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Pharmaceutical Dosage Forms. Vol. 2: Parenteral Medications

Avis, Kenneth E.
0824787714
9780824787714
9780585267005
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Page i
Pharmaceutical Dosage Forms:

Parenteral Medications Volume 2
Second Edition, Revised and Expanded
Edited by
Kenneth E. Avis
The University of Tennessee
Memphis, Tennessee
Herbert A. Lieberman
H.H. Lieberman Associates, Inc.
Consultant Services
Livingston, New Jersey
Leon Lachman
Lachman Consultant Services
Westbury, New York
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Page ii
Library of Congress CataloginginPublication Data

Pharmaceutical dosage forms, parenteral medications / edited by
Kenneth E. Avis, Herbert A. Lieberman, and Leon Lachman. -- 2nd ed.,
rev. and expanded.
p. cm.
Includes bibliographical references and index.
ISBN 0-8247-8576-2 (v. 1 : alk. paper)
1. Parenteral solutions. 2. Pharmaceutical technology. I. Avis,
Kenneth E. II. Lieberman, Herbert A.
III. Lachman, Leon.
[DNLM: 1. Infusions, Parenteral. 2. Technology, Pharmaceutical.
WB 354 P536]
RS201.P37P48 1992
615'. 19--dc20
DNLM/DLC
for Library of Congress
91 -38063
CIP
This book is printed on acid-free paper.
Copyright 1992 by MARCEL DEKKER, INC. All Rights Reserved
Neither this book nor any part may be reproduced or transmitted in any form
or by any means, electronic or mechanical, including photocopying, microfilming,
and recording, or by any information storage and retrieval system,
without permission in writing from the publisher.
MARCEL DEKKER, INC.
270 Madison Avenue, New York, New York 10016
Current printing (last digit):
10 9 8 7 6 5 4 3
PRINTED IN THE UNITED STATES OF AMERICA
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Page iii
Preface
Volume 2 of the first edition of our two-volume treatise on parenterals was published in 1986. In keeping with the
editors' philosophy to update and adequately cover new subject matter, this second volume is now being published as
part of a three-volume second edition of the series.
Volume 1 in the second edition is devoted to parenteral drug history, administration, routes, precautions, problems,
biopharmaceutics, preformulations, small and large volume parenteral formulations, peptide and protein injectables,
sterile diagnostics, different types of parenteral primary packages and closures, and, finally, parenteral products in
hospital and home care. Volume 2 describes processing small and large volume parenterals, freeze drying, the design of
a parenteral and a biopharmaceutical facility, personnel practices and training, environmental control elements in
manufacturing, industrial sterilization, as well as an enlightening coverage of the therapeutics, types of drugs, and
formulation principles for ophthalmic preparations. The final and third volume in this series covers quality assurance,
records and reports, particulate matter, validations, federal regulations, the audit process, regulatory considerations and
other aspects of medical devices, including design, manufacture, and quality assurance.
The editors have consistently guided the contributors to cover each subject with the intent of teaching at the level of the
undergraduate, as well as the graduate student in the pharmaceutical sciences. To accomplish this goal, the writers had
to assume the readers to have little knowledge of the subject matter and then build upon the more basic concepts
presented to reach the more learned and graduate level readers. Further, the materials presented in this series are
intended to benefit the technical readers with the specific information required to guide professionals practicing
industrial or pharmaceutical pharmacy, to assist personnel involved in the design and manufacture of sterile products, as
well as to instruct lawyers and legislators concerned with all types of sterile products.
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All of the first-edition chapters included in this volume have been updated, and additional topics are included in each
revised chapter to more fully cover the changes in the subject matter since the publication of the first edition. Also, new
chapters have been added.
Chapter 1 on the processing of small volume parenterals, has been expanded to include several types of biologic
products, including biotechnology-based preparations such as vaccines and monoclonal antibodies. There is a discussion
on preparing liposomal products, as well as a brief description concerning the manufacture of ophthalmic dosage forms.
The use of form, fill, and seal equipment for small volume parenterals is described in detail with several diagrams and
illustrations included to help provide additional clarity to this subject. Many of the tables have been revised and the list
of references updated. The chapter is designed to provide all the necessary details for setting up and running a state-ofthe-art small volume parenteral facility.
In Chapter 2, the manufacturing processes describing large volume parenterals, has been considerably expanded
compared with the presentation given in the first edition. Recent developments in the technology of parenteral fluid
processing, the latest regulatory requirements, packaging (including currently employed materials), filling, sterilization,
and filtration operations, as all of them pertain to large volume parenterals, are fully covered. In addition, the various
factors involved in manufacturing large volume parenterals are reinforced by offering practical examples of situations
and processes, both for improving production and quality assurance and control purposes.
Chapter 3, "Freeze Drying: Principles and Practice," a new chapter in this edition, presents an overview of the scientific
and engineering principles of freeze drying as it is relevant to the formulation and manufacture of freeze-dried
parenteral products. Methodology for the characterization of freezing behavior is presented from the standpoint of
identifying the maximum allowable product temperature during primary drying, that is, either a collapse temperature
(amorphous solute) or a eutectic temperature (crystalline solute). Temperature and pressure measurement methods used
in freeze drying are reviewed, followed by a discussion of process monitoring strategies. General equipment and
considerations involved in designing a freeze drying system are discussed.
