Pharmaceutical
`
`Third Edition
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`Volume i: Formulation
`
`and Packaging
`
`Dosage Forms:
`Parenteral Medications
`
`John D. Ludwig
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`{Sigma
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`Edited by
`
`Sandeep Nema
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`Forms
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`Pharmaceutical Dosage
`Forms
`
`Parenteral Medications
`
`Third Edition
`
`Volume 1
`
`Formulation and Packaging
`
`Edited by
`
`Sandeep Nema
`
`Pfizer, inc.
`
`Chesterfield, Missouri, U. S.A.
`
`John D. Ludwig
`
`Pfizer, inc.
`
`Chesterfieid, Missouri, U. SA.
`
`informa
`healthcare
`New-York W
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`

`First published in 1984 by Marcel Dekker, lnc., New York, New York.
`This edition published in 2010 by Informa I'Iealthcare, Telephone House, 69 77 Paul Street, London EC2A
`4|.Q, UK.
`
`Simultaneously published in the USA by lnforma llealthcare, 52 Vanderbilt Avenue, 701 Floor, New York,
`NY 1001?, USA.
`
`Informa Healthcare is a trading division of Informa UK Ltd. Registered Office: 37 41 Mortimer Street,
`London W 1T 3Jll, UK. Registered in England and Wales number 1072954.
`
`:r"_:2010 [nforma I-Iealthcare, except as otherwise indicated
`
`No claim to original US. 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 W11J 0LI’, UK, or the
`Copyright Clearance Center,
`lnc., 222 Rosewood Drive, Danvers, MA 01923, USA (http://www.
`copyrightcom/ 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 front 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 pmfessional judgements, so as
`appropriately to advise and treat patients. Save for death or personal injury caused by the 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 ClP record for this book is available from the British Library.
`
`Library of Congress Cataloging in Publication Data available on application
`
`ISBN 13: 9781420086430
`ISBN 13: 9781420086539 (three volume set)
`
`Orders may be sent to: lnforma l lea lthcare, Sheepen l‘lace, Colchester, lissex C03 31.]‘, UK
`Telephone: +44 (0)20 7017 5540
`Email: CSDhcalthcarebooks®informa.com
`Website: http:/ /informahealthcarebookscom/
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`For reprint permissions please contact: Permissions“IC@informa.com
`
`Typeset by MPS Limited, A Macmillan Company
`Printed and bound in India
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`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 Pmfibha Nema and my wife Tina Busch Nemn
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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. Avis 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—
`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 I. Alters
`Baxter BioPlIomm Solutions
`
`Blomrtingtoa, Indiana, USA.
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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 grateful 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,
`le3, and extractables/leachables.
`In addition, we have included chapters on parenteral
`administration devices, siRNA delivery systems, injection site pain assessment, and control,
`I’AT, 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 froth 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’TooleBird (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.
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`at
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`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 Lachinan, and
`Herbert A. Lieberman who edited the earlier editions of this book series.
`
`Smldeep Nenm
`John D. Ludwig
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`Contents
`
`Farmyard Michael ]_ Akers
`
`oii
`
`Preface
`Contributors
`
`ix
`
`xiii
`
`1.
`
`Parenteral dosage forms: introduction and historical perspective
`John D. Ludwig
`
`1
`
`Parenteral drug administration: routes of administration and devices
`Himaiislm Bliaitacharjse and Mara A. Thoma
`
`7
`
`30
`Biopharrnaceutics of NCES and NBES
`Baiaji Agm'am, KflZitix'U Sagawa, Ravi M. Siiaiiker, and Salish .K. Singh
`
`Preformulation
`N. Marti Venuu'i
`
`57
`
`Formulation development of small and large volume injections
`Madam: Kamat and Patrick P. DeLaca
`
`76
`
`134
`Drug solubility and solubilization
`Ching Chiaag So, Lan Kim}, and Michael Hagcmaa
`
`158
`Formulation of depot delivery systems
`James I. Citmliugtmm, Marc J. Kirchmeier, and Saciiia Mittat
`
`Biophysical and biochemical characterization of peptide and protein
`drug product
`194
`Tapaa K. Das and fairies A. Carroll
`
`Formulation of protein- and peptide-based parenteral products
`Gaozlnmg Kim and Y. ,‘aim Wang
`
`222
`
`254
`Development of ophthalmic formulations
`Paramita Baiidyopadhyay, Martin J. Coffey, and Mohamiari Simmer
`
`Glass containers for parenteral products
`Robert Sitiift
`
`287
`
`Plastic packaging for parenteral drug delivery
`Wood D. Vitimtam and Frances L. DeGrazio
`
`305
`
`10.
