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Telephone House, 69-77 Paul Street, London EC2A 4LQ, UK

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Michael J. Akers

DRUGS AND THE PHARMACEUTICAL SCIENCES

Sterile Drug Products

Formulation, Packaging, Manufacturing, and Quality

Sterile

Drug

Prod

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Sterile Drug ProductsFormulation, Packaging, Manufacturing, and Quality

About the bookSterile 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:

• Productdevelopment,includingformulation,package,andprocessdevelopment.

• Manufacturing,includingbasicteachingonalltheprimaryunitoperationsinvolvedinthepreparationofsterile products and the underlying importance of contamination control and compliance to current good manufacturing practice.

• Qualityandregulatory,includingtheapplicationofgoodmanufacturingpracticeregulationsandguidelines,quality systems, good aseptic processing practices, and unique quality control testing of sterile dosage forms.

• Clinicalaspects,involvingroutesofadministration,potentialclinicalhazards,andbiopharmaceuticalconsiderations.

About the authorMiChaelJ.akersPh.D.isseniorDirectorofPharmaceuticalresearchandDevelopmentatBaxterBioPharmasolutionsandleadstheBaxterlyophilizationCenterofexcellenceinBloomington,indiana.Dr.akersreceivedhisB.a.degree fromWabashCollegeandPh.D.degree inPharmaceutics from theUniversityof iowaCollegeof 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, informahealthcare,2002.

fm IHBK072-Akers July 10, 2010 7:17 Trim: 10in× 7in

Sterile Drug Products


DRUGS AND THE PHARMACEUTICAL SCIENCESA Series of Textbooks and Monographs

Executive Editor

James SwarbrickPharmaceuTech, Inc.

Pinehurst, North Carolina

Advisory Board

Larry L. AugsburgerUniversity of MarylandBaltimore, Maryland

Harry G. BrittainCenter for Pharmaceutical

Physics Milford, New Jersey

Jennifer B. DressmanUniversity of Frankfurt

Institute of PharmaceuticalTechnology Frankfurt

GermanyRobert GurnyUniversite de GeneveGeneve, Switzerland

Anthony J. HickeyUniversity of North Carolina

School of PharmacyChapel Hill, North Carolina

Jeffrey A. HughesUniversity of FloridaCollege of PharmacyGainesville, FloridaAjaz Hussain

SandozPrinceton, New Jersey

Vincent H. L. LeeUS FDA Center for DrugEvaluation and ResearchLos Angeles, California

Joseph W. PolliGlaxoSmithKline

Research Triangle ParkNorth Carolina

Kinam ParkPurdue University

West LafayetteIndiana

Stephen G. SchulmanUniversity of FloridaGainesville, Florida Jerome P. Skelly

Alexandria, Virginia

Yuichi SugiyamaUniversity of Tokyo, Tokyo, Japan

Elizabeth M. ToppPurdue University, West Lafayette, Indiana

Geoffrey T. TuckerUniversity of Sheffield

Royal Hallamshire HospitalSheffield, United Kingdom

Peter YorkUniversity of Bradford, School of Pharmacy

Bradford, United Kingdom

Recent Titles in SeriesSterile Drug Products: Formulation, Packaging, Manufacturing, and Quality,

Michael J. AkersAdvanced Aseptic Processing Technology, James Agalloco and James AkersFreeze Drying/Lyophilization of Pharmaceutical and Biological Products, Third Edition,

edited by Louis Rey and Joan C. MayActive Pharmaceutical Ingredients: Development, Manufacturing, and Regulation,

Second Edition, edited by Stanley H. NusimGeneric Drug Product Development: Specialty Dosage Forms, edited by Leon Shargel

and Isadore KanferPharmaceutical Statistics: Practical and Clinical Applications, Fifth Edition, Sanford Bolton

and Charles Bon


Sterile Drug ProductsFormulation, Packaging,

Manufacturing, and Quality

Michael J. Akers, Ph.D.Baxter BioPharma SolutionsBloomington, Indiana, U.S.A.


First published in 2010 by Informa Healthcare, Telephone House, 69-77 Paul Street, London EC2A 4LQ, UK.

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This book contains information from reputable sources and although reasonable efforts have been made to publishaccurate information, the publisher makes no warranties (either express or implied) as to the accuracy or fitnessfor a particular purpose of the information or advice contained herein. The publisher wishes to make it clearthat any views or opinions expressed in this book by individual authors or contributors are their personal viewsand opinions and do not necessarily reflect the views/opinions of the publisher. Any information or guidancecontained in this book is intended for use solely by medical professionals strictly as a supplement to the medicalprofessional’s own judgement, knowledge of the patient’s medical history, relevant manufacturer’s instructionsand the appropriate best practice guidelines. Because of the rapid advances in medical science, any informationor advice on dosages, procedures, or diagnoses should be independently verified. This book does not indicatewhether a particular treatment is appropriate or suitable for a particular individual. Ultimately it is the soleresponsibility of the medical professional to make his or her own professional judgements, so as appropriately toadvise and treat patients. Save for death or personal injury caused by the publisher’s negligence and to the fullestextent otherwise permitted by law, neither the publisher nor any person engaged or employed by the publishershall be responsible or liable for any loss, injury or damage caused to any person or property arising in any wayfrom the use of this book.

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Preface

This book is based primarily on courses that I taught on the basic principles of sterile dosageformulation, packaging, manufacturing, and quality control and assurance over a span of35 years. I have basically added written text to the slides that were presented in my courses. Soany reader who has participated in one of these courses will likely recognize some of the figuresand tables.

This book is written, like the course presented, for the person who either is new to thesterile product field or has some experience, but needs a good refresher tutorial. Although thebasics are presented, deeper concepts and principles are given as appropriate. This book isintended to be a helpful resource for individuals working directly and indirectly with steriledosage forms, be it research, product development (formulation, package, process, analytical),manufacturing, engineering, validation, quality control, quality assurance, regulatory, supplychain, purchasing, scheduling, project management, and any other area that deals with sterileproducts. This book also is intended to be a reference text for educational courses taught inpharmacy schools or continuing education programs. I have written the book with the intent toremain relevant for the indefinite future even though new technologies and new applicationsof 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 withrespect to numbers of drug products in clinical study and on the marketplace. All these advanceshave expanded the need for people to be educated and trained in the field of parenteral scienceand technology. However, such education and training still does not occur to much extent inuniversity education. Such education and training occur “on the job” via both internal andexternal courses.

This book is designed to serve as an educational resource for the pharmaceutical andbiopharmaceutical industry providing basic knowledge and principles in four main areas ofparenteral science and technology:

1. Product development, including formulation, package, and process development(chap. 2–11)

2. Manufacturing, including basic teaching on all the primary unit operations involved inpreparing 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 theclinical 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. Approachestraditionally used to overcome solubility and stability limitations have been emphasized. Spe-cific formulation components such as vehicles, solubilizers, buffers, antioxidants and chelatingagents, cryo- and lyoprotectants, tonicity agents, antimicrobial preservatives, and suspendingand emulsifying agents have been covered in good detail. Some coverage of long-acting drugdelivery 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 learnhow to approach formulation problem solving.


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 aspackaging 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, barriertechnology, labeling and secondary packaging, and some discussion of manufacturing advances.

The area of quality and regulatory includes chapters on good manufacturing practice, thephilosophy of quality as it relates to the sterile dosage form, specific quality control tests uniqueto sterile products, and some coverage of stability testing.

The final area covered is clinical aspect, general discussion of the use of the injectabledosage form in the clinical setting, advantages and disadvantages of sterile products, hazardsof 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 orreview article publications, some with coauthors who I have acknowledged and obtained theirpermission. All in all, this book represents more than 35 years of my teachings, writings, andexperience in the sterile product science and technology world. Of course, a singular perspectivehas its limitations compared with a book that has multiple authors. However, this book doeshave the advantage of consistency of writing style and the ultimate goal of each chapter beingpractical to the reader.