Chapter 4 updates the various design considerations required for a parenteral production facility. Specific reference has
been included to small specialized batch operations where localized and self-contained sterile enclosures may be
applicable, as for example, in the manufacture of lyophilized products. A discussion of clean-in-place (CIP) and
sterilizein-place (SIP) systems has been added. The HEPA filters topic has been updated and expanded in accordance
with the current federal and Institute of Environmental Science standards. Laminar flow rooms with an illustration,
separate gowning and degowning areas, various safety, environmental, hazardous material control, energy conservation,
and building code issues have been reviewed and revised to reflect current pharmaceutical practices.
Chapter 5, which is new, describes the design of biopharmaceutical manufacturing facilities, concentrating on the
physical layout, with particular consideration for the planning and regulatory issues that need to be addressed.
Government regulatory maters, NIH guidelines, and FDA Good Manufacturing Practices as they pertain to the
manufacture of biopharmaceutical products are discussed. The role of validation in the
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Page v
planning process is presented along with a description of the design of the equipment outlay. This chapter highlights the
differences in planning for a biopharmaceutical manufacturing facility as compared with the design of aseptic facilities
for parenteral products.
No text concerned with the manufacture of sterile products would be complete without a description of "Personnel: The
Key Factor in Clean Room Operations," Chapter 6 of this text. The production personnel and the garments they wear
when processing sterile preparations can play a significant role in the risk of contaminating these products in the
manufacturing operations. To minimize this source of contamination, the chapter has provided a description of the
concepts of barrier technology and a lengthy discussion on the design of clean room uniforms, fabrics currently
prescribed, tests used to evaluate fabrics, and the effects of laundering on garment permeability. Several types of face
coverings worn by clean room operators are also described. Hand protection from microbial contamination and various
hand washing techniques utilized by employees working in aseptic areas are discussed. Overall contents of a training
program for clean room operators, as well as a section on management philosophy and their commitment to regulatory
compliance, are included in this chapter.
Chapter 7, "Environmental Control in Parenteral Drug Manufacturing," has been rewritten to include more details
regarding environmental monitoring, validation of airborne and surface contamination, and the implementation of a
routine monitoring program. This chapter discusses the hardware presently recommended for clean room construction
and air filtration and also includes current regulatory requirements on these subjects. New topics included in this chapter
are cleaning, disinfection, and personnel cleanliness requirements needed to achieve adequate environmental conditions
for an aseptic manufacturing facility.
"Industrial Sterilization: A Review of Current Principles and Practices," Chapter 8, describes many of the recent
advances that have been introduced in the health care industry. New concepts and principles relating to sterility
assurance techniques and procedures have been added in this edition. Among the new subjects described are alternatives
to ethylene oxide sterilization (e.g., vapor phase hydrogen peroxide, chlorine dioxide, and peracetic acid), parametric
release, chemical sterility indicators, and continuous sterilizers. Coverage of all the key areas of sterilization technology
have been expanded and include radiation, installation/performance qualification and validation, as well as a discussion
concerning the health effects of ethylene oxide as a sterilant.
Since ophthalmic preparations must be sterile, although not pyrogenfree, the editors have included in this series a new
chapter, Chapter 9, "Development of Ophthalmic Formulations." Although the dosage form is not a parenteral, the
techniques required for sterile formulation development are the same, and in other texts on sterile products, this topic is
not adequately covered. In this chapter, topical ophthalmic products are discussed, andunlike many other pharmacy
textsthe emphasis is on the development of intraocular preparations, particularly irrigating solutions. Included in this
chapter is a review of the anatomy of the eye and the pharmacologic/therapeutic categories of drugs used in
ophthalmology practice. It also includes a flow chart with model formulations for the development of ophthalmic
preparations. Manufacturing procedures for the preparation and packaging of ophthalmic products are briefly described.
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Page vi
The multiauthor approach taken in this volume, as well as the others in the series, provides the editors and readers with
contributors who are scholars knowledgeable as well as experienced in the subject matter of their chapters. No one
author can offer the detailed and learned treatise required to adequately cover such a variety of subjects included in this
volume. The experts chosen in particular areas offer comprehensive knowledge at a level that will satisfy the
requirements of both the novice and the highly experienced reader.
The contributing authors have worked hard to provide our readers with information needed to help them solve problems
in manufacturing all types of sterile parenteral, biologic, and ophthalmic products. We are extremely grateful for the
time and effort each has given to prepare a chapter despite a busy work schedule. We hope that the extensive coverage
of the subject matter in this book will facilitate the reader's tasks, as well as elevate the present technology practiced in
developing and manufacturing parenteral, biologic, and ophthalmic products.
KENNETH E. AVIS
HERBERT A. LIEBERMAN
LEON LACHMAN
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Page vii
Contents
Preface
iii
Contributors
ix
Contents of Pharmaceutical Dosage Forms: Parenteral Medications, Volumes 1 and 3
xi
Contents of Pharmaceutical Dosage Forms: Tablets, Volumes 1-3