`
`‘ll.
`
`12.
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`xii
`
`CONFEMS
`
`13. Elastomeric closures for parenterals
`Renaud Immsm
`
`324
`
`14. Parenteral product container closure integrity testing
`Dana Marian Grmzzn
`
`358
`
`Index
`
`389
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`Contributors
`
`Balaji Agorarn Pfizer, Inc., Sandwich, U.K.
`
`Paramita Bandyopadhyay Bausch & Lomb, Rochester, New York, U.5.A.
`
`Himanshu Bhattacharj ee Department of Pharmaceutical Sciences, College of Pharmacy.
`University of 'l‘ennwsee llealth Science Center, Memphis, Tennessee, U.S.A.
`
`James A. Carrol] Bio'l'herapeutics Pharmaceutical Sciences, Pfizer, Inc., Chesterfield,
`Missouri, USA.
`
`Martin J. Coffey Bausch & Lomb, Rochester, New York, USA.
`
`James J. Cunningham Pharmaceutical Research and [Development Sciences, Merck Research
`Laboratories, West Point, Pennsylvania, U.S.A.
`
`Tapan K. Das BioTherapeutics Pharmaceutical Sciences, Pfizer, Inc., Chesterfield, Missouri, U.S.A.
`
`Frances L. DeGrazio West Pharmaceutical Services, Inc., [,ionville, Pennsylvania, USA.
`
`Patrick P. DeLuca Pharmaceutical Sciences, University of Kentucky College of Pha rmacy,
`Lexington, Kentucky, U.S.i\.
`
`Dana Morton Guazzo RxPax, LLC, Bridgewater, New Jersey, U.S.A.
`
`Michael Hageman Bristol Myers Squibb Research, Princeton, New Jersey. USA.
`
`Renaud Janssen Helvoet Phan‘na, Alken, Belgium
`
`Madhav Kamat Biopharmaceutics REID, Bristol Myers Squibb Company, New Brunswick, New
`Jersey, U.S.A.
`
`Man: J. Kirchmeier Vaccine Formulation Development, Variation Biotechnologies, Inc,
`Cambridge, Massachusetts. USA.
`
`John D. Ludwig Bio'l‘herapeutics Pharmaceutical Sciences, Pfizer, 'lnc., Chesterfield,
`Missouri, U.S.A.
`
`Sachin Mitta] Pharmaceutical Research and Development Sciences, Merck Research Laboratories,
`West Point, Pennsylvania, U.S.A.
`
`Kazuko Sagawa Pfizer Global R&D, Groton, Connecticut, U.5.A.
`
`Ravi M. Shanker Pfizer Global R&D, Groton, Connecticut, U.S.A.
`
`Mohannad Shawer Bausch 8: bomb, Rochester, New York, USA.
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`xiv
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`COM th'U {OHS
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`Satish K. Singh BioTherapeul'ics Pharmaceutical Sciences, Pfizer, Inc., Chesterfield, Missouri,
`U.5.A.
`
`Ching-Chiang Sn Bristol Myers Squibb Research, Princeton, New Jersey, USA.
`
`Robert Swift Amgen, Inc” Thousand Oaks, California, U.5.A.
`
`[Department of Pharmaceutical Sciences, College of Pharmacy, University of
`Laura A. Thoma
`'l‘ennmsee Health Science Center, Memphis, 'J'ennessee, U.S.A.