Just like I always stated when starting every one of my courses, may you learn as muchas possible while at the same time having some fun while reading/studying this book.


Acknowledgments

Since I state that this book represents 35 years of my experience working in the sterile productfield, I need to acknowledge those who influenced me the most to remain active in this fieldall these years. Dr. Gerald Hecht and Dr. Robert Roehrs hired me to join Alcon in 1974 withouthaving 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 teachingand influence of Dr. Kenneth Avis who for decades was considered the world’s leading expertin parenterals. Dr. Joseph Robinson was an influential leader to me primarily through ourinteractions on the former Journal of Parenteral Science and Technology board plus his naturalmentoring skills. Dr. Patrick DeLuca kept me involved in teaching sterile products after joiningEli Lilly by asking me to help him teach the Center for Professional Advancement sterile productscourse that after nearly 30 years I am still teaching. Dr. Steven Nail has been a 30-year colleagueand very close friend, plus a coworker these past few years, who has served as a scientific rolemodel for me. Other mentors over these years, scientists whose work I have admired, includeDr. Michael Pikal, Dr. John Carpenter, Dr. Eddie Massey, Dr. Alan Fites, Mr. Bob Robison, andDr. Lee Kirsch. There are many other scientists, too many to mention, who also have influencedme through their intelligence, creativity, and enthusiasm for the pharmaceutical sciences.

I thank those who helped me write several chapters in this book including Dr. MichaelDeFelippis 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 towrite 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 whodid a lot of the “leg work” helping to obtain reproduction approvals. I thank present andpast Baxter executives (Alisa Wright, Lee Karras, Ted Roseman, and Ken Burhop) who haveencouraged me to write, even admittedly sometimes on company time. I also appreciate myBaxter Bloomington site head, Mr. Camil Chamoun, for his encouragement and support plusallowing 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 sotrue in my case as I express my love and respect for my wife and best friend, Mary (Midge)Akers.


Contents

Preface . . . . vAcknowledgments . . . . 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


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 historyof 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 orwithout a needle), because they are inactivated in the gastrointestinal tract when given bymouth. 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. Aprimary 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 becauseof bioavailability and stability reasons. Since human insulin became the first biotechnologydrug approved by the Food and Drug Administration (FDA) in 1982, over 100 drug products ofbiotechnological origin have been approved and hundreds more will be approved in the yearsahead. Most biotechnology drug products are administered only by the parenteral route. Scienceis advancing to a time when it is likely that some of these drugs can or will be administered byother routes, primarily pulmonary and perhaps someday even orally, but the mainstay route ofadministration for these biopharmaceutical drugs will be by injection.

Any statistic given at the time of writing this section will quickly be outdated by the timethis book is printed and will continually need to be updated. However, it is safe to state that thenumber of injectable products being developed, being studied in the clinic, being approved forcommercial use, and being administered to humans and animals will significantly increase in theyears to come. Perhaps by 2020, the market share of sterile drug products will be approximatelythe same as that for oral solid dosage forms1.

This chapter will address some of the basic questions about the sterile dosage form andthe parenteral route of administration.

Various definitions and end uses of sterile products will be discussed throughout thisbook. This book will also address many aspects of formulation development of these dosageforms, how they are manufactured, how they are packaged, how they are tested and what arethe acceptable conditions during manufacture, and the uses that assure these unique productsmaintain 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 usedinterchangeably. Sterile dosage forms encompass parenteral/injectable dosage forms as well asother sterile products such as topical ophthalmic products, irrigating solutions, wound-healingproducts, 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 biologicalcontamination.

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 themarketplace, either commercial or clinical. Perhaps some day manufacturing procedures andin-process microbiological analysis will guarantee that each and every unit of sterile productwill 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); TuftsCenter for the Study of Drug Development (http://csdd.tufts.edu); Onesource.com; EvaluatePharma.com;IMS; and Datamonitor, to name a few.


2 STERILE DRUG PRODUCTS: FORMULATION, PACKAGING, MANUFACTURING, AND QUALITY

sterile products are produced where the finished product is not terminally sterilized, but ratheris aseptically processed. The difference in sterility assurance is far greater (generally at least3 logs) for terminally sterilized products compared to aseptically processed products. This doesnot mean that aseptically processed products are frequently contaminated; rather it meansthat aseptically processed products cannot be validated to the same level of sterility assurancecompared to terminally sterilized products. Sterility assurance is covered primarily in chapter13 while sterilization is covered in chapters 17 and 18 and aseptic processing is covered inchapter 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 mucousmembranes is to inject a pharmaceutical product directly into the body. Parenteral (the authorprefers the term “sterile”) products must be exceptionally pure and free from physical, chem-ical, and biological contaminants (microorganisms, endotoxins, particles). These requirementsplace 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 andother health care professionals to practice good aseptic practices (GAPs) in dispensing them foradministration to patients.

Injections usually are accomplished using needles, but newer technology avoids the useof needles or use of extremely small diameter needles (covered in chap. 4). As stated already, notall sterile dosage forms are administered by injection. Sterile products that are not parenteral orinjectable products include the following:� Topical ophthalmic medications� Topical wound healing medications� Solutions for irrigation� 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 ofsterile product terms, not intended to be comprehensive, is given in Table 1-1.

The United States Pharmacopeia (USP)2 contains several hundred monographs on steriledrugs or diluent preparations. Most products of biotechnology origin are not included becauseof confidentiality reasons. Some interesting statistics gathered after analyses of these USP mono-graphs are as follows:� About 22% are solid preparations that require solution constitution prior to use.� About 9% are diluent preparations, both small and large volume.� About 10% are radioisotope diagnostic preparations.

Sterile drug products are relatively unstable and are generally highly potent drugsthat require strict control of their administration to the patient. Overcoming solubilityand stability issues and achieving and maintaining sterility and other purity requirementspresent great challenges to those developing, manufacturing, and administering sterile drugproducts.

In this book, the teaching of the principles involved in the product development, productmanufacture, and quality control of medicines delivered by the parenteral route will continue tobe an important and relevant subject. This book is aimed to provide basic principles and practicalapplications of the formulation, packaging manufacture, and quality control of injectable dosageforms; in fact, all sterile dosage forms.

HISTORY OF THE STERILE DOSAGE FORMAvis 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 aboutclinical 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).


INTRODUCTION, SCOPE, AND HISTORY OF STERILE PRODUCTS 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 of0.2 � retains all particles ≥0.2 �.

Action Level—An established microbial or airborne particle level that, when exceeded, should triggerappropriate investigation and corrective action based on the investigation.

Air Lock—A small area with interlocked doors, constructed to maintain air pressure control between adjoiningrooms. Used to stage and disinfect large equipment prior to transfer from lesser-controlled room tohigher-controlled room.

Alert Level—An established microbial or airborne particle level giving early warning of potential drift fromnormal operating conditions, and which triggers appropriate scrutiny and follow-up to address the potentialproblem. 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. Alsoreferred as ampul, ampoule, carpule (French).

Antimicrobial Preservative—Solutes such as phenol, meta-cresol, benzyl alcohol, and the parabens thatprevent the growth of microorganisms. Must be present in multiple dose parenterals.

Antioxidants—Solutes that minimize or prevent drug oxidation. Examples include sodium bisulfite, ascorbicacid, 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 mostcommon means of terminally sterilizing parenteral products.

Barrier—A system having a physical partition between the sterile area (ISO 5) and the nonsterile surroundingarea. A barrier is differentiated from an isolator in that the barrier can exchange air from the fill zone to thesurrounding sanitized area where personnel are located, whereas an isolator cannot exchange air from the fillzone 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. Alsocalled 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 thesterilization cycle efficacy of a physical or chemical process. The specific microorganisms are the mostresistant to the particular sterilization process.

Bubble Point—Used in filter integrity testing; the pressure where a gas will pass through a wetted membranefilter. 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/orsolubility.

Chelating Agents—Solutes that complex metal ions in solution, preventing such metals from forming insolublecomplexes 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 nomore than X particles per cubic foot ≥ 0.5 �m.

