DRUGS AND THE PHARMACEUTICAL SCIENCES
`
`Sterile
`Drug Products
`Formulation, Packaging,
`Manufacturing, and Quality
`
`Akers
`
`Sterile Drug Products
`
`Sterile Drug Products
`Formulation, Packaging, Manufacturing, and Quality
`
`About the book
`Sterile Drug Products: Formulation, Packaging, Manufacturing, and Quality teaches the basic principles of the
`development and manufacture of high quality sterile dosage forms. The author has many years of experience
`in the development and manufacture of sterile dosage forms including solutions, suspensions, ophthalmics and
`freeze dried products. This book is based on the courses he has delivered for over three decades, to over 3000
`participants, and is intended to remain relevant for the indefinite future even as new technologies and new
`applications of old technologies become common.
`
`This is an ideal reference book for those working directly and indirectly with sterile dosage forms, be it
`product development (formulation, package, process, analytical), manufacturing, quality control, quality
`assurance, regulatory, purchasing, or project management. This book is also intended as an educational resource
`for the pharmaceutical and biopharmaceutical industry, and pharmacy schools, providing basic knowledge and
`principles in four main areas of sterile product science and technology:
`
`• Product development, including formulation, package, and process development.
`
`• Manufacturing, including basic teaching on all the primary unit operations involved in the preparation of
`sterile products and the underlying importance of contamination control and compliance to current good
`manufacturing practice.
`
`• Quality and regulatory, including the application of good manufacturing practice regulations and guidelines,
`quality systems, good aseptic processing practices, and unique quality control testing of sterile dosage forms.
`
`• Clinical aspects, involving routes of administration, potential clinical hazards, and biopharmaceutical
`considerations.
`
`About the author
`MiChael J. akers Ph.D. is senior Director of Pharmaceutical research and Development at Baxter BioPharma
`solutions and leads the Baxter lyophilization Center of excellence in Bloomington, indiana. Dr. akers received
`his B.a. degree from Wabash College and Ph.D. degree in Pharmaceutics from the University of iowa College
`of Pharmacy, and has previously been employed at Searle Laboratories, Alcon Laboratories, the University of
`Tennessee College of Pharmacy, and Eli Lilly and Company. Dr. Akers is active in the Parenteral Drug Association
`and is a Fellow of the American Association of Pharmaceutical Scientists. He is Editor-in-Chief of Pharmaceutical
`Development and Technology, and author or editor of six books, including Parenteral Quality Control: Sterility,
`Pyrogen, Particulate, and Packaging Integrity Testing, Third Edition, informa healthcare, 2002.
`
`Telephone House, 69-77 Paul Street, London EC2A 4LQ, UK
`
`52 Vanderbilt Avenue, New York, NY 10017, USA
`www.informahealthcare.com
`
`Michael J. Akers
`
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`DRUGS AND THE PHARMACEUTICAL SCIENCES
`A Series of Textbooks and Monographs
`ExecutiveEditor
`
`James Swarbrick
`PharmaceuTech,Inc.
`Pinehurst,NorthCarolina
`
`Advisory Board
`
`Larry L. Augsburger
`UniversityofMaryland
`Baltimore,Maryland
`
`Harry G. Brittain
`CenterforPharmaceutical
`PhysicsMilford,NewJersey
`
`Robert Gurny
`UniversitedeGeneve
`Geneve,Switzerland
`
`Ajaz Hussain
`Sandoz
`Princeton,NewJersey
`
`Kinam Park
`PurdueUniversity
`WestLafayette
`Indiana
`
`Anthony J. Hickey
`UniversityofNorthCarolina
`SchoolofPharmacy
`ChapelHill,NorthCarolina
`
`Vincent H. L. Lee
`USFDACenterforDrug
`EvaluationandResearch
`LosAngeles,California
`
`Stephen G. Schulman
`UniversityofFlorida
`Gainesville,Florida
`
`Jennifer B. Dressman
`UniversityofFrankfurt
`InstituteofPharmaceutical
`TechnologyFrankfurt
`Germany
`
`Jeffrey A. Hughes
`UniversityofFlorida
`CollegeofPharmacy
`Gainesville,Florida
`
`Joseph W. Polli
`GlaxoSmithKline
`ResearchTrianglePark
`NorthCarolina
`
`Jerome P. Skelly
`Alexandria,Virginia
`
`Yuichi Sugiyama
`UniversityofTokyo,Tokyo,Japan
`
`Elizabeth M. Topp
`PurdueUniversity,WestLafayette,Indiana
`
`Geoffrey T. Tucker
`UniversityofSheffield
`RoyalHallamshireHospital
`Sheffield,UnitedKingdom
`
`Peter York
`UniversityofBradford,SchoolofPharmacy
`Bradford,UnitedKingdom
`
`RecentTitlesinSeries
`Sterile Drug Products: Formulation, Packaging, Manufacturing, and Quality,
`MichaelJ.Akers
`Advanced Aseptic Processing Technology, JamesAgallocoandJamesAkers
`Freeze Drying/Lyophilization of Pharmaceutical and Biological Products, Third Edition,
`editedbyLouisReyandJoanC.May
`Active Pharmaceutical Ingredients: Development, Manufacturing, and Regulation,
`Second Edition, editedbyStanleyH.Nusim
`Generic Drug Product Development: Specialty Dosage Forms, editedbyLeonShargel
`andIsadoreKanfer
`Pharmaceutical Statistics: Practical and Clinical Applications, Fifth Edition, SanfordBolton
`andCharlesBon
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`Sterile Drug Products
`Formulation, Packaging,
`Manufacturing, and Quality
`
`Michael J. Akers, Ph.D.