Contents of Pharmaceutical Dosage Forms: Disperse Systems, Volumes 1 and 2
1. The Processing of Small Volume Parenterals and Related Sterile Products
Richard J. Harwood, Joel Benton Portnoff, And Edward William Sunbery
2. Factors Involved in Manufacturing Large Volume Parenterals
Michael J. Groves, Karen L. Malik, And Nicholas J. Kartinos
xiii
xv
1
93
3. Freeze Drying: Principles and Practice

Steven L. Nail And Larry A. Gatlin
163
4. Design Considerations for a Parenteral Production Facility

A. Michael Keller And Gary L. Hoffman
235
5. Biopharmaceutical Manufacturing Facility Design

Robert Del Ciello
317
6. Personnel: The Key Factor in Clean Room Operations

Cecelia J. Luna
367
7. Environmental Control in Parenteral Drug

Manufacturing
Franco Devecchi
411
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Page viii
8. Industrial Sterilization: A Review of Current Principles and Practices

Frank J. Marino
473
9. Development of Ophthalmic Formulations

Krishna M. Bapatla And 0. J. Lorenzetti
541
Index
583
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Page ix
Contributors
Krishna M. Bapatla, Ph.D. Associate Director, Project Management, Alcon Laboratories, Inc., Fort Worth, Texas
Robert Del Ciello, P.E. Director, Pharmaceutical and Biotechnology Operations, Quasar Engineering, Inc., Princeton,
New Jersey
Franco DeVecchi Chairman of the Board, Veco International, Inc., Farmington Hills, Michigan
Larry A. Gatlin, Ph.D. Section Head, Parenteral and Enteral Liquid Product Development, Pharmaceutical Research and
Development, Glaxo Research Institute, Research Triangle Park, North Carolina
Michael J. Groves, Ph.D. Director, Institute for Tuberculosis Research, College of Pharmacy, University of Illinois at
Chicago, Chicago, Illinois
Richard J. Harwood, Ph.D, Director, Technical Planning, Strategic Management Operations, Bristol-Myers Squibb,
Princeton, New Jersey
Gary L. Hoffman Merck Pharmaceutical Manufacturing Division, West Point, Pennsylvania
Nicholas J. Kartinos, Ph.D. Consultant, Chicago, Illinois
A. Michael Keller, P.E. Project Manager, Budlong & Associates, Agoura Hills, California
O. J. Lorenzetti, Ph.D. Senior Director, Therapeutic Research, Research and Development, Alcon Laboratories, Inc.,
Fort Worth, Texas
Cecelia J. Luna Validation Project Manager, Validation Services, United Engineers & Constructors, Philadelphia,
Pennsylvania
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Page x
Karen L. Malik Baxter Healthcare Laboratories, Inc., Round Lake, Illinois

Frank J. Marino, M.S. Corporate Consultant, Microbiology, Corporate Quality Assurance, Abbott Laboratories, North
Chicago, Illinois
Steven L. Nail, Ph.D. Associate Professor, Industrial and Physical Pharmacy, Purdue University, West Lafayette,
Indiana
Joel Benton Portnoff Executive Director of Development, Analytical and Pharmaceutical Research and Development,
The Liposome Company, Inc., Princeton, New Jersey
Edward William Sunbery, RPh. Manager, Technical Services, WarnerLambert Company, Inc., Lititz, Pennsylvania
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Page xi
Contents of Pharmaceutical Dosage Forms:

Parenteral Medications, Second Edition, Revised and Expanded, Volumes 1 and 3
Volume 1
1. The Parenteral Dosage Form and Its Historical Development, Kenneth E. Avis
2. Parenteral Drug Administration: Routes, Precautions, Problems, Complications, and Drug Delivery Systems, Richard
J. Duma, Michael J. Akers, and Salvatore J. Turco
3. Biopharmaceutics of Injectable Medications, Sol Motola
4. Preformulation Research of Parenteral Medications, Sol Motola and Shreeram N. Agharkar
5. Formulation of Small Volume Parenterals, Patrick P. DeLuca and James C. Boylan
6. Formulation of Large Volume Parenterals, Levit J. Demorest and Jeffrey G. Hamilton
7. Parenteral Products of Peptides and Proteins, Yu-Chang John Wang
8. Sterile Diagnostics, Leif E. Olsen
9. Glass Containers for Parenterals, R. Paul Abendroth and Robert N. Clark
10. Use of Plastics for Parenteral Packaging, John M. Anes, Robert S. Nase, and Charles H. White
11. Elastomeric Closures for Parenterals, Edward J. Smith and Robert J. Nash
12. Parenteral Products in Hospital and Home Care Pharmacy Practice, John W. Levchuk
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Volume 3
1. Quality Assurance
Samir A. Hanna
2. Records and Reports
David C. Fry
3. Particulate Matter
Patrick P. DeLuca and Julius Z. Knapp
4. Validation of Sterilization Processes and Sterile Products
James Agalloco and James Akers
5. Federal Regulation of Parenterals
Terry E. Munson, Jonas L. Bassen, and Bernard T. Loftus
6. Systematic Audits of Parenteral Good Manufacturing Practices
Ronald F. Tetzlaff
7. Medical Devices: Design, Manufacture, and Quality Control
David H. Wayt
8. Quality Assurance for Medical Devices
Carl W. Bruch
9. Regulatory and GMP Considerations for Medical Devices
Larry R. Pilot
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Page xiii

