Pharmaceutical
`
`Dosage Forms:
`
`Parenteral Medications
`
`Volume 2: Facility Design;
`Sterilization ond Processing
`
`John D. Ludwig
`
`, f
`Enigma
`
`Edited by
`
`Sandeep Nema
`
`Pu.e,""' ..I. V.L ...,.-.,,v
`Pufiw I. UL "IAIV
`
`Regeneron Exhibit 1016.001
`Regeneron Exhibit 1016.001
`
`

`

`Pharmaceutical Dosage
`Forms
`
`Regeneron Exhibit 1016.002
`
`

`

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`
`Regeneron Exhibit 1016.003
`
`

`

`

`

`First published in 1984 by Marcel Dekker, Inc., New York, New York.
`This edition published in 2010 by Informa Healthcare, Telephone House, 69 77 Paul Street, London EC2A
`4LQ, UK.
`
`Simultaneously published in the USA by Informa Healthcare, 52 Vanderbilt Avenue, 7th Floor, New York,
`NY 10017, USA.
`
`Informa Healthcare is a trading division of Informa UK Ltd. Registered Office: 37 41 Mortimer Street,
`London WlT 3JH, UK. Registered in England and Wales number 1072954.
`
`?::2010 Informa Healthcare, except as otherwise indicated
`
`No claim to original U.S. Government works
`
`Reprinted material is quoted with permission. Although every effort has been made to ensure that all
`owners of copyright material have been acknowledged in this publication, we would be glad to
`acknowledge in subsequent reprints or editions any omissions brought to our attention.
`
`All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or
`transmitted, in any form or by any means, electronic, mechanical, photocopying, recording, or otherwise,
`unless with the prior written permission of the publisher or in accordance with the provisions of the
`Copyright, Designs and Patents Act 1988 or under the terms of any licence permitting limited copying
`issued by the Copyright Licensing Agency, 90 Tottenham Court Road, London WlP OLP, UK, or the
`Copyright Clearance Center, Inc., 222 Rosewood Drive, Danvers, MA 01923, USA (http:/ /www.
`copyright.com/ or telephone 978 750 8400).
`
`Product or corporate names may be trademarks or registered trademarks, and are used only for
`identification and explanation without intent to infringe.
`
`This book contains information from reputable sources and although reasonable efforts have been made
`to publish accurate information, the publisher makes no warranties (either express or implied) as to the
`accuracy or fitness for a particular purpose of the information or advice contained herein. The publisher
`wishes to make it clear that any views or opinions expressed in this book by individual authors or
`contributors are their personal views and opinions and do not necessarily reflect the views/ opinions of
`the publisher. Any information or guidance contained in this book is intended for use solely by medical
`professionals strictly as a supplement to the medical professional's own judgement, knowledge of the
`patient's medical history, relevant manufacturer's instructions and the appropriate best practice
`guidelines. Because of the rapid advances in medical science, any information or advice on dosages,
`procedures, or diagnoses should be independently verified. This book does not indicate whether a
`particular treatment is appropriate or suitable for a particular individual. Ultimately it is the sole
`responsibility of the medical professional to make his or her own professional judgements, so as
`appropriately to advise and treat patients. Save for death or personal injury caused by tl1e publisher's
`negligence and to the fullest extent otherwise permitted by law, neither the publisher nor any person
`engaged or employed by the publisher shall be responsible or liable for any loss, injury or damage caused
`to any person or property arising in any way from the use of this book.
`
`A CIP record for this book is available from the British Library.
`
`Library of Congress Cataloging in Publication Data available on application
`
`ISBN 13: 9781420086454
`ISBN 13: 9781420086539 (three volume set)
`
`Orders may be sent to: Informa Healthcare, Sheepen Place, Colchester, Essex C03 3LP, UK
`Telephone: +44 (0)20 7017 5540
`Email: CSDhealthcarebooks@informa.com
`Website: http:/ /informahealthcarebooks.com/
`
`For corporate sales please contact: CorporateBooksIHC@informa.com
`For foreign rights please contact: RightsIHC@informa.com
`For reprint permissions please contact: PermissionsIHC@informa.com
`
`Typeset by MPS Limited, A Macmillan Company
`Printed and bound in Tndia
`
`Regeneron Exhibit 1016.005
`
`