`
`N. Murti Vemuri Sanofi Aventis, Bridgewater, New ]ersey, USA.
`
`Vinod D. Vilivalam West Pharmaceutical Services, Inc., Lionville, Pennsylvania, U.S.A.
`
`Y. John Wang Genentech, South San Francisco, California, U.S.A.
`
`Lan Xiao Bristol Myers Squibb Research, Princeton, New Jersey, USA.
`
`Gaozhong Zhu
`
`Shine Human Genetic Therapies, Inc., Cambridge, Massachusetts, U.S.A.
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`1 Parenteral dosage terms: introduction
`and historical perspective
`John D. Ludwig
`
`INTRODUCTION
`
`Parenteral dosage forms are those administered directly into body tissues rather than via the
`alimentary canal. “ arenteral” is derived from the Greek words para (beside) and enters” (the
`intestine) and most often refers to subcutaneous (SC), intramuscular (IM}, or intravenous (IV)
`administration of drugs. Parenteral drug delivery can pose significant risk to the patient since
`the natural barriers of the body (gu t, skin, and mucous membranes} are bypassed. The highest
`standards for quality and purity must be maintained throughout dosage form manufacture to
`protect
`the patient
`from physical, chemical, and microbial contaminants. A single
`contaminated vial out of a batch of thousands can seriously injure a patient (or worse).
`Further, if improper or poor aseptic technique is used while administering an injection the
`patient could be similarly harmed. The minimum quality standards for pharmaceutical
`manufacturers are expressed in the current good manufacturing practices (oCMPs), which are
`constantly evolw'ng as technology advances. An equal burden of responsibility is placed on
`physicians, pharmacists, nurses, and other health professionals to follow strict good aseptic
`practices (GA I’s} as they administer parenteral dosage forms to patients. Nosocornial infections
`associated with parenteral drug therapy remain a significant issue (1 4}.
`
`ADVANTAGES AND DISADVANTAGES OF PARENTERAL DRUG DELIVERY
`
`Parenteral drug delivery provides a number of advantages for the patient. The parenteral route
`provides an effective way to dose patients who are unconscious or those who cannot or would
`not take oral medications. A drug ad ministered pa renterally generally produces an immediate
`therapeutic effect and is therefore desirable in emergency situations. Parenteral administration
`also provides a mechanism for dosing drugs that are not bioavailable via noninjectable routes
`such as many protein and peptide therapeutics. Total parenteral nutrition can be provided for
`seriously ill patients where tube feeding is not an alternative. In addition, large amounts of
`fluid and electrolytes can be given relatively quickly via the IV route to patients with serious
`fluid loss from dehydration or gastrointestinal infections.
`A significant disadvantage of injectable drug administration is that once a drug has been
`dosed it is difficult to reverse its effect. For example, in the event of a closing error (overdose)
`With an oral tablet, gastric lavage, induced emesis, or activated charcoal can be employed. The
`options for reversing an IV overdose are usually very limited. Secondly, the risk of infection is
`always present with parenteral dosing both in the hospital/clinic setting as well as home
`administration. Finally, the cost per dose of parenteral drugs is typically higher than for oral
`medications.
