Pharmaceutical
`
`Third Edition
`
`Volume i: Formulation
`
`and Packaging
`
`Dosage Forms:
`Parenteral Medications
`
`John D. Ludwig
`
`, f
`{Sigma
`
`Edited by
`
`Sandeep Nema
`
`Regeneron Exhibit 1015.001
`
`Regeneron Exhibit 1015.001
`
`

`

`Pharmaceutical Dosage
`Forms
`
`Regeneron Exhibit 1015.002
`
`

`

`This page intentionally left blank
`
`Regeneron Exhibit 1015.003
`
`

`

`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.
`Chesterfield, Missouri, U.S.A.
`
`informa
`
`healthcare
`
`Regeneron Exhibit 1015.004
`
`

`

`First published in 1984 by Marcel Dekker, Inc., New York, New York.
`This edition published in 2010 by lnforma Healthcare, Telephone House, 69 77 Paul Street, London EC2A
`4LQ, UK.
`
`Simultaneously published in the USA by lnforma Healthcare, 52 Vanderbilt Avenue, 7th Floor, New York,
`NY 10017, USA.
`
`lnforma Healthcare is a trading division of lnforma UK Ltd. Register-ed Office: 37 41 Mortimer Street,
`London WU 3JH, UK. Registered in England and Wales number 1072954.
`
`t;2010 lnforma Healthcare, except as otherwise indicated
`
`No dai.m to origioal 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 publkatioi,, we would be glad to
`acknowledge in subsequent reprints or editions a.ny 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, photocopyiJ1g, recording, or otherwise,
`unless with the prior wri.tten 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 W1P OLP, UK, or the
`Copyright Clearance Ceoter, Jnc., 222 Rosewood Drive, Danvers, 1'.1A 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 contaios 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 opiJ1ions 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. At1y 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 mamJfacturer's instructions and the appropriate best pra.ctice
`guidelines. Because of the rapid advances iJ1 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 medicc1l professional to make his or her own professi.ooal judgements, so as
`appropriately to advise and treat patients. Save for death or personal injury caused by tl,e 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 dan,age caused
`to any person or property arisiJ,g in any way from the use of this book.
`
`A Cl.P record for this book is available from. the British Library.
`
`Ubrar.y of Congress Catal.oging in Publication Data c1vailable on applicatioo
`
`ISBN 13: 9781420086430
`ISBN 13: 9781420086539 (three voltune set)
`
`Orders may be sent to: lnforma Healthcare, Sheepen r lace, Colchester, Essex COJ 3LP, VJ<
`Telephone: +44 (0)20 7017 5540
`Email: CSDhealthcarebooks@informa.com
`Website: http://i1lformahealthcarebooks.com/
`
`For corporate sales please contact: CorporateBooksIHC@informa.com
`For foreign rights please contact: RightslHC@informa.com
`For reprint permissions please contact: J>ermissionsIHC@iniorma.com
`
`Typeset by MPS Limited, A Macmillan Company
`Printed and bound in India
`
`Regeneron Exhibit 1015.005
`
`

`

`We dedicate this work to those who have inspired us.
`To 111.y 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 1015.006
`
`

`

`This page intentionally left blank
`
`Regeneron Exhibit 1015.007
`
`

`

`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 1.992. 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. A vis' 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, RNA i delivery, regulatory considerations for excipients, techniques to
`evaltmte 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 1015.008
`
`

`

`This page intentionally left blank
`
`Regeneron Exhibit 1015.009
`
`

`

`Preface
`
`Pharmaceutical Dosage Forms: Parenteral Medicatious 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 manufactt.tring and control
`technologies. In addition, the global regttlatory 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
`manufactt.uing 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 l addresses formulation and packaging
`aspects; volume 2, facility design, sterilization and processing; and volmne 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 drng 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 closme 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. Vohune 2 concludes with a11 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 ftttt.1re of parenteral product manufach.tring.
`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, manufactt.1ring, validation, and
`eventual registration.
`The editors wish to thank Judy Clarkston and Lynn O'Toole-Bird (Pfizer, lnc.) for their
`invaluable assistance and organizational support during this project, and Sherri Niziolek and
`Bianca Turnbull (lnforma Healthcare) for patiently leading us through the publishing process.
`
`Regeneron Exhibit 1015.010
`
`

`

`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. Lieberm11n who edited the e11rlier editions of thi1, book series.
`
`Sandeep Nema
`John D. Ludwig
`
`,::
`0
`
`Regeneron Exhibit 1015.011
`
`