`

`We dedicate this work to those who have inspired us.
`To my parents Walter and Ruth Ludwig and my wife Sue Ludwig
`To my parents Hari and Pratibha Nema and my wife Tina Busch Nema
`
`Regeneron Exhibit 1016.006
`
`

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`Regeneron Exhibit 1016.007
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`

`

`Foreword
`
`I was a faculty member at the University of Tennessee and a colleague of Dr. Kenneth Avis
`when he conceived, organized, and edited (along with H.A. Lieberman and L. Lachman) the
`first edition of this book series that was published in 1984. It was so well received by the
`pharmaceutical science community that an expanded three-volume second edition was
`published in 1992. Dr. A vis did not survive long enough to oversee a third edition, and it was
`questionable whether a third edition would ever be published until two of his graduate
`students, Drs. Nema and Ludwig, took it upon themselves to carry on Dr. Avis' tradition.
`Their oversight of this third edition is work that their mentor would be highly pleased
`and proud of. From 29 chapters in the second edition to 43 chapters in this new edition, this
`three-volume series comprehensively covers both the traditional subjects in parenteral science
`and technology as well as new and expanded subjects. For example, separate chapter topics in
`this edition not found in previous editions include solubility and solubilization, depot delivery
`systems, biophysical and biochemical characterization of peptides and proteins, container(cid:173)
`closure integrity testing, water systems, endotoxin testing, focused chapters on different
`sterilization methods, risk assessment in aseptic processing, visual inspection, advances in
`injection devices, RNAi delivery, regulatory considerations for excipients, techniques to
`evaluate pain on injection, product specifications, extractables and leachables, process
`analytical technology, and quality by design.
`The editors have done an outstanding job of convincing so many top experts in their
`fields to author these 43 chapters. The excellent reputations of the authors and editors of this
`book will guarantee superb content of each chapter. There is no other book in the world that
`covers the breadth and depth of parenteral science and technology better than this one. In my
`opinion, the editors have achieved their primary objectives publishing a book that contains
`current and emerging sterile product development and manufacturing information, and
`maintaining the high standard of quality that readers would expect.
`
`Michael J. Akers
`Baxter BioPharma Solutions
`Bloomington, Indiana, U.S.A.
`
`Regeneron Exhibit 1016.008
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`

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`This page intentionally left blank
`
`Regeneron Exhibit 1016.009
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`

`

`Preface
`
`Pharmaceutical Dosage Forms: Parenteral Medications was originally published in 1984 and
`immediately accepted as a definitive reference in academic institutions and the pharmaceutical
`industry. The second edition was published in 1993. The ensuing years have produced
`incredible technological advancement. Classic small-molecule drugs are now complemented
`by complex molecules such as monoclonal antibodies, antibody fragments, aptamers,
`antisense, RNAi therapeutics, and DNA vaccines. There have been significant innovations in
`delivery devices, analytical techniques, in-silico modeling, and manufacturing and control
`technologies. In addition, the global regulatory environment has shifted toward greater
`emphasis on science-based risk assessment as evidenced by the evolving cGMPs, quality by
`design (QbD), process analytical technology (PAT), continuous processing, real time release,
`and other initiatives. The rapidly changing landscape in the parenteral field was the primary
`reason we undertook the challenging task of updating the three volumes. Our objectives were
`to (i) revise the text with current and emerging sterile product development and
`manufacturing science and (ii) maintain the high standard of quality the readers expect.
`The third edition not only reflects enhanced content in all the chapters, but also more
`than half of the chapters are new underscoring the rapidly advancing technology. We have
`divided the volumes into logical subunits volume 1 addresses formulation and packaging
`aspects; volume 2, facility design, sterilization and processing; and volume 3, regulations,
`validation and future directions. The authors invited to contribute chapters are established
`leaders with proven track records in their specialty areas. Hence, the textbook is authoritative
`and contains much of the collective experience gained in the (bio)pharmaceutical industry over
`the last two decades. We are deeply gratefiil to all the authors who made this work possible.
`Volume 1 begins with a historical perspective of injectable drug therapy and common
`routes of administration. Formulation of small molecules and large molecules is presented in
`depth, including ophthalmic dosage forms. Parenteral packaging options are discussed
`relative to glass and plastic containers, as well as elastomeric closures. A definitive chapter is
`provided on container closure integrity.
`Volume 2 presents chapters on facility design, cleanroom operations, and control of the
`environment. A chapter discussing pharmaceutical water systems is included. Key quality
`attributes of sterile dosage forms are discussed, including particulate matter, endotoxin, and
`sterility testing. The most widely used sterilization techniques as well as processing
`technologies are presented. Volume 2 concludes with an in-depth chapter on lyophilization.
`Volume 3 focuses on regulatory requirements, risk-based process design, specifications,
`QbD, and extractables/leachables. In addition, we have included chapters on parenteral
`administration devices, siRNA delivery systems, injection site pain assessment, and control,
`PAT, and rapid microbiology test methods. Volume 3 concludes with a forward-looking
`chapter discussing the future of parenteral product manufacturing.
`These three volumes differ from other textbooks in that they provide a learned review on
`developing parenteral dosage forms for both small molecules and biologics. Practical guidance
`is provided, in addition to theoretical aspects, for how to bring a drug candidate forward from
`discovery, through preclinical and clinical development, manufacturing, validation, and
`eventual registration.
`The editors wish to thank Judy Clarkston and Lynn O'Toole-Bird (Pfizer, Inc.) for their
`invaluable assistance and organizational support during this project, and Sherri Niziolek and
`Bianca Turnbull (Informa Healthcare) for patiently leading us through the publishing process.
`
`Regeneron Exhibit 1016.010
`
`