Tablets, Second Edition, Revised and Expanded, Volumes 1-3
edited by Herbert A. Lieberman, Leon Lachman, and Joseph B. Schwartz
Volume 1
1. Preformulation Testing, Deodatt A. Wadke, Abu T. M. Serajuddin, and Harold Jacobson
2. Tablet Formulation and Design, George J. Baley, Vincent E. McCurdy, Garnet E. Peck, and Gilbert S. Banker
3. Compressed Tablets by Wet Granulation, Fred J. Bandelin
4. Compressed Tablets by Direct Compression, Ralph F. Shangraw
5. Compression-Coated and Layer Tablets, William C. Gunsel and Robert G. Dusel
6. Effervescent Tablets, Raymond Mohrle
7. Special Tablets, James W. Conine and Michael J. Pikal
8. Chewable Tablets, Robert W. Mendes, Aloysius O. Anaebonam, and Jahan B. Daruwala
9. Medicated Lozenges, David Peters
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Volume 2
1. Mixing,
Russell J. Lantz, Jr. and Joseph B. Schwartz
2. Drying,
Kurt G. Van Scoik, Michael A. Zoglio, and Jens T. Carstensen
3. Size Reduction,
Russell J. Lantz, Jr.
4. Compression,
Eugene L. Parrott
5. Granulation and Tablet Characteristics,
Roger E. Gordon, Dale E. Fonner, Neil R. Anderson, and Gilbert S. Banker
6. Bioavailability in Tablet Technology,
Salomon A. Stavchanskv, James W. McGinity, and Alfred Martin
7. Pharmaceutical Tablet Compression Tooling,
Glen Ebey and George F. Loeffler
Volume 3
1. Principles of Improved Tablet Production System Design,
Garnet E. Peck, Neil R. Anderson, and Gilbert S. Banker
2. Pan Coating of Tablets and Granules,
Stuart C. Porter
3. Particle-Coating Methods,
Dale E. Wurster
4. Sustained Drug Release from Tablets and Particles through Coating,
Rong-Kun Chang and Joseph R. Robinson
5. Pharmaceutical Pilot Plant,
Charles I. Jarowski
6. Tablet Production,
Robert Connelly, Frank Berstler, and David Coffin-Beach
7. Stability/Kinetics,
Samir A. Hanna
8. Quality Assurance,
Samir A. Hanna
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Page xv

Disperse Systems, Volumes 1 and 2
edited by Herbert A. Lieberman, Martin M. Rieger, and Gilbert S. Banker
Volume 1
1. Introduction,
Norman Weiner
2. Theory of Suspensions,
Michael J. Falkowicz
3. Theory of Emulsions,
Stig E. Friberg, Lisa B. Goldsmith, and Martha L. Hilton
4. Theory of Colloids,
John Vanderhoff and Mohamed S. El-Aasser
5. Pharmaceutical Suspensions,
Robert A. Nash
6. Pharmaceutical Emulsions,
Bernard Idson
7. Specialized Pharmaceutical Emulsions,
Morton Rosoff
8. Surfactants,
Martin M. Rieger
9. Rheology of Dispersed Systems,
Donald E. Deem
10. Experimental Design, Modeling, and Optimization Strategies for Product and Process Development,
Robert M. Franz, Jeffrey E. Browne, and Allen R. Lewis
Volume 2
1. A Practical Guide to Equipment Selection and Operating Techniques
Roy R. Scott
2. Preservation of Dispersed Systems
Harun Takruri and Claude B. Anger
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Page xvi
3. Bioavailability of Disperse Dosage Forms

Ronald D. Schoenwald and Douglas R. Flanagan
4. Viscosity-Imparting Agents in Disperse Systems
Joel L. Zatz, Joseph J. Berry, and Daniel A. Alderman
5. Antacids and Clay Products
Richard J. Harwood, Joseph R. Luber, and Edward W. Sunbery
6. Oral Aqueous Suspensions
Clyde M. Ofner III, Roger L. Schnaare, and Joseph B. Schwartz
7. Topical Suspensions
Hridaya N. Bhargava and Daniel W. Nicolai
8. Reconstitutable Suspensions
Clyde M. Ofner III, Roger L. Schaare, and Joseph B. Schwartz
9. Emulsions and Microemulsions
Lawrence H. Block
10. Injectable Emulsions and Suspensions
Joe Bruce Boyett and Craig William Davis
11. Aerosol Suspensions and Emulsions
John J. Sciarra and Anthony J. Cutie
12. Ophthalmic Ointment Suspensions
Krishna M. Bapatla and Gerald Hecht
13. Gels
Joel L. Zatz and Gregory P. Kushla
14. Toothpastes
David Garlen
15. Suppository Development and Production Marion
Gold
16. Liposomes
Mohammad Riaz, Norman Weiner, and Frank Martin
17. Drug Regulatory Affairs
John P. Tomaszewski
18. Quality Assurance
Samir A. Hanna
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Page 583
Index
A
Absorption of drugs from the eye, 555-555
Adrenergic antagonists, 549
Allergenic SVP extracts, 2
Anti-inflammatory agents, 550
Antimicrobial preservatives, 550, 558-559
Antioxidants, 561, 573
Aqueous ophthalmic solution products, 64-66
Aqueous solutions, freezing of, 166-173
Aseptic techniques, 474
for packaging and sealing, 77-80
via form/fill/seal technology, 86-87, 88-89
B
Bacterial vaccines, 67-68
Barrier technology, applications of, for cleanroom operation, 389-391
Benzalkonium chloride, 558
Biological SVP products, 1
Biopharmaceutical manufacturing facility design, 317-366
architectural treatments, 336-341
design methodology, 321-329
construction documents, 329
design basis development, 329
design development, 329
planning, 321
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development of facility layout, 329-336