`Baxter BioPharma Solutions
`Bloomington, Indiana, U.S.A.
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`First 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
`W1T 3JH, UK. Registered in England and Wales number 1072954.
`C(cid:1) 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 W1P 0LP, 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 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 CIP record for this book is available from the British Library.
`
`Library of Congress Cataloging-in-Publication Data available on application
`
`ISBN-13: 9780849339936
`
`Orders may be sent to: Informa Healthcare, Sheepen Place, Colchester, Essex CO3 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 Aptara, Delhi, India
`Printed and bound in the United Kingdom.
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`Preface
`
`This book is based primarily on courses that I taught on the basic principles of sterile dosage
`formulation, packaging, manufacturing, and quality control and assurance over a span of
`35 years. I have basically added written text to the slides that were presented in my courses. So
`any reader who has participated in one of these courses will likely recognize some of the figures
`and tables.
`This book is written, like the course presented, for the person who either is new to the
`sterile product field or has some experience, but needs a good refresher tutorial. Although the
`basics are presented, deeper concepts and principles are given as appropriate. This book is
`intended to be a helpful resource for individuals working directly and indirectly with sterile
`dosage forms, be it research, product development (formulation, package, process, analytical),
`manufacturing, engineering, validation, quality control, quality assurance, regulatory, supply
`chain, purchasing, scheduling, project management, and any other area that deals with sterile
`products. This book also is intended to be a reference text for educational courses taught in
`pharmacy schools or continuing education programs. I have written the book with the intent to
`remain relevant for the indefinite future even though new technologies and new applications
`of old technologies will become common.
`The advent of biotechnology in the late 1970s increased significantly the stature of the par-
`enteral route of administration as the only way to deliver such large and delicate biomolecules.
`With continued advances in proteomics, genomics, monoclonal antibodies, and sterile devices,
`development and manufacture of sterile dosage forms have advanced to new heights with
`respect to numbers of drug products in clinical study and on the marketplace. All these advances
`have expanded the need for people to be educated and trained in the field of parenteral science
`and technology. However, such education and training still does not occur to much extent in
`university education. Such education and training occur “on the job” via both internal and
`external courses.
`This book is designed to serve as an educational resource for the pharmaceutical and
`biopharmaceutical industry providing basic knowledge and principles in four main areas of
`parenteral science and technology:
`
`including formulation, package, and process development
`
`1. Product development,
`(chap. 2–11)
`2. Manufacturing, including basic teaching on all the primary unit operations involved in
`preparing sterile products with emphasis on contamination control (chap. 12–23)
`3. Quality and regulatory, with focus on application of good manufacturing practice regula-
`tions, sterility assurance, and unique quality control testing methods (chap. 24–30)
`4. Clinical aspects, focusing on preparation, use, and administration of sterile products in the
`clinical setting (chap. 1, 30–33).