`

`X
`
`PREFACE
`
`We also acknowledge the assistance of Pfizer, Inc. colleagues Lin Chen and Min Huang for
`reviewing several of the chapters.
`We would like to express special gratitude to the late Kenneth E. Avis (University of
`Tennessee College of Pharmacy) for his dedication to teaching and sharing practical
`knowledge in the area of parenteral medications to so many students over the years,
`including us. Finally, we acknowledge the contributions of Dr Avis, Leon Lachman, and
`Herbert A. Lieberman who edited the earlier editions of this book series.
`
`Sandeep Nema
`John D. Ludwig
`
`Regeneron Exhibit 1016.011
`
`

`

`Contents
`
`Foreword Michael J. Akers
`Preface
`ix
`Contributors
`
`xiii
`
`vii
`
`1
`1. Aseptic manufacturing facility design
`Mark Caldwell, Bob Helt, Beth Holden, Francesca McBride, and Kevi11 Schreier
`
`2. Personnel and their impact on clean room operations
`Jeanne Moldrnhauer
`
`56
`
`3. The fundamentals of an environmental control program
`William H. Miele
`
`80
`
`4. Water systems for parenteral facilities
`Joseph ]. Manfredi
`
`91
`
`5. Particulate matter: subvisible
`D. Scott Aldrich
`
`114
`
`6. Endotoxin testing
`Michael E. Dawson
`
`146
`
`7. The compendia! sterility tests
`Scott V. W. Sutton
`
`187
`
`8.
`
`Industrial sterilization technologies: principles and overview
`Anne F. Booth
`
`195
`
`9. Steam sterilization
`James Agalloco
`
`221
`
`10. Gas, vapor, and liquid chemical sterilization
`James Agalloco
`
`241
`
`11. Dry heat depyrogenation and sterilization
`Deborah Havlik a11d Kevin Trupp
`
`255
`
`268
`12. Radiation sterilization
`Barry P. Fairand and Dusan Razem
`
`Regeneron Exhibit 1016.012
`
`

`

`xii
`
`CONTENTS
`
`297
`13. Filters and filtration
`Maik W. Jornitz and Theodore H. Meltzer
`
`334
`14. Processing of small volume parenterals and large volume parenterals
`Donald A. Eisenhauer, Roland Schmidt, Christine Martin, and Steven G. Schultz
`
`15. Freeze-drying: principles and practice
`Steven L. Nail and Larry A. Gatlin
`
`353
`
`Tndex
`
`.38.3
`
`Regeneron Exhibit 1016.013
`
`