HVAC/environmental system design, 341-350
air handlers, 347-348
control and control devices, 348
design criteria, 342- 343
duct systems, 348
dust control, 347
filtration, 346-347
pressurization, 343-346
system classification, 349-350
temperature and relative humidity, 346
large-scale biosafety level facility requirements, 319
regulatory issues, 318-320
utility systems, 350, 365
aseptic compressed air systems, 364
biological waste treatment systems, 351-356
clean-in-place systems, 360-362, 363
clean (sterile) steam systems, 363-364
electrical service, 364
temperature control systems, 364-365
water systems, 356-360
Buffering agents, 559, 572
C
Cake filters, 123
Carbon steel piping, 268
Cartridge filters, 135
Center for Biologics of the Food and Drug Administration, 318
Chelating agents, 573
Chlorine compounds for sterilization, 500
page_583
Chlorobutanol, 558-559
Cleanroom operations personnel, 367-410
application of barrier technology to the cleanroom operation, 389-391
contamination, 368-370, 451-452
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Page 584
microbial contamination, 370

particulate contamination, 368-370
management role in cleanroom operations, 404-409
development of a positive attitude, 408-409
management philosophy and commitment to regulatory compliance, 407
motivation of employees, 405-406
personnel characteristics, 370-374
bacterial load, 370-371
body area shedding organisms, 371-372
the carrier concept, 374
male vs. female shed rates, 373
types of microorganisms, 371
personnel factors required to control contamination, 376-386
personnel practices and procedures, 386-389
general cleanroom procedures, 387-389
practices related to gowning, 386-387
safety procedures, 388-389
selection of cleanroom personnel, 374-376
characteristics of employees, 374-376
training program for cleanroom employees, 391-404
advantages of such a program, 403-404
development of the program, 391-394
three-step program, 394-403
Cleanrooms
environmental control of, 438-451
air motion, 439-445
basis for cleanroom design, 445-451
page_584
isolation, 438-439
maintenance procedures for, 16, 17
Collapse temperatures, 172
of various compounds, 174
Contamination
by cleanroom operations personnel, 368-370, 415, 416
control of, 376-386, 451-452
factors required to control, 376-386
air as a source of contamination, 416-417
equipment and materials used in manufacturing as a source of contamination, 414
Copper piping, 268-269
Current Good Manufacturing Practices (CGMP) regulations of the Food and Drug Administration, 94
Cycloplegics, 549-550
D
Density, 98-99
Dental SVP products, 2
Depth filters, 122-123
advantages and disadvantages of, 126-127
Designing a parenteral production facility, 235-316
(see also Biopharmaceutical manufacturing facility design)
design concepts, 254-315
compressed air, 293-300
compressed gases, 300-302
filling suites, 254-257
heating, ventilating, and air conditioning, 274-278
laminar flow, 286-289
page_584
mechanical services, 264-274

miscellaneous controlled area details, 261-263
steam, 289-293
wall and floor treatment, 257-261
warehousing, 263-264
waste disposal, sanitation, and equipment cleaning, 312-315
water for injection, 304-312
water treatment, 302-304
facility area use planning, 239-254
area planning, 245-254
general operational assessments, 240-245
site selection, 236-239
air quality, 238
basic plant requirements, 236-237
energy, 237-238
nontechnical factors, 239
waste disposal, 238-239
water, 238
typical layout of a parenteral plant, 235, 236
Dextran, collapse temperature of, 174
Diagnostic SVP agents, 1-2
Distribution records, 5, 7
Dry eye syndrome, medications for, 550
Dry heat sterilization, 490-491
characteristics of, 488
loading considerations for, 506
D value
E
Environmental control in parenteral drug manufacturing, 411-472
page_584
cleaning and disinfection procedures, 452-454

cleanrooms, 438-451
air motion, 439-445
basis for cleanroom design, 445-451
isolation, 438-439
control of contamination, 414-417
air as a source of contamination, 416-417
equipment and materials used in manufacturing, 414
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Page 585
personnel, 415, 416

definitions of, 474-475
environmental contamination control system design, 417-438
heating, ventilation, and air conditioning systems, 418-438
personnel contamination control, 451-452
test methods, 454-469
airborne microbial sampling in critically controlled environments, 467-468
airborne particle count test, 459-462
airflow patterns test, 463-465
airflow uniformity test, 454-455
enclosure induction leak test, 462-463
HEPA filter leak test, 458-459
humidity control test, 456
particle dispersion test, 465-466
pressurization control test, 457
recovery test, 467
surface sampling, 468-469
temperature control test, 456
Environmental records, 5, 6
Enzymatic products, 550
Equipment for freeze drying, 222-227
Ethylene oxide sterilization, 495-498
Exposure time, 479-480
Eye, absorption of drugs from, 551-555
Eye, anatomy of, 542-547
page_585
ciliary body, 546