Clean Room—A room designed, maintained, and controlled to prevent particle and microbiologicalcontamination of drug products. Such a room is assigned and reproducibly meets an appropriate aircleanliness classification.

Colony Forming Unit (CFU)—A microbiological term that describes the formation of a single macroscopiccolony 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 arubber 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—Time in minutes (or dose for radiation sterilization) of exposure at a given temperature that causes aone-log or 90% reduction in the population of specific microorganisms.

Disinfection—Process by which surface bioburden is reduced to a safe level or eliminated. Some disinfectionagents are effective only against vegetative microorganisms.

Endotoxin—Extracellular pyrogenic compounds.HEPA—High Efficiency Particulate Air filters, capable of removing 99.97% of all particles 0.3 � and higher.

(continued)



Table 1-1 Glossary of Terms Related to Parenteral Drug Technology (Continued)

Isolator—A decontaminated unit, supplied with Class 100 (ISO 5) or higher air quality that providesuncompromised, continuous isolation of its interior from the external environment. Isolators can be closed oropen.Closed—exclude external contamination from the isolator’s interior by accomplishing material transfer

via aseptic connection to auxiliary equipment, rather than by use of openings to the surroundingenvironment.

Open—allow for continuous or semicontinuous ingress and/or egress of materials during operations throughone or more openings. Openings are engineered, using continuous overpressure, to exclude the entry ofexternal contamination into the isolator.

Laminar Flow—An airflow moving in a single direction and in parallel layers at constant velocity from thebeginning to the end of a straight line vector.

Lyophilization—The removal of water or other solvent from a frozen solution through a process of sublimation(solid conversion to a vapor) caused by combination of temperature and pressure differentials. Also calledfreeze-drying.

Media Fill—Microbiological evaluation of an aseptic process by the use of growth media processed in a mannersimilar to the processing of the product and with the same container/closure system being used.

Micron (�)—One millionth of a meter. Also referred to as micrometer (�m).Needle Gauge—Either the internal (ID) or external (OD) diameter of a needle. The larger the gauge the smaller

the diameters. For example, a 21-G needle has an ID of 510 � and an OD of 800 �. A 24-G needle has an IDof 300 � and an OD of 550 �. An 18-G needle has an ID of 840 � and OD of 1,250 �.

Nominal Rating—The size of particles, which are retained at certain percentages. A 0.2 � nominal membranefilter indicates that a certain percentage of particles 0.2 � and higher are retained on the filter.

Overkill Sterilization Process—A process that is sufficient to provide at least a 12-log reduction of a microbialpopulation having a minimum D-value of 1 minute.

Parenteral—Literally, to avoid the gastrointestinal tract. Practically, the administration of a drug product that isnot given by mouth, skin, nose, or rectal/vaginal. Parenteral conveys the requirement for freedom frommicrobiological contamination (sterile), freedom from pyrogens, and freedom from foreign particulate matter.

Pyrogen—Fever producing substances originating from microbial growth and death.Reverse Osmosis—A process used to produce water for injection whereby pressure is used to force water

through a semipermeable membrane where the solute content (ions, microbes, foreign matter) of the solutionis retained on the filter while the solvent (pure water) passes through.

Sterile—The complete lack of living (viable) microbial life.Sterility—An acceptably high level of probability that a product processed in an aseptic system does not contain

viable microorganisms.Sterility Assurance Level—The probability of microbial contamination. A SAL of 10−6 means that there is a

probability of one in one million that an article is contaminated. Also called probability of nonsterility or sterilityconfidence level.

Surface Active Agents—Solutes that locate at the surface of water and air, water and oil, and/or water andsolid to reduce the interfacial tension at the surface and enable substances to come together in a stable way.Examples include polysorbate 80 and sodium lauryl sulfate.

Terminal Sterilization—A process used to produce sterility in a final product contained in its final packagingsystem.

Tonicity Agents—Solutes used to render a solution isotonic, meaning similar in osmotic pressure to the osmoticpressure of biological cells. Sodium chloride and mannitol are examples of tonicity agents.

ULPA—Ultra-Low Penetration Air filter with minimum 0.3 �m particle retaining efficiency of 99.999%.Validation—The scientific study of a process to prove that the process is doing what it is supposed to do and

that the process is under control. Establishing documented evidence that provides a high degree of assurancethat a specific process will consistently produce a product meeting its predetermined specifications and qualityattributes.

Worst Case—A set of conditions encompassing upper and lower processing limits and circumstances, includingthose within standard operating procedures that pose the greatest chance of process or product failure.

add the author’s own research into this area. Table 1-2 summarizes the highlights of the historyof the development and application of inventions and advances in sterile drug manufacturingand therapy.

In 1656, the first experimental injection was performed on dogs by Christopher Wren, thearchitect of St. Paul’s cathedral in London. The first primary packaging system was an animal(goose) bladder, and the first type of needle used was the quill of a feather. In 1662, the firstrecorded injection into man was performed by J. D. Major and Johannes Elsholtz, as depicted



Table 1-2 Summary of the History of Sterile Drug Technology

1656 First experimental injection by C. Wren in dogs (first container was an animal bladder and first needlewas a feather quill)

1662 First injection (opium) in man1796 E. Jenner used intradermal injections of cowpox virus to inoculate children against smallpox1831 Introduction of IV therapy treatment of cholera with salt, bicarbonate, water1855 First use of hypodermic syringe for subcutaneous injection1860s Pasteur/Lister/Koch all contributed to discovery of germ theory of disease, concerns for sterility and

development of sterilization methods (but not accepted for decades)1884 Use of first autoclave for sterilization1890s Crude filters (asbestos) used for filtering drugs1923 Florence Siebert discovered cause of pyrogenic reactions1938 Food, Drug, Cosmetic Act passed by Congress (after sulfanilamide disaster). Ethylene oxide

sterilization introduced1940s Penicillin started being used1941 Freeze-drying introduced1961 HEPA filters, laminar airflow introduced in pharmaceutical industry1963 Clean room standards introduced, FDA first published proposed GMP regulations1965 Parenteral nutrition introduced1970s Emergence of biotechnology, LAL test for endotoxins1980s Introduction of controlled IV devices, controlled delivery, home health care First drug product

(Humulin R©) from recombinant DNA technology approved by FDA1987 First publication of FDA Aseptic Processing Guidelines and Guidelines for Process Validation1990s Barrier isolator technology, aseptic process validation, process validation, pre-approval inspections,

biotechnology growth1992 The International Conference on Harmonisation (ICH) of Technical Requirements for Registration of

Pharmaceuticals for Human Use Established1996 European Union published Guidance on Manufacture of the Finished Dosage Form issued1997 First human monoclonal antibody approved (Rituxan R©, rituximab to treat cancer)2000s Monoclonal antibodies, impact of genomics and proteomics on new parenteral drug therapy, Quality by

Design, disposable technologies2004 FDA publishes revision to Aseptic Processing Guidelines.2010 Possibilities include vast new numbers of biosimilar products approved, more advances in aseptic

processing to the point that parametric release of products produced by aseptic processing can bedone, advances in on-line 100% measurement of quality parameters, oral delivery of proteins,complete automation of filling, stoppering and sealing processes, most product manufacturingoutsourced; the possibilities are as many as can be imagined.

in Figure 1-1. The drug injected was opium. While the poor human receiving this injectionmay have had his pain alleviated, he likely was going to die, eventually from microbial andpyrogenic contamination introduced using this crude means of injection. Other drugs injectedinto humans during those early days were jalap resins, arsenic, snail water, and purging agents.It is improbable that the initial pioneers of injectable therapy had much appreciation about theneeds for cleanliness and purity when injecting these medications. After 1662, injecting drugsolutions into humans was not commonly practiced until late in the 18th century.