`

`Contributors
`
`James Agalloco Agalloco & Associates, Belle Mead, New Jersey, U.S.A.
`
`D. Scott Aldrich Ultramikro, LLC, Richland, Michigan, U.S.A.
`
`Anne F. Booth Booth Scientific, Inc., Hendersonville, North Carolina, U.S.A.
`
`Mark Caldwell Jacobs Engineering Group, Inc., Conshohocken, Pennsylvania,
`U.S.A.
`
`Michael E. Dawson Associates of Cape Cod, Inc., Falmouth, Massachusetts, U.S.A.
`
`Donald A. Eisenhauer Abbott Laboratories, North Chicago, Illinois, U.S.A.
`
`Barry P. Fairand Sterigenics International, Dublin, Ohio, U.S.A.
`
`Larry A. Gatlin PK, LLC, Groton, Connecticut, U.S.A.
`
`Deborah Havlik R&D Microbiology, Hospira, Inc., Lake Forest, Illinois, U.S.A.
`
`Bob Helt Jacobs Engineering Group, Inc., Conshohocken, Pennsylvania, US.A.
`
`Beth Holden Jacobs Engineering Group, Inc., Conshohocken, Pennsylvania, U.S.A.
`
`Maik W. Jornitz Sartorius Stedim North America, Inc., Bohemia, New York, U.S.A.
`
`Joseph J. Manfredi GMP Systems, Inc., Fairfield, New Jersey, U.S.A.
`
`Christine Martin Abbott GmbH & Co. KG, Ludwigshafen, Germany
`
`Francesca McBride Jacobs Engineering Group, Inc., Conshohocken, Pennsylvania, U.S.A.
`
`Theodore H. Meltzer Capitola Consultancy, Bethesda, Maryland, U.S.A.
`
`William H. Miele Pfizer Global Manufacturing, Kalamazoo, Michigan, U.S.A.
`
`Jeanne Moldenhauer Excellent Pharma Consulting, Mundelein, Illinois, U.S.A.
`
`Steven L. Nail Baxter Pharmaceutical Solutions, Bloomington, Indiana, U.S.A.
`
`Dusan Razem Ruder Boskovic Institute, Zagreb, Croatia
`
`Roland Schmidt Abbott GmbH & Co. KG, Ludwigshafen, Germany
`
`Kevin Schreier Jacobs Engineering Group, Inc., Conshohocken, Pennsylvania, U.S.A.
`
`Regeneron Exhibit 1016.014
`
`

`

`xiv
`
`CONTRIBUTORS
`
`Steven G. Schultz Abbott Laboratories, North Chicago, Illinois, U.S.A.
`
`Scott V. W. Sutton Microbiology Network, Inc., Rochester, New York, U.S.A.
`
`Kevin Trupp Global Sterilization Engineering, Hospira, Inc., Lake Forest, Illinois, U.S.A.
`
`Regeneron Exhibit 1016.015
`
`

`

`Aseptic manufacturing facility design
`
`Mark Caldwell, Bob Helt, Beth Holden, Francesca McBride, and Kevin Schreier
`
`INTRODUCTION
`Sterile products may be in liquid or powder form (among others) as drug products and may be
`presented in formats including ampoules, vials, prefilled syringes, presterilized bottles, and
`blow-fill-seal containers. Product form and presentation influence processing conditions,
`equipment selection, and therefore, facility design. The sterile envelope refers to all the steps
`carried out during and following the final sterile filtration step through process completion,
`which occurs after filled product containers are sealed and a risk of environmental
`contamination to the product is eliminated. These steps include:
`
`• Adjuvant, buffer and media formulation
`• Addition of excipients
`• Adjustment of concentration to achieve target potency
`• Sterile filtration
`• Component preparation
`• Filling, stoppering/plugging, and sealing of product in final dosage containers
`
`The design of the facility must meet all applicable regulatory guidelines, and meet GMP
`and safety guidelines. Current Good Manufacturing Practice (GMP) requires that areas of
`operation used for aseptic processing must prevent contamination from particles and microbes
`that may be present in the air, on product contact surfaces, or shed from personnel (1 5).
`When processing biological products, such as live virus vaccines, attenuated vaccines
`and viral vectors, the biohazard nature of these products place extra demands on the facility.
`Potent compounds, like some biological products, also pose a risk to the operator and
`environment. Therefore, the facility and process design must also ensure both product and
`personnel safety.
`This chapter establishes a basis for compliance with the global regulatory expectations
`for facility design, equipment interfaces, and utility requirements applicable to sterile
`processing and the manufacture of sterile products (6 10).
`
`FACILITY DESIGN DRIVERS
`As each facility is being designed, process requirements specific to each product must be
`considered. Each different type of product has different facility needs. Also, the number of
`products to be manufactured and the production campaign strategy will impact the facility
`design.
`
`Product Types
`Chemical Bulk Drug Substances (API)
`Sterile chemical bulk drug substances are derived from chemical reactions. Facilities producing
`sterile API will be required to provide protection of the product during synthesis, isolation,
`and bulk filling. An adjuvant produced by precipitation is an example of a sterile APL
`
`Potent Compounds
`Potent compounds are classified as those chemical drug substances that are considered to be
`toxic to humans when exposure limits are exceeded, and may cause allergic reactions, birth
`defects, cancer, or other conditions. For this reason, it is required to ensure protection of
`operators working with potent compounds, ensure containment of all operations, and
`prevent release of products into the environment. It is acceptable to permit production of
`potent compounds in multiproduct facilities, provided the suite is segregated from other
`operations.
`
`Regeneron Exhibit 1016.016
`
`