`
`Chapters on product development present the basic principles of formulation develop-
`ment of sterile solution, suspension, and freeze-dried (lyophilized) dosage forms. Approaches
`traditionally used to overcome solubility and stability limitations have been emphasized. Spe-
`cific formulation components such as vehicles, solubilizers, buffers, antioxidants and chelating
`agents, cryo- and lyoprotectants, tonicity agents, antimicrobial preservatives, and suspending
`and emulsifying agents have been covered in good detail. Some coverage of long-acting drug
`delivery systems, especially the polymers used in commercial formulations, are included. Chap-
`ter 11 focuses on overcoming formulation problems, with 14 case studies to help the reader learn
`how to approach formulation problem solving.
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`vi
`
`PREFACE
`
`Development of sterile dosage forms not only includes the formulation but also the pack-
`age and the process. Glass, rubber, and plastic chemistry are covered to some extent, as well as
`packaging delivery systems and devices, both traditional (e. g., vials, syringes) and more novel
`(e. g. needleless injectors, dual chambered systems).
`The area of manufacturing includes chapters on process development and overview,
`contamination control, facilities, water, air, personnel practices, preparation of components,
`sterilization, filtration, filling, stoppering and sealing, lyophilization, aseptic processing, barrier
`technology, labeling and secondary packaging, and some discussion of manufacturing advances.
`The area of quality and regulatory includes chapters on good manufacturing practice, the
`philosophy of quality as it relates to the sterile dosage form, specific quality control tests unique
`to sterile products, and some coverage of stability testing.
`The final area covered is clinical aspect, general discussion of the use of the injectable
`dosage form in the clinical setting, advantages and disadvantages of sterile products, hazards
`of administration, and biopharmaceutical considerations.
`I have taken the liberty to use my own published materials, with appropriate approvals,
`to reproduce in this book. Indeed, several chapters are based on previous book chapter or
`review article publications, some with coauthors who I have acknowledged and obtained their
`permission. All in all, this book represents more than 35 years of my teachings, writings, and
`experience in the sterile product science and technology world. Of course, a singular perspective
`has its limitations compared with a book that has multiple authors. However, this book does
`have the advantage of consistency of writing style and the ultimate goal of each chapter being
`practical to the reader.
`Just like I always stated when starting every one of my courses, may you learn as much
`as possible while at the same time having some fun while reading/studying this book.
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`Acknowledgments
`
`Since I state that this book represents 35 years of my experience working in the sterile product
`field, I need to acknowledge those who influenced me the most to remain active in this field
`all these years. Dr. Gerald Hecht and Dr. Robert Roehrs hired me to join Alcon in 1974 without
`having any formal training or experience in sterile products so that is where I got my start.
`Joining the faculty at the University of Tennessee three years later exposed me to the teaching
`and influence of Dr. Kenneth Avis who for decades was considered the world’s leading expert
`in parenterals. Dr. Joseph Robinson was an influential leader to me primarily through our
`interactions on the former Journal of Parenteral Science and Technology board plus his natural
`mentoring skills. Dr. Patrick DeLuca kept me involved in teaching sterile products after joining
`Eli Lilly by asking me to help him teach the Center for Professional Advancement sterile products
`course that after nearly 30 years I am still teaching. Dr. Steven Nail has been a 30-year colleague
`and very close friend, plus a coworker these past few years, who has served as a scientific role
`model for me. Other mentors over these years, scientists whose work I have admired, include
`Dr. Michael Pikal, Dr. John Carpenter, Dr. Eddie Massey, Dr. Alan Fites, Mr. Bob Robison, and
`Dr. Lee Kirsch. There are many other scientists, too many to mention, who also have influenced
`me through their intelligence, creativity, and enthusiasm for the pharmaceutical sciences.
`I thank those who helped me write several chapters in this book including Dr. Michael
`DeFelippis of Eli Lilly and Company (chap. 9), Mr. Mark Kruszynski of Baxter BioPharma Solu-
`tions (chap. 19), and Dr. Dana Morton Guazzo who graciously updated chapter 30. I acknowl-
`edge many of my Baxter Bloomington R&D colleagues, besides Steve Nail, who helped me to
`write chapters 4 and 7 (Dr. Gregory Sacha, Ms. Karen Abram, and Ms. Wendy Saffell-Clemmer),
`or helped me by providing needed figures and photos (Dr. Gregory Sacha, Ms. Lisa Hardwick,
`and Dr. Wei Kuu).
`I greatly appreciate the administrative support I received from Ms. Angie Krusynski who
`did a lot of the “leg work” helping to obtain reproduction approvals. I thank present and
`past Baxter executives (Alisa Wright, Lee Karras, Ted Roseman, and Ken Burhop) who have
`encouraged me to write, even admittedly sometimes on company time. I also appreciate my
`Baxter Bloomington site head, Mr. Camil Chamoun, for his encouragement and support plus
`allowing me to use many photos from the Bloomington site.