conjunctiva, 542
cornea, 544-546
corneal endothelium and Descemet's membrane, 545
corneal epithelium, 545
corneal stroma and Bowman's membrane iris, 545-546
crystalline lens, 546-547
lacrimal system, 542-544
optic nerve and optic disc, 547
vitreous chamber, 547
F
Ficoll, collapse temperature of, 174
Filling areas, design concepts for, 254-257
Filtration in the LVP manufacturing process, 119-136
advantages and disadvantages of screen and depth filters, 126-127
advantages of membrane filters, 134-135
classification of filtration operations, 122-123
ideal filter criteria, 127-128
membrane support systems, 135-136
testing and validation of filters, 130-134
theories of filtration, 124-126
utilization of filters, 128-130
Formaldehyde gas for sterilization, 500-501
Fractional sterilization, 490
Freeze-dried powder formula for SVPs, preparation of, 51-61
Freeze drying, 163-233
development of freeze-dried protein formulation (case study), 227-230
freeze dry equipment, 222-227
condenser design, 225-226
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general construction considerations, 226

heat transfer fluid, 225
refrigeration, 225
sterilization of freeze dryers, 226-227
vacuum integrity testing, 227
vacuum system, 223-225
freeze process, 166-185
characterization of freezing behavior, 173-185
freezing of aqueous solutions, 166-173
phase diagram of water, 166
thermal treatment, 173
primary drying process, 185-205
behavior of gases at low pressure, 187-191
heat transfer in primary drying, 191-201
mass transfer in primary drying, 201-205
sublimation of ice, 185-187
transfer operations, 187
process monitoring, 208-222
pressure measurement, 213-217
process monitoring techniques, 218-222
temperature measurement, 208-213
process overview, 164-165
secondary drying, 205-208
role of residual water in stability of freeze-dried products, 207-208
Fructose, collapse temperature of, 174
F0 value, 478-479
G
Garments for cleanroom operations personnel, 378-383, 386-387
Gelatin, collapse temperature of, 174
page_585
Gels, 576
Genetically engineered SVP products, 2
preparation of, 66-69
bacterial vaccines, 67-68
recombinant DNA techniques, 69
toxoids, 68-69
viral vaccines, 68
Glaucoma, agents for treatment of, 549
Glucose, collapse temperature of, 174
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Page 586
Heating, ventilation, and air conditioning (HVAC) systems

airborne contamination control, 419-427
aerosol behavior, 419-421
air filtration, 421
efficiency testing, 427
evaluation of air filter system, 422-424
filter classification, 421-422
high efficiency filters, 424-426
integrity testing, 427
for biopharmaceutical manufacturing facility, 341-350
components of the HVAC system, 432-438
air distribution network, 433-436
air handling unit, 347-348, 433
control devices, 348, 436-438
monitoring and alarm devices, 438
constant airflow systems, 431-432
ventilation, 432
design concepts for, 274-286
pressure differential control, 429-431
recirculation ratio (dilution of contamination), 427-429
temperature and humidity control, 418-419
Heat transfer, 102-106
conduction, 102
convection, 103
radiation, 103
Hydrogen peroxide for low temperature sterilization, 498, 499
page_586
I
Industrial sterilization, 473-540
health physics, 537-538
overview of sterilization processes, 486-501
chlorine compounds, 500
dry heat, 490-491
ethylene oxide, 495-498
formaldehyde, 500-501
fractional sterilization, 490
hydrogen peroxide, 498, 499
moist heat, 487-490
peracetic acid, peracetate, 499-500
radiation, 491-495
principal definitions, 473-486
aseptic technique, 474
the D value, 475-476
environmental control, 474-475
exposure time, 479-480
the F value, 478-479
packaging, 479
principles of microbial resistance, 481-482
pyrogen, 482
the Q10 value, 478
sterility, 473-474
sterilization assurance, 482-486
thermal death time and thermal chemical death time, 480-481
the Z value, 476-478
process considerations, 504-512
data analysis, 512
page_586
discipline or training requirements, 511-512

economic considerations, 506-507
regulatory considerations, 507
safety requirements, 507-511
typical sterilization loading characteristics, 504-506
process development, 519-525
calibration, 523-525
instrumentation for process control, 522-523
microbiological criteria, 519-522
parametric studies, 519
process selection, 502-504
packaging, 503-504
product consideration, 503
process specifications, 513-519
equipment, 514
facilities and space requirements, 514
installation and facilities, 515-516
processing hardware, 516-519
relationship to total operational process, 514-515
specifications, 515
technology, 513-514
validation of process and equipment, 525-537
biological validation, 525-526
process control and equipment, 526-537
Inositol, collapse temperature of, 174
Intraocular products, 550-551, 562-567
irrigating solution of, 500, 562-564, 577-578
ocular safety assessment of, 567-568
L
page_586
Lactose, collapse temperature of, 174