Intravenous (IV) therapy was first applied around 1831 when cholera was treated by theIV injection of a solution containing sodium chloride and sodium bicarbonate in water. Normalsaline was used by Thom Latts to treat diarrhea in cholera patients using intravenous infusions.Intravenous feeding was first tried in 1843, when Claude Bernard used sugar solutions, milk,and egg whites to feed animals. By the end of the 19th century, the intravenous route ofadministration was a widely accepted practice. Injections of emulsified fat in humans werefirst accomplished by Yamakawa in 1920 although, not surprisingly, major problems existed informulating and stabilizing fatty emulsions.

It is conjecture who really was the first person to invent and use a syringe. According tomedhelpnet.com, a French surgeon, Charles Gabriel Pravaz (Fig. 1-2), and a Scottish physician,Alexander Wood, independently invented the hypodermic syringe in the mid-1850s. Otherreferences credit G. V. LaFargue for inventing the first syringe used for subcutaneous injectionsin 1836 with wood, using it to inject morphine. Charles Hunter first used the word “hypodermic”



Figure 1-1 Depiction of early intravenous injection. Source: Courtesy of United States National Library ofMedicine, Bethesda, MD.

Figure 1-2 Earliest syringes. Source: From Ref. 3.



after noting that this route of injection resulted in systemic absorption. Robert Koch in 1888developed the first syringe that could be sterilized and Karl Schneider built the first all-glasssyringe in 1896. Becton, Dickinson and Company created the first mass-produced disposableglass syringe and needle, developed for Dr. Jonas Salk’s mass administration of one millionAmerican children with the new Salk polio vaccine.

Like many other critical technologies in sterile product manufacturing (e.g., freeze drying,rubber closures, clean rooms), the sterile, prefilled, disposable syringe was developed duringWorld War II. A precursor to the syringe was the Tubex cartridge system developed by Wyeth(4). The injection solution was filled into a glass cartridge having a needle already permanentlyattached to the cartridge. The prefilled cartridge was then placed in a stainless steel administra-tion device.

Early practice of administering drugs by injection occurred without knowledge of theneed for solution sterility plus no one appreciated what caused pain and local irritation whileinjecting solutions subcutaneously. It was not until around 1880 when a pharmacist namedL. Wolff first recognized the role of isotonicity in minimizing pain and irritation when introduc-ing drug solutions to the body. Intramuscular (IM) injections were first performed by AlfredLuton, who believed that this route would be less painful and irritating for acidic, irritating, orslowly absorbed drugs.

Pasteur, Lister, and Koch all contributed to discovery of the germ theory of disease,concerns for sterility, use of aseptic techniques, and development of sterilization methods duringthe 1860s. However, their concerns for the need to sterilize and maintain sterility of injectionswere not accepted or implemented for decades. It was not until 1884 that the autoclave wasintroduced by Charles Chamberland for sterilization purposes. Gaseous sterilization was firstdiscovered using formaldehyde in 1859 and ethylene oxide in 1944. It was also in the early 1940sthat radiation, beginning with ultraviolet light, was used as a means of sterilization.

Filtration methods began in the mid-1850s when Fick described “ultrafilter” membraneson ceramic thimbles by dipping them in a solution of nitrocellulose in ether. Crude filters,using asbestos, began to be used in the 1890s. Zsigmondy and Bachmann in 1918 coined theterm “membrane filter.” Beckhold developed a method to determine the pore size of membranefilters, the method we know now as the “bubble point” method.

Pyrogenic reactions were still commonplace until Florence Siebert in 1923 discovered thecause of these reactions. She was the first person to suggest that fever reactions after injectionswere microbial in origin. She also proposed that these microbial derivatives were nonliving,nonproteinaceous, and could not be eliminated by sterilization methods. Also, she developedthe rabbit pyrogen test, used for decades for the detection of pyrogenic contamination, and stilla USP method, although most products today are tested for bacterial endotoxin by the LimulusAmebocyte Lysate (LAL) test discovered by the Johns Hopkins researchers, Levin and Bangin 1964.

Intravenous nutrition using hyperalimentation solutions started in 1937 when W. C. Roseidentified amino acids as necessary for the growth and development of rats. This mode oftherapy was established first in dogs and then in humans (1967) by S. J. Dudrick who developeda safe method for long-term catheterization of the subclavian vein that permitted these highlyconcentrated and hyperosmolar solutions to be administered without damaging venous vessels.

Although the first book to be used as a standard for national use, the United States Phar-macopeia, was published in 1820, it was not until the fifth edition of the National Formularyin 1926 that the first parenteral monographs were accepted. In 1938, the Food, Drug, Cosmetic(FD&C) Act was passed by Congress after the sulfanilamide disaster where 107 people includ-ing many children died after ingesting a liquid form of this drug dissolved in diethylene glycol.This Act also established the Food and Drug Administration to enforce the Act and requiredmanufacturers to prove to the government that drug products introduced into the market-place were safe. The legal basis for cGMPs and other FDA regulations are related to the 1938FD&C Act.

Penicillin started being used in the 1940s, further opening the door for parenteral therapyas a means to save thousands of lives. More companies started to develop parenteral drugs.Because so many injectable drugs were unstable in solution and because of the need to provideblood in a stable form during World War II, freeze-drying was introduced in 1942.



Table 1-3 Injectable Drugs—Therapeutic Classes and Examples

Drug class Some examples of brand namesa

Antiemetic agents Anzemet, Kytril, ZofranAnti-infective agents AmBisome, Vancomycin, Zyvox All Cephalosporin Injectables, Nebcin,

Garamycin, etc.Antiparkinsons agents ApokynAntipsoriatic agents Amevive, Enbrel, RaptivaAntipsychotic agents Geodon, Risperdal, ConstaAntiretroviral agents FuzeonAsthma agents XolairBisphosphonates Aredia, ZometaCardiovascular agents DobutamineChelating agents DesferalCoagulation factors Advate, Alphanate, AlphaNine-SC, Autoplex T, Bebulin VH, BeneFIX, Feiba

VH, Helixate-FS, Hemofil M, Humate-P, Hyate: C, Koate0DVI, KogenateFS, Monarc-M, Monoclate-P, Mononine, NovoSeven, Profilnine SD,Proplex T, Recombinate, ReFacto

Colony-stimulating factors Leukine, Neulasta, NeupogenContraceptive agents Depo-ProveraDystonia agents Botox, MyoblocEndocrine and metabolic agents Humulin, Novolin, Sandostatin, Sandostatin LAR, ThyrogenEnzyme replacement therapy Aldurazyme, Aralast, Cerezyme, Fabrazyme, Prolastin, ZemairaGlucocortoids Solu-MedrolGonadotropin-releasing Eligard, Lupron, Plenaxis,Hormone analogues Trelstar Depot/LA ZoladexGrowth hormone agents Genotropin, Humatrope, Norditropin, Nutropin, Nutropin AQ/Depot, Saizen,

Serostim, Zorbtive,Growth hormone receptor Somavert Antagonist:H2 antagonists Pepcid, Tagamet, ZantacHepatitis C agents Infergen, Intron-A, Pegasys, Peg-Intron, Rebetron, Roferon-AHormone deficiency agents Deltestryl, Delestrogen, Depo-Estradiol(androgens and estrogens) Depo-TestrosteroneHyaluronic acid derivatives Hyalgan, Orthovisc, Supartz, SynviscImmune globulins Carimune NF, Flebogamma, Gamimune N S/D, Gammagard S/D, Gammar

P.I.V., Gamunex, Iveegam EN, Octagam, Panglobulin NF, Polygam S/D,RhoGAM, Rhophylac, Venoglobulin-S, WinRho SDF

Immunizations PrevnarInfertility agents Antagon, Cetrotide, Chorex, Fertinex, Follistim AQ, Gonal-F, Novarel,

Pergonal, Pregnyl, Profasi, RepronexInterferons Actimmune, Alferon-NMigraine agents D.H.E. 45, ImitrexMultiple sclerosis Avonex, Betaseron, Copaxone, Novantrone, RebifOphthalmic agents Macugen, VisudyneOsteoporosis agents Forteo, MiacalcinPituitary hormone DDAVPRecombinant human

erythropoietinAranesp, Epogen, Procrit

Respiratory syncytial virusprophylaxis agents

Synagis

Rheumatoid arthritis agents Enbrel, Humira, Kineret, Methotrexate, Myochrysine, RemicadeSexual dysfunction agents CaverjectThrombocytopenia agents NeumegaChemotherapeutic agents Abraxane, Adriamycin, Adrucil, Alimta, Alkeran, Avastin, BiCNU, Blenoxane,