`
`PARENTERAL DRUG DELIVERY ROUTES
`
`Routes of parenteral drug delivery are summarized in Table 1. SC, 1M, and IV are the most
`common modes of administration. The fastest onset of action is achieved via the IV route since
`
`the injection is directly into a vein. Relatively large amounts of fluid can be delivered quickly
`and efficiently using the IV route. Slower and more variable onset of action typically occurs
`following SC and IM administration since the drug must be absorbed into the bloodstream
`from the site of injection. The absorption step can be exploited for drugs requiring chronic
`administration. Formulations can be designed to provide sustained—release profiles therefore
`reducing the number of injections required and the associated risk. Examples of "depot”
`formulations include DEPO—PROVERA'“' Contracgptive Injection, which is administered deep
`IM every 13 weeks and depo—subQ provera 104 which is administered SC in the anterior
`thigh or abdomen every 12 to 14 weeks. Intravitreal dosing has increased significantlyin recent
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`VOLUME 1' PUHMULAHOFI' AM) PACKAGING
`
`Parenteral Dmg Delivery Floutes
`Table 1
` Route Administration volume
`
`
`Low, generally <2 mL
`Subcutaneous (SC)
`Medium. 2 mL 5 mL
`Intramuscular (IM)
`High
`Intravenous (IV)
`Low, generally <0.1 mL
`Intravitreal
`Low, 0.1 mL
`Intradermal (ID)
`Medium
`Intra articular
`Low
`Intrathecal
`Low
`Intraepidural
`Medium
`Intracisternal
`High
`Intra arterial
`Medium
`Intracardiac
`Medium
`Intrapleural
`High
`Intraperitoneal
`
`Intraosseous Medium
`
`years because of new treatments for neovascular wet age-related macular degeneration {AMD}
`such as Lucentis'n' (ranibizumb injection} and Macugen"" (pegaptanid sodium injection). The
`intradermal (ID) route is commonly used for very small volume injections (0.1 mL} such as the
`tuberculosis skin test [or tuberculin purified protein derivative (PPD) test].
`Intra—articular
`injections directly into joint synovial fluid are routinely used to administer corticosteroids or
`hyaluronic acid derivatives to relieve the symptoms of osteoarthritis. lntrathecal (intraspinal)
`and intraepidural injections are used to deliver anesthesia, analgesics, anti—infectives, and
`some cancer therapies. Intracisternal administration is used to deliver critical therapeutics
`directly to the caudal region of the brain. Less common parenteral routes include intra-arterial,
`intracardiac (e.g.. epinephrine for cardiac resuscitation), intrapleural,
`intraperitoneal, and
`intraosseous (bone) (5,6).
`
`QUALITY ATI'HIBUTES 0F PAHENTEFIAL DOSAGE FORMS
`
`Quality attributes specific to parenteral dosage forms are shown in Table 2. lnjectable products
`must be manufactured using the highest quality active drug substance and excipients. The
`regulatory review process requires that each ingredient in the formulation must be justified as
`
`Table 2 Quality Aspects of Parenteral Dosage Forms
` Attribute Comment
`
`
`Highest level of purity for the active drug substance
`and excipients
`Formulation containing the fewest number and the
`simplest excipients possible
`Physical and chemical stability
`Container closme system with low extractable’
`Ieachable profile
`Sterile
`Pyrogen free
`
`Free from visible particulate matter
`
`Container closure integrity
`
`lnicction site tolerability
`
`Detailed dosing and administration instructions
`including evaluation of compatibility with
`coadministered drugs
`
`Highly purified "parenteral grade“ excipients are
`available.
`The presence and amount of each excipient must be
`justified in regulatory filings.
`Minimal degradation during shelf life.
`Minimize the impact of the container on product
`purity and stabiity
`Sterility assurance is critical for patient safety.
`Pyrogens cause febrile response. The most potent
`pyrogens are bacterial endotoxins.
`Subvisible particulate matter must be excluded as
`much as possible as defined by compendial
`requirements.
`Product container maintains microbiological integrity
`during shelf life.
`Formulation does not cause significant injection site
`irritation or tissue damage. Products are frequently
`formulated as isotonic solutions.
`In clinical practice. multiple drugs are frequently
`administered through the same IV line to avoid the
`risk of an additional venipuncture.