`

`2
`
`VOLUME 2: FACILITY DESIGN, STERILIZATION AND PROCESSING
`
`Following filling, it is recommended to wash the exterior of vials produced in potent
`compound facilities to limit uncontrolled exposure to the product during downstream
`operations.
`
`Antibiotics
`Antibiotics are drugs produced to treat bacterial or fungal infections. Antibiotics are considered
`to be sensitizers and can generate mild to severe allergic reactions in patients and operators. It is
`required to segregate production operations from personnel outside the production area.
`Campaigns of antibiotic must be segregated from other products, as the potential for cross(cid:173)
`contamination between products can occur. In addition, ~-lactam (penicillin) and nonpenicillin
`based (cephalosporin) antibiotic products are not permitted to be produced in the same facility,
`as there is evidence that intolerance can occur for one antibiotic type, and not another.
`To accomplish this segregation, it is a requirement that a separate dedicated suite be
`constructed for each antibiotic family. This suite can be housed inside a common structure
`with other functions. At no time should antibiotic production personnel come into contact with
`personnel operating in media or fermentation areas while gowned.
`Following filling, it is recommended to wash the exterior of vials produced in antibiotic
`facilities to limit uncontrolled exposure to the product during downstream operations.
`
`Biological Product
`This category includes therapeutic proteins generated by fermentation or cell culture and
`inactivated vaccines. The facility is to be designed in same way as API production, except that
`terminal sterilization is often not feasible, due to the fragility of the product.
`
`Live Virus Vaccines
`Vaccines containing a live virus, or viral vector, must be designed to provide containment of
`the organism to protect both operators and the environment. Viral vectors are virus-like
`particles that inject genetic material into the cells of the organism being treated and are treated
`in a similar manner to live viruses. The biosafety level designated for the organism will drive
`decisions regarding the level of environmental controls that is required for the facility.
`Typically, these products require the use of adjuvants and will be suspension products,
`incapable of being filter sterilized. Products cannot be terminally sterilized. Live virus vaccine
`products can be campaigned in a multiproduct facility, as long as the vaccine production area
`is segregated from the remainder of the facility. Following the completion of the live virus
`campaign, the suite will need to be completely decontaminated prior to use for another
`product.
`
`Facility Types
`Single Product, Dedicated
`This facility is designed to produce a single product at any one time, throughout the year,
`without concern for cross-contamination with a second product. The facility can be operated to
`produce multiple products in a series of campaigns, converting between products.
`
`Multiproduct Multisuite
`This facility is designed to produce multiple products simultaneously in multiple sterile suites.
`Sterile operations in each suite are to be segregated from one another to ensure that cross(cid:173)
`contamination is prevented. It is a recommendation to clean and decontaminate any used
`components or equipment prior to exiting the suite and entering the return corridor.
`
`Production Area Description
`Conventional Aseptic Technology: Open
`In conventional aseptic processing, the product is exposed to the room environment during
`operation. For this reason, aseptic operations are required to be performed under ISO 5
`
`Regeneron Exhibit 1016.017
`
`