Busulfex, Campath, Camptosar, Cerubidine, Clolar, Cosmegen,Cytosar-U, Cytoxan/Neosar, DaunoXome, DepoCyt, Doxil, DTIC-Dome,Ellence, Eloxatin, Elspar, Erbitux, Fludara, FUDR, Gemzar, Herceptin,Hycamtin, Idamycin, Ifex, Leustatin, Lupron, Methotrexate, Mustargen,Mutamycin, Mylotarg, Navelbine, Nipent, Novantrone, Oncaspar, Ontak,Paraplatin, Platinol-AQ, Plenaxis, Proleukin, Rituxan, Taxol, Taxotere,TheraCys, TICE BCG, Trelstar Depot/LA, Trisenox, Valstar, Vantas,Velcade, VePesid/Toposar, Viadur, Vidaza, Vinblastine, Vincasar, Vumon,Zanosar, Zoladex

Chemotherapeutic adjunctive Anzemet, Aredia, Ativan, Ethyol,Agents (not already listed) Kepivance, Kytril, Osmitrol, Mesnex, Zinecard

aAll brand name drug products are registered ( R©).



Clean room technologies, including the use of laminar air flow units, high efficiencyparticulate air (HEPA) filters, and room classification for particles were not discovered until theearly 1950s to the early 1960s. Original clean rooms were used by the United States BiologicalLaboratories at Fort Detrick, MD, during the 1950s. The HEPA filter was first described in theearly 1940s, but not applied to laminar airflow technology until W. J. Whitfield combined HEPAfilters and laminar airflow units in 1961. The United States government first proposed cleanroom classifications in 1962 (Federal Standard 209).

It was also in 1962 that authority was given to the FDA to establish cGMPs, Parts 210 and211 (21 CFR Parts 210 and 211), issued under section 501(a)(2)(B) of the Federal Food, Drug,and Cosmetic Act (21 U.S.C. 351(a)(2)(B) with the first proposed cGMP regulations publishedin 1963. In 1976 the FDA proposed to revise and expand these regulations and a final rule bythe FDA commissioner was published in the Federal Register on September 29, 1978. Althoughsome changes have occurred since 1978 (e.g., April 2008 changes that included requirement forvalidation of depyrogenation of sterile containers)3, and likely minor changes will continue tooccur, the great majority of GMP requirements finalized in 1978 remain enforced within thepharmaceutical industry today.

As air classifications became standard for clean rooms, developments in the equipmentused in sterile product manufacture also occurred in rapid fashion. Stainless steel and itsfabrication into tanks, pipes, and other equipment was refined to provide heliarc weldingof joints and fittings as well as the electropolishing of surfaces to reduce potential productreactivity. Clean-in-place and sterilize-in-place technologies were developed in the 1970s thatallowed larger equipment to be cleaned and sterilized without dismantling; it also greatlyreduced the variability in manual cleaning.

Biotechnology emerged in the 1970s, resulting in significant growth in the development,manufacture, and use of parenteral drugs. Biotechnology, in turn, gave rise to the significantgrowth of controlled drug delivery systems, convenient delivery systems for home health care,monoclonal antibodies, and the advent of proteomics and genomics. To give one example,the monoclonal antibody market of commercial products is poised to double in number andestimated sales value from 2007 to 2012 (5).

It was also in the 1970s that FDA began to enforce the practice of process validation,starting with validation of sterilization processes. Today, validation of processes, methods, andcomputers are standard practices because validation practices are continuously being refinedand updated.

The 1990s witnessed the advent of barrier isolator technology, preapproval GMP inspec-tions, significant growth of biotechnology processes, and much increased focus and enforcementof aseptic process validation.

Advances will continue in the 21st century in the areas of parenteral drug targetingand controlled release, convenience packaging and delivery systems, aseptic processing, high-speed manufacturing, disposable technologies, rapid methods for chemical and microbiologicaltesting, and GMP regulatory requirements.

Table 1-3 presents a list of therapeutic classes of injectable drugs and some examples ofeach class. This list will grow not only in number but also in clinical significance and marketshare. Injectable or parenteral drug science and technology is a wonderful and exciting fieldof study and endeavor in which to be involved and engaged. It is the author’s hope that thereaders of this book will readily see the truth of this belief.

REFERENCES1. Avis KE. The parenteral dosage form and its historical development. In: Avis KE, Lieberman HA,

Lachman L, eds. Pharmaceutical Dosage Forms: Parenteral Medications. Vol 1. 2nd ed. New York:Marcel Dekker, 1992:1–16.

2. Turco SJ, King RE. Sterile Dosage Forms: Their Preparation and Clinical Application. 3rd ed. Philadel-phia, PA: Lea & Febiger, 1978.

3. http://www.general-anesthesia.com/people/charles-pravaz.html. [email protected][David Pearce, BLTC Research, Brighton, United Kingdom, 2004, last updated 2008].

3 Federal Register /Vol. 73, No. 174 /Monday, September 8, 2008 /Rules and Regulations, starting at page 51919.



4. Turco S, King RE. Sterile Dosage Forms: Their Preparation and Clinical Application. 3rd ed. Philadel-phia: Lea & Febiger, 1987:267–269.

5. Monoclonal Therapeutics and Companion Diagnostic Products, Report Code BIO016G, 2008,http://www.bccresearch.com/report/BIO016G.html.

BIBLIOGRAPHYAllen LV, Popovich NG, Ansel HC, eds. Ansel’s Pharmaceutical Dosage Forms and Delivery Systems.

8th ed. Philadelphia, PA: Lippincott Williams & Wilkins, 2005.Ahern TJ, Manning MC, eds. Stability of Protein Pharmaceuticals, Part A and Part B books. New York:

Plenum, 1992.Akers MJ. Antioxidants in pharmaceutical products. J Parenter Sci Technol 1982; 36:222–228.Akers MJ. Considerations in selecting antimicrobial preservative agents for parenteral product develop-

ment. Pharm Tech 1984; 8:36–46.Akers MJ, Fites AL, Robison RL. Formulation design and development of parenteral suspensions. J Parenter

Sci Technol 1987; 41:88–96.Akers MJ. Parenterals: Small volume. In: Swarbrick J and Boylan J, eds. Encyclopedia of Pharmaceutical

Technology. New York: Dekker, 1995.Akers MJ, DeFelippis MR. Formulation of protein dosage forms: Solutions. In: Hovgaard L, Frokjaer S,

eds. Pharmaceutical Formulation Development of Peptides and Proteins. London, UK: Taylor & Francis,2000.

Akers MJ. Excipient-drug interactions in parenteral formulations. J Pharm Sci 2002; 91:2283–2297.Akers MJ. Parenterals. In: Remington’s Pharmaceutical Sciences. 21st ed. Philadelphia, PA: Lippincott

Williams & Wilkins, 2005:802–836.Bontempo J, ed. Development of Parenteral Biopharmaceutical Dosage Forms. New York: Marcel Dekker,

1997.Boylan JC, Fites AL, Nail SL. Parenteral Products. In: Banker GS and Rhodes CT, eds. Modern Pharmaceu-

tics. 3rd ed. New York: Dekker, 1995:chap 12.Carpenter JF, Crowe JH. The mechanism of cryoprotection of proteins by solutes. Cryobiology 1988; 25:

244–250.Carpenter JF, Pikal MJ, Chang BS, et al. Rational design of stable lyophilized protein formulations: Some

practical advice. Pharm Res 1997; 14:969–975.Carpenter JF, Chang BS, Garzon-Rodriquez W, et al. Rational design of stable lyophilized protein for-

mulations: Theory and Practice. In: Carpenter JF, Manning MC, eds. Rational Design of Stable ProteinFormulations. New York: Kluwer Academic, 2002.