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`PAHEMt-HAL 00838.5 tot-EMS: 1W! HUUUC f JUN AM) Hfo'OHfCAL PEHSPECHW:
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`to why it was included and the relative amount. As a general rule, formulations with the
`fewest excipients and simplest composition are highly desired. The quality and robustness of
`the container—closure system must also be described and justified relative to extractables/
`leachables, container integrity (microbiological, oxygen transmission, moisture transmission),
`and intended clinical use. Parenteral products must be sterile, pyrogen—free, and free from
`visible particulate matter and remain so throughout shelf—life. Adverse injection site events are
`widely reported and can cause significant
`tissue damage. Often,
`the formulation can be
`modified to increase injection site tolerability, for example, by changing buffers and / or
`decreasing buffer concentration as well as rendering the dosing solution isotonic. The
`compatibility of the formulation should be assessed with the most likely drugs that will be
`coadministered with the new product. Compatibility results are generally included in the
`approved dosing instructions to assist pharmacists, nurses, and other health care providers.
`
`MILESTONES IN PARENTERAL DRUG THERAPY
`
`Various scholars have summarized the development of parenteral drug therapy (7 13). A
`compiled historical timeline is presented in Table 3. The reader should be aware there is
`disagreement in the literature about exact dates as well as who was "first," particularly for
`
`Table 3 Historical Milestones in Parenteral Drug Delivery
`Year
`Milestone
`
`1616
`1656
`
`1666
`1?96
`
`1818
`1831
`
`1832
`
`1855
`
`186?
`
`18605 18805
`
`18?!)
`1834
`
`1891
`1912
`
`1918
`
`1923
`
`1923
`
`1923
`1924
`1933
`
`1938
`
`William Harvey described the circulation of blood. His findings were published in 1628.
`Christopher Wren infused dogs with opiates and alcoholic beverages using a sharpened quill and
`animal bladder.
`Johannes Eschottz described techniques for IV infusion of drugs into humans.
`Edward Jenner vaccinated children against smallpox using intradermal administration with
`cowpox virus.
`James Blundell performed a successful blood transfusion following postpartum hemorrhage.
`William O'Shaughnessy studied the blood of cholera patients and developed the concepts for IV
`water and electrolyte replacement therapy.
`Thomas Latta established the first clinical practice of IV infusions of water and salts to treat
`cholera patients, based on O'Shaughnessy's work.
`Alexander Wood developed the first modern hypodermic syringe with a steel barrel and hollow
`steel needle.
`Joseph Lister developed the concepts of antisepsis using carbolic acid (phenol) solutions to
`sanitize hands, instruments, and wounds to reduce postsurgery infections.
`Louis Pasteur confirmed the germ theory of disease, discovered techniques for pasteurization of
`milk, and developed vaccinations against chicken cholera, bovine anthrax, and rabies.
`Charles Chamberland invented the autoclave.
`Charles Chamberland invented the “Chamberland filter" (porcelain) that removed bacteria from
`solutions prior to dosing.
`FLM. Matas demonstrated the effective use of IV saline solutions to treat shock.
`Using a rabbit model, E.C. Hort and W.J. Penfold determined the pyrogenic response following
`many IV iniections was caused by a substance produced by gram negative bacterial
`contamination of the solution (14 16].
`Ftichard Zsigrnondy and W. Bachman developed technology to manufacture microporous
`membrane filters from cellulose esters (nitrocellulose, acetyl cellulose, cellulose acetate].
`Florence Siebert and LB, Mendel developed a definitive rabbit pyrogen test model and showed
`that endotoxin from gram negative bacteria was the substance responsible for the pyrogenic
`response following injection with sterile solutions (17 19.20].
`Frederick Banting and J.J.Fl. Macleod share the Nobel Prize in Physiology or Medicine for the
`extraction of insulin and demonstration of clinical efficacy.
`Purified insulin product marketed ("min“).
`RM. Matas demonstrates continuous IV "drip" (21).
`L. Rademaker reported that after installation of a distilled water system for pharmaceutical
`production, pyrogenic reactions by surgery patients to parenteral injections dropped from 30%
`to 4% (22).
`Lloyd A. Hall and Carroll L. Griffith patented the use of ethylene oxide to sterilize and preserve
`spices. This technology was applied to sterile pharmaceutical product manufacturing during
`the 1940s
`
`(Continued)
`
`Regeneron Exhibit 1015.018
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`3 D
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`Table 3 Historical Milestones in Parenteral Drug Delivery (Continued)
` Year Milestone
`
`
`VOLUME 1' iUHMULAti'Ofl AM) PACKAGWG
`
`1942
`1940s
`
`1946
`1950s
`1961
`
`1961
`
`1964
`
`196?