`

`ASEPTIC MANUFACTURING FACILITY DESIGN
`
`3
`
`conditions, by sufficiently gowned operators, trained in aseptic technique. Sterility assurance
`levels for aseptic operations, including filling of vials or syringes, can be maximized through
`the use of barriers such as restricted access barrier systems or isolators to limit the size of the
`aseptic environment and remove operators from the ISO 5 fill area.
`
`Terminally Sterilized Product
`Whenever possible, it is required to terminally sterilize filled units of product. Application of
`an "overkill" sterilization methodology can provide a sterility assurance level of 10-6
`, or better.
`Sterilization can be by steam, dry heat, gas, or radiation.
`
`Restricted Access Barrier: Open and Closed
`As defined by ISPE: A restricted access barrier system (RABS) is an advanced aseptic
`processing system that can be utilized in many applications in a fill-finish area. RABS provides
`an enclosed environment to reduce the risk of contamination to product, containers, closures,
`and product contact surfaces compared to the risks associated with conventional clean
`room operations. RABS can operate as "doors closed" for processing with very low risk of
`contamination similar to isolators, or permit rare "open door interventions" provided
`appropriate measures are taken (11).
`In representative installations recently constructed, there is a wide variety of equipment
`configurations referred to as RABSs. In construction detail, some approximate isolators in their
`level of segregation of the clean environment from the background environment, while other
`examples employ less rigorous segregation between the clean environment and the
`background room.
`When barrier doors are required to be opened, the opening must be protected within an
`ISO 5 zone, to the extent necessary to ensure continuous ISO 5 coverage. The door must be
`permitted to be opened without leaving the ISO 5 zone.
`
`Isolation Technology
`As defined by ISPE: An isolator is a leak-tight enclosure designed to protect operators from
`hazardous/potent processes or protect processes from people or detrimental external environ(cid:173)
`ments or both. A basic enclosure consists of a shell, viewing window, glove/ sleeve assemblies,
`supply and exhaust filters, light (s), gauge (s), input and output openings (equipment door
`airlocks, RTPs, etc.), and various other penetrations. There are two types of isolators:
`
`Closed isolators.
`Isolators operated as closed systems do not exchange unfiltered air or
`contaminants with adjacent environments. Their ability to operate without personnel access to
`the critical zone makes isolators capable of levels of separation between the internal and
`external environment unattainable with other technologies. Because the effectiveness of this
`separation, closed isolators are ideally suited for application in the preparation of sterile
`and/or toxic material. Aseptic and containment isolators are two types of closed isolators.
`
`Open isolators. Open isolators differ from closed isolators in that they are designed to allow
`for the continuous or semicontinuous egress of materials during operation while maintaining a
`level of protection over the internal environment. Open isolators are decontaminated while
`closed, and then opened during manufacturing. Open isolators typically are used for the
`aseptic filling of finished pharmaceuticals (11).
`
`Closed Processing
`Closed system sterile processing. A closed system is one that does not contain any open
`aseptic manipulations or interventions by design or operation and does not allow microbial
`ingress. Validated sterilization cycles must be provided. The product is separated from the
`surrounding room environment by a sterilizing grade vent filters. Leak testing must occur pre(cid:173)
`and post use to demonstrate the system integrity.
`
`Regeneron Exhibit 1016.018
`
`