`

`Contents
`
`Foreword Michael J. Akers
`Preface
`ix
`Contrilmtors
`
`xiii
`
`vii
`
`1. Parenteral dosage fom1s: introduction and historical perspective
`John D. Ludwig
`
`1
`
`2. Parenteral drug administration: routes of administration and devices
`Hi111a11sh11 Bhattacharjee and Laura A. Thoma
`
`7
`
`30
`3. Biopharmaceutics of NCEs and NBEs
`Balaji Agoram, J.(pzuko Sagawa, Ravi M. Shanker, and Satish K. Singh
`
`4. Preformulation
`N. Murti Vemuri
`
`57
`
`5. Formulation development of small and large volume injections
`Madhav Kamat and Pat1ick P. DeLuca
`
`76
`
`6. Drug solubility and solubilization
`134
`Ching Chiang Su, Lan Xiao, and Michael Hageman
`
`7. Formulation of depot delivery systems
`158
`James J. Cunningham, Marc J. Kirchmeier, and Sachi11 Mittal
`
`8. Biophysical and biochemical characterization of peptide and protein
`drug product
`194
`Tapan K. Das and James A. Carroll
`
`9. Formulation of protein- and peptide-based parenteral products
`Gaozhong Zh11 and Y. John Wang
`
`222
`
`254
`10. Development of ophtbalmic formulations
`Paramita Bandyopadhyay, Martin J. Coffey, and Molwmwd Shawer
`
`11. Glass containers for parenteral products
`Robert Swift
`
`287
`
`12. Plastic packaging for parenteral drug delivery
`Vinod D. Vilivalam and Frances L. DeGrazio
`
`305
`
`Regeneron Exhibit 1015.012
`
`

`

`xii
`
`CONTENTS
`
`13. Elastomeric closures for parenterals
`Renaud Janssen
`
`324
`
`14. Parenteral product container closure integrity testing
`Dana Morton Guazzo
`
`358
`
`Index
`
`389
`
`Regeneron Exhibit 1015.013
`
`

`

`Contributors
`
`Balaji Agoram Pfizer, fnc., Sandwich, U.K.
`
`Paramita Bandyopadhyay Bausch & Lomb, Rochester, New York, U.S.A.
`
`Himanshu Bhattachatjec Department of Pharmaceutical Sciences, College of Pharmacy.
`University of Tennessee Health Science Center, Memphis, Tennessee, U.S.A.
`
`James A. Carroll BioTherapeutics Phnrmc1ceutical Sciences, Pfizer, Inc., Chesterfield,
`Missouri, U.S.A.
`
`Martin J. Coffey Bausch & Lomb, Rochester, New York, U.S.A.
`
`James J. Cunningham Phc1rmaceutical Research and Development Sciences, Merck Research
`Laboratories, West Point, Pennsylvania, U.S.A.
`
`Tapan K. Das Bio Therapeutics Pharmaceutical Sciences, Pfizer, Inc., Chesterfield, Missouri, U.S.A.
`
`Frances L. DeGrazio West Pharmaceutical Services, fnc., Lionville, Pennsylvania, U.S.A.
`
`Patrick P. Del uca Pharmaceutical Sciences. University of Kentucky College of Phnrmacy.
`Lexington, Kentucky, U.S.A.
`
`Dana Morton Guazzo RxPax, LLC, Bridgewater, New Jersey, U.S.A.
`
`Michael Hageman Bristol Myers Squibb Research, Princeton, New Jersey. U.S.A.
`
`Renaud Janssen Helvoet Phanna, Alken, Belgium
`
`Madhav Kamat Biopharmaceutics R&D, Bristol Myers Squibb Company, New Brunswick, New
`Jersey, U.S.A.
`
`Marc J. Kirchmeier Vnccine Formulation Development, Variation Biotechnologies, fnc.,
`Cambridge, Massachusetts, U.S.A.
`
`John D. Ludwig BioTherapeutics Pharmaceutical Sciences, Pfizer, lnc., Chesterfield,
`Missouri, U.S.A.
`
`Sachin MittaJ Pharmaceutical Research and Development Sciences, Merck Research Laboratories,
`West Point, Pennsylvania, U.S.A.
`
`Kazuko Sagawa Pfizer Global R&D, Groton, Connecticut, U.S.A.
`
`Ravi M. Shanker Pfizer Global R&D, Groton, Connecticut, U.S.A.
`
`Mohannad Shawer Bausch & Lomb, Rochester, New York, U.S.A.
`
`Regeneron Exhibit 1015.014
`
`

