allocate their inspectional and review resources.
`Emanating from the International Conference on Harmonization (ICH) efforts to
`produce a harmonized approach to pharmaceutical regulation, risk - based compli-
`ance has been adopted in Europe, Japan, and the United States [4, 5] . Sterile prod-
`ucts, especially those made by aseptic processing, have been properly identifi ed as
`a high priority by the global regulatory community. Several risk analysis approaches
`have been developed that can help the practitioner review practices with the goal
`of minimizing risk to the patient [6 – 8] .
`
` 2.1.2
`
` PROCESS SELECTION AND DESIGN
`
` The production of sterile products is profoundly impacted both by formulation and
`the selection of primary packaging components. Design parameters for a facility and
`selection of appropriate manufacturing technologies for the product require that
`the formulation process and packaging components be chosen and evaluated in
`advance.
`
` 2.1.2.1
`
` Formulation and Compounding
`
` The vast majority of parenteral formulations are solutions requiring a variety of
`tankage, piping, and ancillary equipment for liquid mixing (or powder blending),
`fi ltration, transfer, and related activities. Suspensions, ointments, and other similar
`products, including the preparation of the solutions for lyophilized products, can be
`manufactured in the same or very similar equipment. The scale of manufacturing
`can vary substantially, with the largest batches being well in excess of 5000 L (typi-
`cally for large - volume parenteral production), down to less than 50 mL for radio-
`pharmaceuticals or biologicals customized for a particular patient.
` The majority of this equipment is composed of 300 series austenitic stainless steel,
`with tantalum or glass - lined vessels employed for preparation of formulations sensi-
`tive to iron and other metal ions. The vessels can be equipped with external jackets
`for heating and/or cooling and various types of agitators, depending upon the mixing
`requirements of the individual formulation. In many facilities, a variety of tank sizes
`are available for use. Larger facilities may have the high - capacity tanks permanently
`installed and permanently connected to process utilities. Smaller vessels are gener-
`ally mobile and positioned in individual processing booths or rooms as needed.
`
`Novartis Exhibit 2336.0015
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`102
`
`STERILE PRODUCT MANUFACTURING
`
`After sterilizing fi ltration (or sterilization by heat or other means), comparably sized
`vessels are sometimes utilized to contain the product prior to and during the fi lling
`process. These holding vessels are often steam sterilized along with the connecting
`piping prior to use. There are a number of fi rms that fi ll directly from the compound-
`ing vessel using in - line fi ltration eliminating the intermediate vessel. When this
`approach is used, a small moist - heat - sterilized surge tank or reservoir tank may be
`required, particularly with modern time – pressure fi lling systems. This practice may
`reduce initial facility and equipment cost but places additional constraints
`on operational fl exibility. The use of disposable equipment for compounding and
`holding of sterile formulations is coming into greater use. This eliminates the clean-
`ing of vessels prior to reuse, but confi rmation of material compatibility is required.
`Disposable equipment is often used with products manufactured in small to moder-
`ate volumes, and while reducing initial equipment expenses disposable equipment
`also results in contaminated waste, which cannot be recycled or reused and must be
`treated appropriately.
` Aseptic compounding as required for suspensions and other formulations in
`which open - vessel processes are required mandate an ISO 5 environment providing
`ideally > 400 air changes/hour in which these steps can be performed with minimal
`opportunity for adventitious contamination. This could be accomplished using a
`protective curtain and a unidirectional fl ow hood (UFH) or other more evolved
`designs such as a restricted access barrier (RABs) system or an isolator (technolo-
`gies that provide a higher level of employee separation from the area in which
`materials are handled can get by with lower air exchange rates). All activities requir-
`ing opening of processing lines such as sampling or fi lter integrity testing should be
`performed using similar protective measures. The preparation of sterile suspensions
`requires a facility/equipment design capable of safe addition of sterile solids to a
`liquid vehicle and is conventionally performed using a specifi cally designed process-
`ing area to minimize contamination potential. Comparable and greater complexity
`is generally required for creams, ointments, emulsions, and the increasingly common
`liposome formulations.