DeFelippis MR, Akers MJ. Formulation, manufacture, and control of protein suspension dosage forms.In: Hovgaard L, Frokjaer S, eds. Pharmaceutical Formulation Development of Peptides and Proteins.London, UK: Taylor & Francis, 2000.

ICH: Q8(R2): Pharmaceutical Development, http://www.fda.gov/cder/guidance/index.htm. AccessedAugust 2009.

Nail SL, Akers MJ, eds. Development and Manufacture of Protein Pharmaceuticals. New York: Kluwers-Plenum, 2002.

Nema S, Ludwig J, eds. Pharmaceutical Dosage Forms: Parenteral Medications. 3rd ed. 3 vols. New York,NY: Informa Healthcare, 2010.

Pearlman R, Wang YJ, eds. Formulation, characterization, and stability of protein drugs, Vol 9.In: Borchardt R, series ed. Pharmaceutical Biotechnology, New York: Plenum, 1995.

Sinko PJ, ed. Martin’s Physical Pharmacy and Pharmaceutical Sciences. 5th ed. Philadelphia, PA: LippincottWilliams & Wilkins, 2005.

Tonnesen HH, ed. Photostability of Drugs and Drug Formulations. Boca Raton, FL: CRC Press, 2004.Wang YJ, Pearlman R, eds. Stability and characterization of protein and peptide drugs. Vol 5.

In: Borchardt R, series ed. Pharmaceutical Biotechnology. New York: Plenum, 1993.


2 Characteristics of sterile dosage forms

Sterile dosage forms are unique pharmaceutical dosage forms largely because of their seven pri-mary characteristics that will be featured in this chapter (Table 2-1). Also, specific characteristicsof sterile dosage forms that are discussed in the United States Pharmacopeia (USP), primarilygeneral chapter will be featured.

SEVEN PRIMARY CHARACTERISTICS OF STERILE DOSAGE FORMS

SafetySterile dosage forms, with some exceptions, are injected directly into the body and, thus, avoidthe body’s natural barriers for invasion of entities that could harm the body. Therefore, anycomponent of an injectable product must be proven safe at the quantitative level it is injected.Certainly, any substance, if injected in large quantities, can be unsafe.

With respect to safety, formulation of sterile dosage forms can be both easier and moredifficult compared to formulation of nonsterile dosage forms. This is because of safety consider-ations when selecting additives to combine with the active ingredient to overcome one or moreproblems related to drug solubility, stability, tonicity, and controlled or sustained delivery. If anyof these problems exist with a nonsterile dosage form, the formulation scientist has a plethora ofchoice with respect to additives safe to use for administration other than by injection. However,for overcoming these problems with sterile dosage forms, the requirement for safety prohibitsthe use of many additives that could be effective.

Under the Kefauver-Harris Amendments to the Federal Food, Drug, and Cosmetic Act,most pharmaceutical preparations are required to be tested for safety in animals. Because itis entirely possible for a parenteral product to pass the routine sterility test, pyrogen and/orendotoxin test, as well as the chemical analyses, and still cause unfavorable reactions wheninjected, a safety test in animals is essential, particularly for biological products, to provideadditional assurance that the product does not have unexpected toxic properties.

The FDA has published guidance for safety evaluation of pharmaceutical ingredients (1)that is periodically updated. Many general chapters of the USP also provide specific instruc-tions for safety evaluation of pharmaceutical excipients. Also, there exists the InternationalPharmaceutical Excipients Council (IPEC), a federation of three independent regional industryassociations headquartered in the United States (IPEC-Americas), Europe (IPEC Europe), andJapan (JPEC). The following is a quote from their Web site:

� Each association focuses its attention on the applicable law, regulations, science, and businesspractices of its region. The three associations work together on excipient safety and publichealth issues, in connection with international trade matters, and to achieve harmonizationof regulatory standards and pharmacopoeial monographs.

� Over 200 national and multinational excipient makers, producers, and companies, whichuse excipients in finished drug dosage forms are members of one or more of the three IPECregional units. Over 50 U.S. companies are IPEC members. (2)

SterilityObviously, sterility is what defines/differentiates a sterile product. Achieving and maintainingsterility are among the greatest challenges facing manufacturers of these dosage forms. Thereare many factors that contribute to achieving and maintaining sterility and these will be coveredin more detail in chapters 13, 17, 18, 21, and 23. Suffice to state at this point that the characteristicof sterility is achieved via valid sterilization procedures for all components during manufac-turing of the product, valid procedure for sterile (better term is aseptic) filtration, design andmaintenance of clean rooms meeting all requirements for preparing sterile products (discussed



Table 2-1 Seven Basic Characteristics of Sterile Product Dosage Forms

1. Safety (freedom from adverse toxicological concerns)2. Sterility (freedom from microbiological contamination)3. Nonpyrogenic (freedom from pyrogenic—endotoxin—contamination)4. Particle-free (freedom from visible particle contamination)5. Stability (chemical, physical, microbiological)6. Compatibility (formulation, package, other diluents)7. Tonicity (isotonic with biological fluids)

in chap. 14), validation of aseptic processes, training and application of good aseptic practices,use of antimicrobial preservatives for multiple-dose products, and valid testing for sterility ofthe product and maintenance of container/closure integrity.

Freedom from Pyrogenic ContaminationPyrogens are discussed extensively in chapters 13 and 28. Pyrogens are fever-producing entitiesoriginating from a variety of sources, primarily microbial. In sufficient amounts followinginjections, pyrogens can cause a variety of complications in the human body. Because of theadvent of the in-vitro test, Limulus Amebocyte Lysate (LAL), for the quantitative detection of themost ubiquitous type of pyrogen called bacterial endotoxins, all marketed injectable productsmust meet requirements for pyrogen (or endotoxin) limits.

To achieve freedom from pyrogenic contamination, like achieving and maintaining prod-uct sterility, many factors contribute toward this goal. Depyrogenation methods will be dis-cussed in chapter 13, which include cleaning validation, time limitations, validated depyrogena-tion cycles for glassware, validation of pyrogen/endotoxin removal from rubber closures andother items that depend on rinsing techniques, validated water systems, and use of endotoxin-free raw materials.

Freedom from Visible Particulate MatterMost aspects of particulate matter will be discussed in chapters 22 and 29. Visible particulatematter implicates product quality and perhaps safety. It definitely reflects the quality of opera-tions of the product manufacturer. Both ready-to-use solutions and reconstituted solutions areto be free from any evidence of visible particulate matter and must meet compendial specifica-tions for numbers of subvisible particles no greater than certain sizes, those particle sizes beingfor most compendia no greater or equal to 10 �m and no greater or equal to 25 �m.

Like other product characteristics, several factors contribute to the presence or absence offoreign particulate matter. These include valid cleaning methods of all equipment and packag-ing materials, valid solution filtration procedures, adequate control of production and testingenvironments, adequate training of personnel in manufacturing, testing and using sterile prod-uct solutions, and employment of required compendial testing procedures for detection of bothvisible and subvisible particulate matter.

StabilityAll dosage forms have stability requirements. All dosage forms are required to be stable underpredetermined manufacturing, packaging, storage, and usage conditions. Sterile dosage forms,like all other dosage forms, need to maintain both chemical and physical stability throughoutthe shelf-life of the product. The achievement of chemical and physical stability is the greatestchallenge of scientists responsible for developing sterile dosage forms. With the exception ofovercoming solubility challenges, often related to long-term physical stability, addressing andsolving stability problems occupies most of the time and effort of scientists in the product devel-opment process. With much more complicated chemical structures and vulnerabilities to envi-ronmental conditions (temperature, light, pH, shear, metal impurities, oxygen, etc.) stabilizationof therapeutic peptides and proteins offer enormous challenges. Achieving and maintainingchemical and physical stability starts with the active ingredient and how it is stored, shipped,and handled. Stability challenges continue with the compounding, mixing, filtration, filling,


CHARACTERISTICS OF STERILE DOSAGE FORMS 13

stoppering, and sealing of the product. So many injectable drugs are so unstable in solution thatthey must exist in the solid state so lyophilization processes and maintaining stability duringlyophilization offer lots of challenges to the development scientist. Maintaining stability in thefinal container/closure system, while being stored, shipped, and manipulated prior to beingadministered to people or animals, all present enormous challenges that must be overcome.