`Finally, of course, the old phrase “behind every good man is even a great woman” is so
`true in my case as I express my love and respect for my wife and best friend, Mary (Midge)
`Akers.
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`Contents
`
`Preface . . . . v
`Acknowledgments . . . . vii
`
`1. Introduction, scope, and history of sterile products 1
`
`2. Characteristics of sterile dosage forms 11
`
`3. Types of sterile dosage forms 20
`
`4. Sterile product packaging systems 29
`
`5. Overview of product development 48
`
`6. Formulation components (solvents and solutes)
`
`58
`
`7. Sterile products packaging chemistry 72
`
`8. Formulation and stability of solutions 96
`
`9. Dispersed systems
`
`115
`
`10. Formulation of freeze-dried powders 138
`
`11. Overcoming formulation problems and some case studies 169
`
`12. Overview of sterile product manufacturing 180
`
`13. Contamination control 194
`
`14. Sterile manufacturing facilities 211
`
`15. Water and air quality in sterile manufacturing facilities
`
`221
`
`16. Personnel requirements for sterile manufacturing 236
`
`17. Sterilization methods in sterile product manufacturing 247
`
`18. Sterile filtration 267
`
`19. Sterile product filling, stoppering, and sealing 278
`
`20. Freeze-dry (lyophilization) processing 294
`
`21. Aseptic processing 313
`
`22. Inspection, labeling, and secondary packaging 328
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`CONTENTS
`
`ix
`
`23. Barrier and other advanced technologies in aseptic processing 346
`
`24. Stability, storage, and distribution of sterile drug products 362
`
`25. Good manufacturing practice
`
`372
`
`26. Quality assurance and control 382
`
`27. Microorganisms and sterility testing 400
`
`28. Pyrogens and pyrogen/endotoxin testing 415
`
`29. Particles and particulate matter testing 434
`
`30. Sterile product-package integrity testing 455
`
`31. Administration of injectable drug products
`
`473
`
`32. Clinical hazards of injectable drug administration 481
`
`33. Biopharmaceutical considerations with injectable drug delivery 486
`
`Index . . . . 495
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`1 Introduction, scope, and history
`of sterile products
`
`Sterile dosage forms have always been an important class of pharmaceutical products in dis-
`ease diagnosis, therapy, and nutrition. Certain pharmaceutical agents, particularly peptides,
`proteins, and many chemotherapeutic agents, can be administered only by injection (with or
`without a needle), because they are inactivated in the gastrointestinal tract when given by
`mouth. Administration of drugs by the parenteral (parenteral and injectable will be used inter-
`changeably) route has skyrocketed over the past several years and will continue to do so. A
`primary explanation for this enormous growth lies with the advent of biotechnology, the prod-
`ucts of which are biomolecules that cannot be readily administered by any other route because
`of bioavailability and stability reasons. Since human insulin became the first biotechnology
`drug approved by the Food and Drug Administration (FDA) in 1982, over 100 drug products of
`biotechnological origin have been approved and hundreds more will be approved in the years
`ahead. Most biotechnology drug products are administered only by the parenteral route. Science
`is advancing to a time when it is likely that some of these drugs can or will be administered by
`other routes, primarily pulmonary and perhaps someday even orally, but the mainstay route of
`administration for these biopharmaceutical drugs will be by injection.
`Any statistic given at the time of writing this section will quickly be outdated by the time
`this book is printed and will continually need to be updated. However, it is safe to state that the
`number of injectable products being developed, being studied in the clinic, being approved for
`commercial use, and being administered to humans and animals will significantly increase in the
`years to come. Perhaps by 2020, the market share of sterile drug products will be approximately
`the same as that for oral solid dosage forms1.
`This chapter will address some of the basic questions about the sterile dosage form and
`the parenteral route of administration.
`Various definitions and end uses of sterile products will be discussed throughout this
`book. This book will also address many aspects of formulation development of these dosage
`forms, how they are manufactured, how they are packaged, how they are tested and what are
`the acceptable conditions during manufacture, and the uses that assure these unique products
`maintain their special properties.