`

`xiv
`
`CONTRIBUTORS
`
`Satis l'l K. Singh BioTherapeutics Phannaceutical Sciences, Pfizer, Inc., Chesterfield, Missouri,
`U.S.A.
`
`Ching-Chiang Su Bristol Myers Squibb Research, Princeton, New Jersey, U.S.A.
`
`Robert Sw ift Amgen, lnc., Thousand Oaks, California, U.S.A.
`
`Laura A. Thoma Department of Pharmaceutical Sciences, College of Pharmacy, University of
`Tennessee Health Science Center, Memphis, Tennessee, U.S.A.
`
`N. Murti Vemuri Sanofi Aventis, Bridgewater, New Jersey, U.S.A.
`
`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,
`
`lew Jersey, U.S.A.
`
`Gaozhong Zhu Shire Human Genetic Therapies, Inc., Cambridge, Ylassachusetts, U.S.A.
`
`Regeneron Exhibit 1015.015
`
`

`

`t:
`0
`
`Parenteral dosage forms: introduction
`and historical perspective
`
`John D. Ludwig
`
`INTRODUCTION
`Parenteral dosage forms are those administered directly into body tissues rather than via the
`alimentary canal. "Parenteral" is derived from the Greek words para (beside) and enferon (the
`intestine) and most often refers to subcutaneous (SC), intramuscular (IM), or intravenous (TV)
`administration of drugs. Parenteral drug delivery can pose significant risk to the patient since
`the natural barriers of the body (gut, skin, and mucous membranes) are bypassed. The highest
`standards for quality and purity must be maintained throughout dosage form mamtfacture 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 (cGMPs), which are
`constantly evolving as technology advances. An equal burden of responsibility is placed on
`physicians, pharmacists, nurses, and other health professionals to follow strict good aseptic
`practices (GAPs) as they administer parenteral dosage forms to patients. Nosocomial 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 administered parenterally generally produces an imrnediate
`therapeutic effect and is therefore desirable in emergency sittiations. Parenteral administration
`also provides a mechanism for dosiJ1g 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 tt1be 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 dosing error (overdose)
`with an oral tablet, gastric lavage, induced emesis, or activated charcoal can be employed. The
`options for reversing an [V overdose are usually very limited. Secondly, the risk of infection is
`always present with parenteral dosing boili 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, IM, 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 lV route. Slower and more variable onset of action typically occurs
`following SC and IM administration since the drug must be absorbed iJ1to 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 .it Contractptive Injection, which is administered deep
`IM every 13 weeks and depo-subQ provera 104 T, which is administered SC in the anterior
`thigh or abdomen every 12 to 14 weeks. lntravitrea 1 dosing has increased significantly in recent
`
`Regeneron Exhibit 1015.016
`
`

`

`2
`
`VOLUME 7: FORMULA(ION ANO PACKAGING
`
`Table 1 Parenteral Drug Delivery Routes
`
`Route
`
`Subcutaneous (SC)
`Intramuscular {IM)
`Intravenous {IV)
`lntravitreal
`lntradermal (ID)
`Intra articular
`lntrathecal
`lntraepidural
`lntracisternal
`Intra arterial
`lntracardiac
`lntrapleural
`lntraperitoneal
`lntraosseous
`
`Administration volume
`
`Low, generally < 2 ml
`Medium, 2 ml 5 ml
`High
`Low, generally < 0.1 ml
`Low, 0.1 ml
`Medium
`Low
`Low
`Medium
`High
`Medium
`Medium
`High
`Medium
`
`years because of new treatments for neovascular wet age-related macular degeneration (AMD)
`such as Lttcentis'r,. (ranibizttmb injection) and Macugen\'11- (pegaptanid sodium injection). The
`intradermal (ID) route is commonly used for very small volume injections (0.1 m L) such as the
`tuberculosis skin test for tuberci1lin 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. lntracisternal 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 ATTRIBUTES OF PARENTERAL DOSAGE FORMS
`Quality attributes specific to parenteral dosage forms are shown in Table 2. Injectable products
`must be manufactured using the highest quaUty 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 !he fewest number and the
`simplest excipients possible
`Physical and chemical stability
`Container closure system with low extractable/
`leachable profile
`Sterile
`Pyrogen free
`
`Free from visible particulate matter
`
`Container closure integrity
`
`Injection 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 stability.
`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 compendia!
`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.
`
`Regeneron Exhibit 1015.017
`
`

`

`PARENTERAL DOSAGE FORMS: INTRODUCTION AND HISTORICAL PERSPECTIVE
`
`3
`
`to why it was included and the relative amount. As a general ntle, formulations with the
`fewest excipients and simplest composition are highly desired. The quality and robustness of
`the container-closme 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 resuJts 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
`
`1616
`1656
`
`1665
`1796
`
`1818
`1831
`
`1832
`
`1855
`
`1867
`
`18605 18805
`
`1879
`1884
`
`1891
`1912
`
`1918
`
`1923
`
`1923
`
`1923
`1924
`1933
`
`1938
`
`Milestone
`
`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 tor 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 posipartum 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 patienis, 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.
`R.M. 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 injections was caused by a substance produced by gram negative bacterial
`contamination of the solution (14 16).
`Richard Zsigmondy and W. Bachman developed technology to manufacture microporous
`membrane filters from cellulose esters (nitrocellulose, acetyl cellulose, cellulose acetate).
`Florence Siebert and L.B. 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.R. Macleod share the Nobel Prize in Physiology or Medicine for the
`extraction of insulin and demonstration of clinical efficacy.
`Purified insulin product marketed {lletin "· ).
`R.M. 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.
`
`(Conti1111ed)
`
`Regeneron Exhibit 1015.018
`
`