Sterile dosage forms also have one extra requirement related to stability and that is main-taining sterility as a function of stability. So, with sterile dosage forms, product stability encom-passes not only chemical and physical properties, but also includes microbiological stability (i.e.,maintenance of sterility) throughout the shelf-life and usage of the product. Stability aspects ofdosage forms are covered in chapters 8 through 11 and stability testing is discussed in chapter 24.

CompatibilityMost pharmaceutical dosage forms are consumed by patients without the patient or healthcare professional needing to do any manipulation with the dosage form prior to consumingit. While this is also true for many sterile dosage forms, there are also a significant numberof sterile dosage forms that must be manipulated prior to injection. For example, freeze-driedproducts are released by the manufacturer, but must be manipulated by the user and/or healthcare professional prior to administration. The product must be reconstituted by sterile dilution,withdrawn into a syringe, and, often, then combined with another solution, perhaps a largevolume infusion fluid, for administration. What all this means is that the sterile product must beshown to be compatible with diluents for reconstitution and diluents for infusion. Furthermore,many infusions contain more than one drug, so obviously the two or more drugs in the infusionsystem must be compatible.

IsotonicityBiological cells maintain a certain “tone”; that is a certain biological concentration of ions,molecules, and aggregated species that give cells specific properties, the most important phar-maceutically of which is its osmotic pressure. Osmotic pressure is a characteristic of semiper-meable cell membranes where osmotic pressure is the pressure where no water migrates acrossthe membrane. Osmosis is the phenomenon where solutes will diffuse from regions of high con-centration to regions of low concentration. So, if a formulation is injected that has an osmoticpressure less than that of biological cells, that is, the solution is hypotonic, the solvent from theinjection will move across the cell membranes and could cause these cells to burst. If the cells arered blood cells, this bursting effect is called hemolysis. Conversely, if the formulation injectedhas an osmotic pressure greater than that of biological cells, that is, the solution is hypertonic,the solvent or water from the cell interior will move outside the cell membranes and could causethese cells to shrink, for example, crenation.

Ideally, any injected formulation should be isotonic with biological cells to avoid thesepotential problems of cells bursting or shrinking. Large-volume intravenous injections andsmall-volume injections by all routes other than the intravenous route must be isotonic to avoidmajor problems such as pain, tissue irritation, and more serious physiological reactions. Small-volume intravenous injections, while desirable to be isotonic, do not absolutely have to beisotonic because small volumes do not damage an excessive number of red cells that cannot bereplaced readily.

It is well known that 0.9% sodium chloride solution and 5% dextrose solution are isotonicwith biological cells. Why the difference in isotonic concentrations between these two commonlarge-volume solutions? It has to do with the ability of the solute to dissociate into more thanone species. Dextrose is a nonelectrolyte that in solution exists as a single entity; therefore, theosmotic pressure of a nonelectrolyte solution is proportional to the concentration of the solute.Sodium chloride is an electrolyte in solution that dissociates into two ionic species. Thus, theosmotic pressure of a solution containing an electrolyte dissociating into two species would beat least twice that of a solution containing a nonelectrolyte. The fact that the concentration ofisotonic dextrose solution is over five times that of isotonic sodium chloride solution may beexplained by the fact that ionic species attract solvent molecules, thus holding solvent moleculesin solution and reducing their tendency to migrate across the cellular membrane. This, inturn, elevates osmotic pressure of the electrolytic solution such that a lower concentration of



electrolyte solute is required to exert that same osmotic pressure as a nonelectrolyte solution.More information about tonicity and formulation is covered in chapters 6 and 8. The UnitedStates Pharmacopeia contains general chapter that defines osmotic pressure, osmolalityand osmolarity, and measurement of osmolality.

CHARACTERISTICS OF STERILE DOSAGE FORMS FROMTHE UNITED STATES PHARMACOPEIAThe first general chapter of the USP is entitled “ INJECTIONS.” Within this section arethe following subcategories with the content under each subcategory summarized. Of course,wording of these characterizations might change over time so the reader must consult thecurrent edition of the USP for current wording.

IntroductionParenteral products are defined as preparations intended for injection through the skin orother external boundary tissue where the active ingredient is introduced directly into a bloodvessel, organ, tissue, or lesion. Parenteral products are to be prepared scrupulously by methodsdesigned to ensure that they meet Pharmacopeial requirements for and, where appropriate,contain inhibitors of the growth of microorganisms.

� Sterility� Pyrogens� Particulate Matter� Other Contaminants

NOMENCLATURE AND DEFINITIONSThere are five general types of parenteral preparations listed in the USP:

� [Drug] Injection: Liquid preparations that are drug substances or solutions thereof.� [Drug] for Injection: Dry solids that, upon the addition of suitable vehicles, yield solutions

conforming in all respects to the requirements of injections.� [Drug] Injectable Emulsion: Liquid preparations of drug substances dissolved or dispersed

in a suitable emulsion medium.� [Drug] Injectable Suspension: Liquid preparations of solids suspended in a suitable liquid

medium.� [Drug] for Injectable Suspension: Dry solids that, upon the addition of suitable vehicles,

yield preparations conforming in all respects to the requirements of Injectable Suspensions.

Definitions included in the USP are as follows:

� Pharmacy Bulk Package: A pharmacy bulk package is a single product containing a steriledrug injection, sterile drug for injection, or sterile drug injectable emulsion (i.e., suspensionscannot be contained in pharmacy bulk packages. A pharmacy bulk package contains manysingle doses of the active ingredient to be used for the preparation of admixtures for infu-sion, or, using a sterile transfer device, for filling empty sterile syringes. The closure of thebulk package shall be penetrated only once with a sterile device that will allow measureddispensing of the contents.

� Large- and Small-Volume Injections: The demarcation of volume differentiating a small-from large-volume injection is 100 mL. Any product 100 mL or less is a small-volumeinjection. The main purpose for differentiating large- from small-volume injections is themethod of sterilization. With perhaps a single exception for blood products, all large-volumeinjections must be terminally sterilized while most small-volume injections are not terminallysterilized.

� Biologics: This definition simply states that pharmacopeial definitions for sterile preparationsfor parenteral use do not apply to biologics because of their special nature and licensingrequirements. Biologic requirements are covered in USP general chapter.



IngredientsThree general types of ingredients discussed in this section of the USP are aqueous vehicles,other vehicles, and added substances.

Aqueous vehicles must meet the requirements of the Pyrogen Test or the BacterialEndotoxins Test whichever is specified. Water for injection is the vehicle unless theindividual monograph specifies another aqueous vehicle.

Other vehicles refer to fixed oils that must be of vegetable origin. Oils must meet severalcompendial requirements, including solid paraffin (under mineral oil); a saponification valuebetween 185 and 200 and an iodine value between 79 and 141 (fats and fixed oils ); andtests for unsaponifiable matter and free fatty acids. Saponification is the reaction of an ester witha metallic base and water to produce soap. It is also defined as the alkaline hydrolysis of oil orfat, or the neutralization of a fatty acid to form soap. Unsaponifiable matter is a substance thatis incapable of being saponified; that is, it cannot react with a basic substance to form soap.

Added substances are formulated into injectable products to increase stability or useful-ness, but must be harmless in the amounts administered and do not interfere with the therapeuticefficacy of the drug or responses to specific assays and tests. USP clearly states that no coloringagent may be added to a parenteral product. Any product with a volume of injection morethan 5 mL should not use added substances unless their inclusion is clearly justified and in safeconcentrations.