`There are three terms used interchangeably to describe these products—parenteral, ster-
`ile, and injectable. Parenteral and injectable basically have the same meaning and are used
`interchangeably. Sterile dosage forms encompass parenteral/injectable dosage forms as well as
`other sterile products such as topical ophthalmic products, irrigating solutions, wound-healing
`products, and devices. The coverage of devices in this book will be minimal.
`Here is a definition of sterile dosage forms:
`
`A product introduced in a manner that circumvents the body’s most protective barriers,
`the skin and mucous membranes, and, therefore, must be “essentially free” of biological
`contamination.
`
`Ideally, a sterile dosage form is absolutely free of any form of biological contamina-
`tion, and, of course, is the ultimate goal of every single unit of sterile product released to the
`marketplace, either commercial or clinical. Perhaps some day manufacturing procedures and
`in-process microbiological analysis will guarantee that each and every unit of sterile product
`will indeed be absolutely free of biological contamination. However, the modifier words “essen-
`tially free” are added to this definition because most small-volume (≤100 mL per container)
`
`1 Among many resources for keeping current with new drug products and trends are Burrill & Company
`(www.burrillandco.com); Pharmaceutical Research and Manufacturers of America (www.phrma.org); Tufts
`Center for the Study of Drug Development (http://csdd.tufts.edu); Onesource.com; EvaluatePharma.com;
`IMS; and Datamonitor, to name a few.
`
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`2
`
`STERILEDRUGPRODUCTS:FORMULATION,PACKAGING,MANUFACTURING,ANDQUALITY
`
`sterile products are produced where the finished product is not terminally sterilized, but rather
`is aseptically processed. The difference in sterility assurance is far greater (generally at least
`3 logs) for terminally sterilized products compared to aseptically processed products. This does
`not mean that aseptically processed products are frequently contaminated; rather it means
`that aseptically processed products cannot be validated to the same level of sterility assurance
`compared to terminally sterilized products. Sterility assurance is covered primarily in chapter
`13 while sterilization is covered in chapters 17 and 18 and aseptic processing is covered in
`chapter 21.
`The term “parenteral” comes from two Greek words, “par” meaning “avoid” and “enteral”
`meaning “alimentary canal.” Therefore, the word “parenteral” literally means “beside the intes-
`tine.” The only way to avoid the alimentary canal and to circumvent the skin and mucous
`membranes is to inject a pharmaceutical product directly into the body. Parenteral (the author
`prefers the term “sterile”) products must be exceptionally pure and free from physical, chem-
`ical, and biological contaminants (microorganisms, endotoxins, particles). These requirements
`place a heavy responsibility on the pharmaceutical industry to practice current good manufac-
`turing practices (cGMPs) in the manufacture of sterile dosage forms and upon pharmacists and
`other health care professionals to practice good aseptic practices (GAPs) in dispensing them for
`administration to patients.
`Injections usually are accomplished using needles, but newer technology avoids the use
`of needles or use of extremely small diameter needles (covered in chap. 4). As stated already, not
`all sterile dosage forms are administered by injection. Sterile products that are not parenteral or
`injectable products include the following:
`r Topical ophthalmic medications
`r Topical wound healing medications
`r Solutions for irrigation
`r Sterile devices (e.g., syringes, administration sets, and implantable systems)
`There are many terms that will be used throughout this book. A glossary of definitions of
`sterile product terms, not intended to be comprehensive, is given in Table 1-1.
`The United States Pharmacopeia (USP)2 contains several hundred monographs on sterile
`drugs or diluent preparations. Most products of biotechnology origin are not included because
`of confidentiality reasons. Some interesting statistics gathered after analyses of these USP mono-
`graphs are as follows:
`r About 22% are solid preparations that require solution constitution prior to use.
`r About 9% are diluent preparations, both small and large volume.
`r About 10% are radioisotope diagnostic preparations.
`Sterile drug products are relatively unstable and are generally highly potent drugs
`that require strict control of their administration to the patient. Overcoming solubility
`and stability issues and achieving and maintaining sterility and other purity requirements
`present great challenges to those developing, manufacturing, and administering sterile drug
`products.
`In this book, the teaching of the principles involved in the product development, product
`manufacture, and quality control of medicines delivered by the parenteral route will continue to
`be an important and relevant subject. This book is aimed to provide basic principles and practical
`applications of the formulation, packaging manufacture, and quality control of injectable dosage
`forms; in fact, all sterile dosage forms.