Laminar flow, design concepts for, 286-289, 292
Large volume parenterals (LVPs),
manufacture of, 93-162
batch mixing, 113-119
lipid emulsions, 118-119
simple solutions, 113-118
Specialized products, 119
cleaning process equipment and lines, 136-144
cleaning and sanitization, 139-142
compressed gases, 143-144
mixing and filling equipment, 139
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Page 587
[Large volume parenterals (LVPs)]

production planning, 139
water systems, 136-139
containers and closures, 144-154
air tubes, 151
caps, 151
glass bottle handling, 147-148
glass bottle washing, 148-150
materials, 144-146
plastic containers, 151-152
rubber closures, 150-151
filling, 154
filtration, 119-136
advantages and disadvantages of screen and depth filters, 126-127
advantages of membrane filters, 134-135
classification of filtration operations, 122-123
ideal filter criteria, 127-128
membrane support systems, 135-136
testing and validation of filters, 130-134
theories of filtration, 124-126
utilization of filters, 128-130
final product testing, 157-160
particulate testing, 160
use of isolators, 157-159
fluid dynamics and heat flow, 95-106
flow of fluids in an autoclave, 101-102
heat transfer, 102-106
page_587
properties of fluids, 95-101

labeling, 155-157
new directions, 160-161
process validation, 160
raw materials, 110-113
definition, 110-111
distribution and inventory control, 113
qualification and stability, 111-112
receiving, 112
storage/quarantine area, 113
sealing, 154-155
water: the essential raw material, 106-110
definition, 106
distillation, 108-110
pretreatment, 106-107
reverse osmosis, 107-108
Liposome and lipid SVP products, 2
preparation of, 69-70, 71, 72
Lyophilization (see Freeze drying)
M
Maintenance procedures for sterile areas in SVP manufacturing facilities, 16-17, 18
Maltose, collapse temperature of, 174
Management role in the cleanroom operation, 404-409
Manufacturing large and small volume parenterals [see Large volume parenterals (LVPs), manufacture of; Small
volume parenterals (SVPs), manufacture of products]
Master file, 5
Material logs, 5, 6-7
page_587
Mechanical services, design concepts for, 264-274

distribution system, 266-267
joining techniques, 270
materials, 268-269
surface finish, 269-270
utility service connection arrangement, 273-274
valving, 270-273
Membrane filters, 129-130
advantages of, 134-135
Methylcellulose, collapse temperature of, 174
Methylparaben, 559
Microbial resistance, principles of, 481-482
Miotics, 550
Moist heat as a sterilizing agent, 487-490
loading considerations for, 504-506
Monosodium glutamate, collapse temperature of, 174
Mydriatics, 549-550
O
Ointments, 577
Ophthalmic formulations, 541-581
anatomy of the eye, 542-547
ciliary body, 546
conjunctiva, 542
cornea; 544-546
crystalline lens, 546-547
lacrimal system, 542-544
optic nerve and optic disc, 547
vitreous chamber, 547
page_587
development of, 546-571

absorption of drugs from the eye, 551-555
examples of formulation development, 569-571
formulation development, 555-569
pharmacological/therapeutic categories of ophthalmic products, 548-551
gels, 576
historical background, 541-542
intraocular irrigating solution, 577-578
ointments, 577
preparation of aqueous solution for SVP products, 64-66
preparation of sterile ophthalmic
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Page 588
[Ophthalmic formulations]
suspension products, 66
solutions, 571-574
active drug substance, 571
antioxidants, 573
buffers, 572
chelating agents, 573
manufacturing process, 574
osmolarity-adjusting agents, 572
preservatives, 571-572
viscosity-increasing agent, 573
Osmolarity-adjusting agents, 560-561, 572
Ovalbumin, collapse temperature of, 174
P
Packaging, 479
[see also Small volume parenterals (SVPs), packaging and sealing]
preparation of packaging components for SVPs, 22-34
glass components, 29-33
plastic containers, 33-34
rubber components, 22-29
selecting suitable material for, 503-504
Parasympathomimetics, 549
Peracetic acid for sterilization, 499-500
Personnel in the cleanroom operations, 367-410
application of barrier technology to the cleanroom operation, 389-391
contamination, 368-370, 451-452
page_588

management role in cleanroom operations, 404-409
personnel characteristics, 370-374
bacterial load, 370-371
body area shedding organisms, 371-372
the carrier concept, 374
male vs. female shed rates, 373
types of microorganisms, 371
personnel factors required to control contamination, 376-386
personnel practices and procedures, 386-389
general cleanroom procedures, 387-388
practices related to gowning, 386-387
safety procedures, 388-389
selection of cleanroom personnel, 374-376
characteristics of employees, 374-376
training program for cleanroom employees, 391-404
Pharmaceutical SVP products, 1
Phenylethyl alcohol, 559
Piping systems, design concepts for, 268-269
carbon steel, 268
copper, 268-269
Type 304 stainless steel, 269
Type 316 stainless steel, 269
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Polyquat (polyquaternium-l), 559