`
`1969
`19?1
`
`19?3
`19?6
`
`19?8 19?9
`19805
`
`Rabbit pyrogen test (Seibert and Mendel) published in the US. Pharmacopeia.
`High Efficiency Particulate Air (HEPA) filters designed and installed for clean air supply in
`rudimentary cleanrooms at Manhattan project sites and biological weapons research
`laboratories at Fort Detrick, Maryland (10.23.24).
`Parenteral Drug Association founded.
`Cleanrooms with HEPA fiftered air supply widely used for pharmaceutical fillifinish (10,23,241.
`Willis J. Whitfield pioneered the concept of laminar air flow and constructed the first modern
`cleanroom at Sandia Corporation in Albuquerque, New Mexico (10,23,24)._
`Arvid Wretlind and O. Schuberth formulated the first lipid emulsion, lntralipid P", suitable for IV
`infusion (7,25).
`Arvid Wretlind developed a total parenteral nutrition {TPN} program providing half of the calories
`from lipid and half from glucose. Recognized as the father of TPN (7,25).
`Stanley J. Dudrick reported comprehensive technique to provide long term total parenteral
`nutrition (TPN) (125).
`DW Wilmore and Stanley J Dudrick used an in line filter to reduce the risk of IV infusions (Y, 25).
`James F. Cooper, Jack Levin, and HM. Wagner Jr. pioneered use of the Iimulus amebocyte
`lysate test for screening parenteral drug products for endotoxin contamination (26).
`Infusion Nurses Society founded.
`Food and Drug Administration publishes Current Good Manufacturing Practice in the
`Manufacture, Processing, Packing, or Holding of Large Volume Parenterats (never formally
`adopted).
`Human insulin cloned. Human growth hormone cloned.
`First steps toward barrier isolator technology for aseptic fillifinish operations gray side
`maintenance (24).
`Sterilizable isolators introduced for compendial sterility testing (2?).
`Humulin “ (human insulin recombinant] marketed.
`ProtropinTL (somatrem for injection) and Somatonorm “- (somatrem) marketed. (methionyl human
`somatropin).
`Orthoclone" OTK3 marketed to treat the rejection of transplanted organs.
`FDA publishes industry Guideline on Sterite 0mg Products Produced by Aseptic Processing and
`Guidetine on Generat Principies of Process Vatidation.
`Humatrope“ (somatropin recombinant) and Genotropin“ [somatropin (rDNA) for injection]
`marketed.
`_
`First dual chamber pen injector launched (KabiPen F‘).
`Barrier isolator technology for tillifinish operations Restricted Access Barrier Systems (RABS)
`and lsolators (24).
`The lntemational Conference on Harmonisation of Technical Requirements for Registration of
`Pharmaceuticals for Human Use (ICH) is established.
`FDA publishes Guidance for industry for the Submission Documentation for Sterilization Process
`Vatidation in Aoptications for Human and Veterinanr Drug Products.
`Note for Gurdance on Manufacture of the Finished Dosage Form issued by the Committee For
`Proprietary Medicinal Products (CPMP), CPMPiQWPMBfiiQS.
`First monoclonal antibody to treat cancer approved Flituxan “ (rituximab).
`Decision Trees for the Setection of Steritization Methods finalized by the CPMP, CPMPiOWPt
`054198.
`Pharmaceutical Compounding Sterile Preparations (397:3 became official in the US.
`Pharmacopeia.
`European Commission: Ad Hoc GlVIP Inspections Services Group, EC Guide to Good
`Manufacturing Practice Revision to Annex 1. Title: Manufacture of Sterite Medicinat Products.
`FDA publishes Guidance for industry Sterile Drug Promcts Produced by Aseptic Processing
`Current Good Manufacturing Practice (replaces 198?