`
`HISTORY OF THE STERILE DOSAGE FORM
`Avis published probably the most detailed review of the history of the sterile dosage form (1).
`Turco and King’s last book also is a good general resource not only about history but also about
`clinical applications of sterile dosage forms (2). This chapter will highlight these references plus
`
`2 In general, referencing the USP also applies to other primary compendia, European Pharmacopeia (EP or PhEur)
`and Japanese Pharmacopeia (JP).
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`INTRODUCTION,SCOPE,ANDHISTORYOFSTERILEPRODUCTS
`
`3
`
`Table 1-1 Glossary of Terms Related to Sterile Drug Technology
`
`Absolute Rating—The size of the largest spherical particle completely retained on the filter. An absolute filter of
`0.2 ␮ retains all particles ≥0.2 ␮.
`Action Level—An established microbial or airborne particle level that, when exceeded, should trigger
`appropriate investigation and corrective action based on the investigation.
`Air Lock—A small area with interlocked doors, constructed to maintain air pressure control between adjoining
`rooms. Used to stage and disinfect large equipment prior to transfer from lesser-controlled room to
`higher-controlled room.
`Alert Level—An established microbial or airborne particle level giving early warning of potential drift from
`normal operating conditions, and which triggers appropriate scrutiny and follow-up to address the potential
`problem. Alert levels are always lower than action levels.
`Ampule—A final container that is totally glass in which the open end after filling a product is sealed by heat. Also
`referred as ampul, ampoule, carpule (French).
`Antimicrobial Preservative—Solutes such as phenol, meta-cresol, benzyl alcohol, and the parabens that
`prevent the growth of microorganisms. Must be present in multiple dose parenterals.
`Antioxidants—Solutes that minimize or prevent drug oxidation. Examples include sodium bisulfite, ascorbic
`acid, and butylated hydroxyanisole.
`Aseptic—Lack of disease-producing microorganisms. Not the same as sterile.
`Aseptic Processing—Manufacturing drug products without terminal sterilization. The drug product is sterile
`filtered, then aseptically filled into the final package and aseptically sealed.
`Autoclave—A system that sterilizes by superheating steam under pressure. The boiling point of water, when
`pressure is raised 15 psig above atmospheric pressure, is increased to 121◦C (250◦F). This is the most
`common means of terminally sterilizing parenteral products.
`Barrier—A system having a physical partition between the sterile area (ISO 5) and the nonsterile surrounding
`area. A barrier is differentiated from an isolator in that the barrier can exchange air from the fill zone to the
`surrounding sanitized area where personnel are located, whereas an isolator cannot exchange air from the fill
`zone to the sterilized surrounding area where personnel are located.
`Bioburden—Total number of microorganisms detected in or on an article prior to a sterilization treatment. Also
`called microbial load.
`Biological Indicator—A population of microorganisms inoculated onto a suitable medium (e.g., solution,
`container, closure, paper strip) and placed within an appropriate sterilizer load location to determine the
`sterilization cycle efficacy of a physical or chemical process. The specific microorganisms are the most
`resistant to the particular sterilization process.
`Bubble Point—Used in filter integrity testing; the pressure where a gas will pass through a wetted membrane
`filter. Each filter porosity and type has a given bubble point.
`Buffers—Solutes used to minimize changes in pH, important for many drugs to maintain stability and/or
`solubility.
`Chelating Agents—Solutes that complex metal ions in solution, preventing such metals from forming insoluble
`complexes or catalyzing oxidation reactions. Example: ethylenediaminetetraacetic acid (EDTA)
`Class X—A Federal Standard for clean room classes. Whatever X is, for example, 100, means that there are no
`more than X particles per cubic foot ≥ 0.5 ␮m.
`Clean Room—A room designed, maintained, and controlled to prevent particle and microbiological
`contamination of drug products. Such a room is assigned and reproducibly meets an appropriate air
`cleanliness classification.
`Colony Forming Unit (CFU)—A microbiological term that describes the formation of a single macroscopic
`colony after the introduction of one or more microorganisms to microbiological growth media.
`Coring—The gouging out of a piece of rubber material caused by improper usage of a needle penetrating a
`rubber closure.
`Critical Area—An area designed to maintain sterility of sterile materials.
`Critical Surfaces—Surfaces that may come into contact with or directly affect a sterilized product or its
`containers or closures. Critical surfaces are rendered sterile prior to the start of the manufacturing operation,
`and sterility is maintained throughout processing.
`D-Value—