Polyvinylpyrrolidone, collapse temperature of, 174
Primary freeze drying process, 165, 185-205
behavior of gases at low pressure, 187-191
heat transfer in primary drying, 191-201
mass transfer in primary drying, 201-205
sublimation of ice, 185-187
transfer operations in primary drying, 187
Process logs, 5, 6
Propylparaben, 559
Protein formulation, freeze-dried, development of (case study), 227-230
Pyrogens, 482
Q
Q10 value, 478
R
Radiation for sterilization and preservation, 491-495
Radiopharmaceutical SVP products, 2
Returned goods record, 5, 7
Reverse osmosis (RO), 107-108
Ribose, collapse temperature of, 174
S
Sanitation, design concepts for, 313-314
Screen filters, 122
advantages and disadvantages of, 126-127
Secondary freeze drying process, 165, 205-208
role of residual water in stability of freezedried products, 207-208
page_588
Site selection for a parenteral production facility, 236-239

air quality, 238
basic plant requirements, 236-237
energy, 237-238
nontechnical factors, 239
waste disposal, 238-239
water, 238
Small volume parenterals (SVPs), 1-92
categories of, 1-2
inspection of the final product, 87
labeling, 87-89
manufacture of the product, 34-70
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Page 589
[Small volume parenterals (SVPs)]

preparation of aqueous ophthalmic solution products, 64-66
preparation of genetically engineered or biotechnology products, 66-69
preparation of liposome and lipid products, 69-70, 71, 72
preparation of sterile ophthalmic suspension products, 66
preparation of an SVP solution, 34-42, 43
preparation of typical freeze-dried powder formula, 51-61
preparation of typical sterile dry fill powder for constitution, 61-64
preparation of typical suspension formula, 42-51, 55
overview of, 2, 3
packaging and sealing, 70-87
aseptic packaging via form/fill/seal technology, 86-87, 88-89
aseptic subdivision, 77-80
filling equipment, 73-77
inert gas treatment, 70-73
prefilled syringes, 82-86
sealing, 80-82
preliminary stages in the processing of, 2-34
documentation control, 4-7
equipment and facilities management, 7-8
materials management, 4
personnel management, 4
planning and scheduling, 2-3
preparation of equipment, 11-22
preparation of facilities, 9-11
preparation of packaging equipment, 22-34
Sorbitol, collapse temperature of, 174
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Stability records, 5, 6
Stainless steel piping, 269
Standard operating procedures, 5
Sterile ophthalmic suspension products, 66
Sterility, definition of, 473-474
Sterilization (see also Industrial sterilization) sterilization assurance, definition of, 482-486
Sucrose, collapse temperature of, 174
Surface tension (of fluids), 99-100
Surfactants, 561
Suspensions, 574-576
suspension formula for SVPs, 42-51, 55
Sympathomimetics, 549
T
Test methods used for effective environmental control, 454-469
airborne microbial sampling in critically controlled environments, 467-468
airborne particle count test, 459-462
airflow patterns test, 463-465
airflow uniformity test, 454-455
enclosure induction leak test, 462-463
HEPA filter leak test, 458-459
humidity control test, 456
particle dispersion test, 465-466
pressurization control test, 457
recovery test, 467
surface sampling, 468-469
temperature control test, 456
Thermal chemical death time (TCDT), 480-481
Thermal death time (TDT), 480-481
Thermal resistance, 103-106
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Thimerosal, 558
Toxoids, 68-69
Training program for cleanroom employees, 391-404
classroom/orientation training, 394-399
documentation, 400
evaluation, 400-403
on-the-job training, 399-400
technical training, 399
Trehalose, collapse temperature of, 174
Type 304 stainless steel piping, 269
Type 316 stainless steel piping, 269
V
Validation records, 5-6
Vapor pressure, 100-101
Viral vaccines, 68
Viscoelastic agents, 550, 564-567
Viscosity, 95-98
Viscosity-increasing agents, 561, 573
W
Warehousing, design concepts for, 263-264
Waste disposal, design concepts for, 312-313
Water, 238
phase diagram for, 166
treatment for (design concepts), 302-304
Water for injection (WFI), 106-110, 304-312
control components, 311-312
page_589
definition, 106
distillation, 108-110, 306
distribution, 309-311
pretreatment, 106-107
reverse osmosis, 107-108
storage, 306-309
Z
Z value, 476-478
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Lachman Vol2

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Start of Citation[PU]Marcel Dekker, Inc.[/PU][DP]1992[/DP]End of Citation

Pharmaceutical Dosage Forms. Vol. 2: Parenteral Medications

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Pharmaceutical Dosage Forms:

Start of Citation[PU]Marcel Dekker, Inc.[/PU][DP]1992[/DP]End of Citation

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Library of Congress CataloginginPublication Data

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Contents of Pharmaceutical Dosage Forms: Parenteral Medications, Volumes 1 and 3

Contents of Pharmaceutical Dosage Forms: Tablets, Volumes 1-3

3. Freeze Drying: Principles and Practice

4. Design Considerations for a Parenteral Production Facility

5. Biopharmaceutical Manufacturing Facility Design

6. Personnel: The Key Factor in Clean Room Operations

7. Environmental Control in Parenteral Drug

Start of Citation[PU]Marcel Dekker, Inc.[/PU][DP]1992[/DP]End of Citation

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8. Industrial Sterilization: A Review of Current Principles and Practices

9. Development of Ophthalmic Formulations

Start of Citation[PU]Marcel Dekker, Inc.[/PU][DP]1992[/DP]End of Citation

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Karen L. Malik Baxter Healthcare Laboratories, Inc., Round Lake, Illinois

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Contents of Pharmaceutical Dosage Forms:

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