USP provides upper limits (unless higher limits are justified) for several specific additives:

Mercury-containing additives 0.01%Cationic surfactants 0.01%Chlorobutanol, cresol, phenol 0.5%Sulfurous acid salt or equivalent 0.2%

Injections intended for multiple-dose containers must contain an additive to prevent thegrowth of microorganisms, regardless of the method of sterilization. Three exceptions to this ruleare: (i) if there are different directions in the individual monograph; (ii) if the substance containsa radionuclide with a physical half-life of less than 24 hours; and (iii) if the active ingredientitself is antimicrobial. The antimicrobial preservative agent must meet the requirements ofAntimicrobial Effectiveness Testing and Antimicrobial Agents—Content .

LabelingInformation that is contained on a product label includes the following:� For liquid products: Percentage content of the drug or amount of drug in a specified volume.� For dry products: The amount of active ingredient.� The route of administration.� A statement of storage conditions and an expiration date.� The name and place of business of the manufacturer, packer, or distributor.� Identifying lot number—The lot number is capable of yielding the complete manufacturing

history of the specific package, including all manufacturing, filling, sterilizing, and labelingoperations.

If the formulation is not specified in the individual monograph, the product label mustcontain the specific quantitative amount of each ingredient. For liquid preparations, the per-centage content of each ingredient or the amount of each ingredient in a specified volume mustbe listed. Ingredients that are added to adjust pH or make the solution isotonic do not needto be quantified, but must be declared by name and their effect stated on the label. For drypreparations or those preparations to which a diluent will be added before use, items that mustbe included on the label include the following:� The amount of each ingredient� The composition of the recommended diluent(s)� The amount to be used to attain a specific concentration of the active ingredient� The final volume of the solution



� Description of the physical appearance of the constituted solution� Directions for proper storage of the constituted solution� An expiration date limiting the storage period during which the constituted solution may

be expected to have the required or labeled potency if stored as directed.

Strength and Total Volume for Single- and Multiple-Dose Injectable Drug ProductsThe primary and prominent expression on the principal display panel of the label needs to bethe strength of the active ingredient per total volume, for example:� Strength per vial: 500 mg/10 mL (or in units per total volume)� Strength per mL: 50 mg/mL (or in units per mL)

If the container volume is less than 1 mL, then the strength per fraction of 1 mL should bethe expression, for example, 12.5 mg/0.0625 mL

Medication errors cannot completely be eliminated by prominent strength labels as insulinis a primary example. However, meeting this requirement for label strength prominence cer-tainly will help to reduce the potential for medication errors.

Aluminum in LVPs, SVPs, and PBPs Used in TPN TherapyThe aluminum content of large-volume parenterals (LVPs) used in total parenteral nutrition(TPN) therapy must not exceed 25 �g per liter. The package insert (see the “Precautions” section)of LVPs used in TPN therapy must state that the drug product contains no more than 25 �gof aluminum per milliliter. For small-volume parenterals (SVPs) and pharmacy bulk packages(PBPs), the immediate container label used in the preparation of TPN parenterals should state,“Contains no more than 25 �g/L of aluminum.” The maximum level of aluminum as expirymust be stated on the immediate container label of all SVPs and PBPs used in preparation ofTPN parenterals with the statement “Contains no more than �g/L of aluminum” (the USPleaves this blank, to be filled in by the manufacturer). This maximum amount of aluminummust be stated as the highest of either the highest level for the batches produced during the pastthree years or the highest level for the latest fiveb batches.

The package insert for any and all products used in the preparation of TPN productsmust contain a warning statement in the “Warning” section of the labeling with the warningstatement being word-for-word what is published in this section of the USP Injections.

Packaging

Containers for InjectionThe packaging system must not interact physically or chemically with the product stored withinthe package. The container must be composed of materials that allow inspection of the contents.Individual monographs will state the type of glass (or plastic) preferable for each parenteralpreparation.

Containers are closed or sealed to prevent contamination or loss of contents. Containerclosure integrity testing must be performed to validate the integrity of the packaging systemagainst any kind of microbial contamination or chemical or physical impurities. The packagingsystem must be able to protect the product when exposed to anticipated extreme conditions ofmanufacturing, storage, shipment, and distribution.

Closures for multiple-dose containers must permit the withdrawal of the contents withoutremoval or destruction of the closure. The closure must seal itself after the needle is removed toprotect the product against contamination. Validation of multiple-dose container integrity mustinclude verification that such a package prevents microbial contamination or loss of productcontents under simulated use conditions of multiple entry and use.

Potassium Chloride for Injection Concentrate and Neuromuscular Blocking andParalyzing AgentsThe USP contains two very specific paragraphs for two kinds of injectable products—potassiumchloride for injection concentrate and neuromuscular blocking and paralyzing agents. A blackclosure system on a vial (black flip-off seal and black ferrule to hold the elastomeric closure)



Table 2-2 United States Pharmacopeia General Chapter RecommendedExcess Volume in Containers Containing Injectable Solutions

Recommended Excess Volume

Label size For mobile liquids For viscous liquids

0.5 mL 0.10 mL 0.12 mL1.0 mL 0.10 mL 0.15 mL2.0 mL 0.15 mL 0.25 mL5.0 mL 0.30 mL 0.50 mL

10.0 mL 0.50 mL 0.70 mL20.0 mL 0.60 mL 0.90 mL30.0 mL 0.80 mL 1.20 mL50.0 mL or more 2% 3%

or a black band at the neck of a glass ampul can only be used for potassium chloride forinjection concentrate containers. All injectable preparations of neuromuscular blocking agentsand paralyzing agents must be packaged in vials with a cautionary statement printed on theferrules or cap overseals that warn what product is in the containers.

Containers for Sterile SolidsContainers and closures for sterile dry solids also must not interact physically or chemically withthe product. Such containers will permit the addition of a suitable solvent and withdrawal ofparts of the resulting solution of suspension without compromising the sterility of the product.

Volume in ContainerEach container of an injection must be filled with sufficient excess to allow the labeled amount ofvolume of product to be withdrawn from the container. General chapter is referenced where under “Injections” in that chapter, there is a table thatprovide the recommended excess volume for injectables labels of various volume sizes to bewithdrawn (Table 2-2).

Determination of Volume of Injection in ContainersThis section of the USP contains a procedure of how to determine product volume in a container.

1. The labeled volume of the container will determine how many containers are to be used inthe test. If the container volume is ≥10 mL, three or more containers are used. If the containervolume is ≤3 mL, five or more containers are used.

2. Individually take up the contents of each container into a dry hypodermic syringe of a ratedcapacity not exceeding three times the volume to be measured and fitted with a 21-gaugeneedle not less than 2.5 cm (one inch) in length.

3. Expel any air bubbles from the syringe and needle and then discharge the contents ofthe syringe, without emptying the needle, into a standardized, dry cylinder (graduated tocontain rather than to deliver the designated volumes) of such size that the volume to bemeasured occupies at least 40% of the cylinder’s rated volume.a. Alternatively, the contents of the syringe may be discharged into a dry, tared beaker,

the volume, in mL, being calculated as the weight, in grams, of injection taken dividedby its density.

4. The contents of up to five 1- or 2-mL containers may be pooled for the measurement usinga separate dry syringe for each container.

5. The content of containers holding 10 mL or more may be determined by opening them andemptying the contents directly into the graduated cylinder or tared beaker.

6. The volume is not less than the labeled volume in the case of containers examined individ-ually or, in the case of the 1- and 2-mL containers, is not less than the sum of the labeledvolumes of the containers taken collectively.



The USP also has specific guidance, not repeated here, for determination of volume ofinjection for the following special containers: multiple dose, containers with oily contents,cartridges, syringes, and large-volume solutions.

Printing on Ferrules and Cap OversealsOnly cautionary statements are to be printed on these parts of the drug product container. Theprinting must be of contrasting color and conspicuous under conditions of use. Examples ofcautionary statements include “Warning,” “Dilute Before Using,” “Paralyzing Agent,” “IM UseOnly,” and “Chemo

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