`

`>, O
`
`..
`
`~
`:?.'!
`:::.
`
`0
`t:
`0
`
`.q
`& . a
`" :::,
`6
`~ ~
`,J:, <> e :g
`0 -
`0
`" :: ~ 0
`8 ~
`'5 8..
`]5
`..=:t..
`§
`]
`s 0
`~
`"O .. 0
`"8
`]
`0
`0
`
`4
`
`VOLUME 1: FORMULAtlON AND PACKAGING
`
`Table 3 Historical Milestones in Parenteral Drug Delivery (Continued)
`
`Year
`
`1942
`19405
`
`1946
`1950s
`1961
`
`1961
`
`1964
`
`1967
`
`1969
`1971
`
`1973
`1976
`
`1978 1979
`19805
`
`19805
`1982
`1985
`
`1986
`1987
`
`1987
`
`1987
`1990s
`
`1992
`
`1994
`
`1996
`
`1997
`1999
`
`2003
`
`2003
`
`2004
`
`2006
`2008
`
`2009
`
`Milestone
`
`Rabbit pyrogen test (Seibert and Mendel) published in the U.S. 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 filtered air supply widely used for pharmaceutical fill/finish (10,23,24).
`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 0. Schuberth formulated the first lipid emulsion, lntralipid "' , 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} (7,25).
`OW Wilmore and Stanley J Dudrick used an in line filter to reduce the risk of IV infusions (7, 25).
`James F. Cooper, Jack Levin. and H.N. Wagner Jr. pioneered use of the limulus 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 Parentera/s (never formally
`adopted) .
`Human insulin cloned. Human growth hormone cloned.
`First steps toward barrier isolator technology for aseptic fill/finish operations gray side
`maintenance (24).
`Sterilizable isolators introduced for compendia! sterility testing (27).
`Humulin;t\ (human insulin recombinant) marketed.
`Protropin ii (somatrem for injection) and Somatonorm:"' (somatrem) marketed. (methionyl human
`somatropin).
`OrthocloneA OTK3 marketed to treat the rejection of transplanted organs.
`FDA publishes Industry Guideline on Sterile Drug Products Produced by Aseptic Processing and
`Guideline on General Principles of Process Validation.
`Humatrope 1l (somatropin recombinant) and Genotropin" [somatropin (rDNA) for injection)
`marketed.
`First dual chamber pen injector launched (KabiPen'"').
`Barrier isolator technology for fill/finish operations Restricted Access Barrier Systems (RABS)
`and Isolators (24).
`The International 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
`Validation in Applications for Human and Veterinary Drug Products.
`Note for Guidance on Manufacture of the Rnished Dosage Form issued by the Committee For
`Proprietary Medicinal Products (CPMP), CPMP/QWP/486/95.
`First monoclonal antibody to treat cancer approved Rituxan " (rituximab).
`Decision Trees for the Selection of Sterilization Methods finalized by the CPMP, CPMP/QWP/
`054/98.
`Pharmaceutical Compounding Sterile Preparations < 797> became official in the U.S.
`Pharmacopeia.
`European Commission: Ad Hoc GMP Inspections Services Group, EC Guide to Good
`Manufacturing Practice Revision to Annex 1. Title: Manufacture of Sterile Medicinal Products.
`FDA publishes Guidance for Industry Sterile Drug Products Produced by Aseptic Processing
`Current Good Manufacturing Practice (replaces 1987 version).
`Infusion Nurses Society publishes updated Infusion Nursing Standards of Practice (28).
`Heparin recalls due to intentional contamination during production of active pharmaceutical
`ingredient.
`European Commission: Eudralex The Rules Governing Medicinal Products in the European
`Union, Volume 4, EU Guidelines to Good Manufacturing Practice, Medicinal Products for
`Human and Veterinary Use, Annex 1, Manufacture of Sterile Medicinal Products (replaces
`2003 version).
`
`Abbreviation: IV. intravenous.
`
`Regeneron Exhibit 1015.019
`
`

`

`PARENTERAL DOSAGE FORMS: INTRODUCTION ANO HISTORICAL PERSPECTIVE
`
`5
`
`discoveries prior to the 20th century. Therefore, the author attempted to arrive at re