` Some sterile powder formulations (these are predominantly, but not exclusively,
`antibiotics) may require sampling, mixing, milling, and subdivision activities similar
`to those found in oral powder manufacturing. The facilities and equipment utilized
`for these products is substantially different from that used for liquids, and the pro-
`duction area bears little resemblance to that utilized for liquids. These materials are
`received sterile and must be processed through sterilized equipment specifi cally
`intended for powder handling in a fully aseptic environment with ISO 5 protection
`over all open container activities.
`
` 2.1.2.2
`
` Primary Packaging
`
` The primary package for parenteral formulations provides protection to the sterile
`materials throughout the shelf life. The components of the primary package are
`every bit as important to contamination control and hence safety of the fi nished
`product as the formulation itself, and their preparation must be given a comparable
`level of consideration. The most commonly used container is glass; vials are still the
`most common, although increasingly prefi lled syringes are chosen. Glass ampoules
`are still seen. However, although convenient from a manufacturing perspective, the
`
`Novartis Exhibit 2336.0016
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`PROCESS SELECTION AND DESIGN
`
`103
`
`diffi culty involved in opening ampoules while at the same time avoiding problems
`with glass particulate or microbial contamination has reduced their popularity. The
`use of plastic containers (as vials, ampoules, or syringes) is increasingly common
`given their reduced weight and resistance to breakage. Blow - fi ll seal (BFS) and
`form - fi ll seal (FFS) are utilized for the fi lling of numerous ophthalmic and other
`noninjectable formulations in predominantly low - density polyethylene (LDPE)
`containers. With the exception of ampoules and BFS/FFS, an elastomeric closure
`system is also necessary to seal the containers. Some delivery systems (i.e., prefi lled
`syringes, multichamber vials, and others may require more than one elastomeric
`component to operate properly. In the case of vials, an aluminum crimp is applied
`to secure the closure to the vial. Prefi lled syringes may require the preparation and
`assembly of additional components such as needles, needle guards, stoppers, dia-
`phragms, or plungers, depending on the specifi cs of the design. Lyophilization is
`required to ensure the stability of some formulations and requires the use of clo-
`sures that allow venting of the container during the freeze - drying process. Full
`seating of the closure is accomplished within the lyophilizer using moving shelves
`to seat the closure.
` Glass is ordinarily washed prior to sterilization/depyrogenation to reduce con-
`tamination with foreign material prior to fi lling. In aseptic fi ll processes, the glass is
`then depyrogenated using dry heat. This can be accomplished using either a continu-
`ous tunnel (common for larger volumes and high - speed lines) or a dry heat oven
`(predominantly for small batches). The depyrogenation process serves to sterilize
`the glass at the same time, and thus the glass components must be protected post-
`processing. This is generally accomplished by short - term storage in an ISO 5 envi-
`ronment often accompanied by covering within a lidded tray. There are suppliers
`that offer depyrogenated glass vials and partially assembled syringes in sealed pack-
`ages for fi lling at a customer ’ s site. In this instance, the supplier assumes responsibil-
`ity for the preparation, depyrogenation, and aseptic packaging. Glass ampoules are
`available presealed and depyrogenated; the end user has merely to open, fi ll, and
`reseal the syringe under appropriate conditions.
` Plastic components (whether container or closure) can be sterilized using steam,
`ethylene oxide, hydrogen peroxide, or ionizing radiation. The γ irradiation is accom-
`plished off - site by a subcontractor with appropriate expertise as these methods are
`considered the province of specialists because of the extreme health hazards directly
`related to the sterilization method. Electron beam sterilization may also be done
`by a contractor, although compact lower energy electron beam systems have been
`introduced that allow sterilization in - house. Steam sterilization is ordinarily per-
`formed in house, though many common components are becoming available prest-
`erilized by the supplier. Preparation steps prior to sterilization vary with the
`component and the methods used to produce the component. Rubber components
`are washed to reduce particles, while this is less common with plastic materials.
` Syringes vary substantially in design details and can be aseptically assembled
`from