`

`4
`
`VOLUME 2: FACILITY DESIGN, STERILIZATION AND PROCESSING
`
`EQUIPMENT AND PROCESS SYSTEM IMPACT ON FACILITY
`It is important to start the facility design with an understanding of each process step involved
`with the manufacture of a sterile product. In this section, an overview is provided for some of
`the more common process steps, including a description of the major equipment, material
`flows, and facility impacts.
`
`Nonactive Materials
`Nonactive materials are transported from the warehouse to the weigh/dispense area, where
`they are dispensed into containers under a hood with high efficiency particulate air (HEP A)
`filtration. The hoods used in the dispensing operation shall be designed for protection of the
`product and may also need to protect the operator from exposure to potentially hazardous
`materials used in the formulation process.
`The number of hoods, and type, will be determined by evaluating the number of
`weighing operations that must be performed, the size of the weighing operations, the
`compatibility of materials that must be weighed, and any special ergonomic or personnel
`safety concerns. Materials that are not compatible may need to be dispensed in separate hoods
`to prevent any cross-contamination concerns. Also, dispensing operations involving large bulk
`containers will require either a lift assist or pallet jack access to prevent operator injury,
`requiring the hood to be designed as a walk-in type.
`Hoods being designed for product protection typically recirculate air back to the
`dispensing room to reduce the HV AC consumption for the area. However, when weighing
`hazardous materials, the air from the hood may need to be captured and exhausted to the roof
`through some type of environmental control device. Hoods of this type are typically designed
`to be negatively pressurized with respect to the dispensing room.
`Containers may be either single-use or reusable. Single-use containers are disposable.
`Reusable containers are required to be tracked and controlled to prevent cross-contamination
`of clean and used containers. Prior to reuse, used containers should be brought to a parts
`preparation washroom for cleaning and then placed in controlled storage.
`Nonactive materials are dispensed into bags or plastic bottles and can be placed into
`plastic bins as part of preassembled kits. Preweighed nonactive materials are stored as kits and
`staged until they are ready to be transferred to the formulation area. Identifying labels should
`be placed on the containers.
`It is typical to provide a local WFI drop feeding a sink in the weigh/ dispense area, with
`WFI temperature controlled by a local WFI drop cooler. The WFI drop is periodically flushed
`and sampled per SOP. WFI is used to prepare solutions of nonactive materials in bottles. This
`operation may be performed with equipment such as a laboratory agitator.
`Bench scales are used for dispensing of smaller-scale materials. Floor scales are used for
`larger quantities. Balances and measuring equipment should be of an appropriate range and
`precision.
`
`Active Materials
`Receipt/Storage
`Active materials, API or drug substance (DS), may be received in a wide variety of container
`types, in either frozen or liquid form, or as a solid. Careful consideration should be given to the
`form and container type, since this affects the storage, transport, preparation, and handling of
`APL The following list is provided to indicate the diversity of some common examples.
`
`1. Frozen in cryovessels, ranging in size from 50 to 300 L
`2. Frozen in small containers, ranging in size from 1 to 20 L
`3. As liquid in small containers, ranging in size from <1 to 20 L
`4. As powder in canisters, ranging in size from <1 to 50 kg
`
`Weighing and dispensing can occur for either sterile or nonsterile material.
`It is recommended that sterile material be dispensed in an isolator to prevent
`contamination. The isolator should be fitted with a rapid decon antechamber to facilitate the
`addition of product and containers to be dispensed.
`
`Regeneron Exhibit 1016.019
`
`

`

`

`

`6
`
`VOLUME 2: FACILITY DESIGN, STERILIZATION AND PROCESSING
`
`Thawing
`If API is received in frozen form, an area adjacent to the formulation area should be designated
`as an API thaw room. Sufficient space shall be provided, depending on the API production
`requirements and duration of the thaw cycle.
`If frozen in cryovessels, ample thaw/shaker stations shall be provided for the required
`number of cryovessels. At each station, a shaker mechanism is provided to gently mix the API
`during the thawing process. The thaw module will allow for precise control of the temperature
`profile during the process.
`If frozen in small containers, consideration will be given to the selection of the thawing
`equipment. A shaker thaw bath will thaw several containers quickly, but needs a water supply.
`An environmental chamber will also thaw several bottle, but the operation will be performed
`at a much slower rate, due to the lower heat transfer rate of the air. The number of units will be
`determined by the quantity of bottles to be thawed for each batch, and the time allotted to
`perform the operation. If there are concerns regarding the accumulated time out of
`refrigeration, more units may be required.
`Local freezers and refrigerators should be provided in the thaw area to provide staging
`space for material that is awaiting the thaw process as well as thawed material that is awaiting
`transport to the formulation room. The refrigerators and freezers should employ some system
`for segregation to maintain lot-to-lot integrity of the same material as well as containers of
`different products, avoiding any potential cross-contamination and product loss.
`If live virus product is thawed, secondary containment is required during the thawing
`operation in the event of a container rupture. This can be accomplished by use of an overwrap
`or use of the thaw bath as secondary containment. Any use of water as a thawing medium for
`live virus should be routed to biowaste collection.
`
`Formulation
`The typical formulation module includes one formulation tank, positioned inside the
`formulation room, adjacent to a utility panel on the wall. Piping, electrical and instrumentation
`for the tank are connected to the utility panel. This tank has been cleaned via CIP and has been
`sanitized by clean steam. Following the sanitization operation, it has been maintained under
`positive pressurize with filtered process air.
`Room height should account for elevation of equipment, including open charging
`operations, agitator clearance, and vent filters. Portable equipment must be able to fit under
`the door frame without disassembly. Room lay