Handbook of Pharmaceutical Manufacturing Formulations - Sterile Products (Volume 6 of 6)

363 Pages·2004·3.085 MB·English

by  Sarfaraz Niazi

H A N D B O O K O F
Pharmaceutical
Manufacturing
Formulations
Sterile Products
V O L U M E 6
© 2004 by CRC Press LLC
Handbook of
Pharmaceutical Manufacturing Formulations
Volume Series
Sarfaraz K. Niazi
Volume 1
Handbook of Pharmaceutical Manufacturing Formulations:
Compressed Solid Products
Volume 2
Handbook of Pharmaceutical Manufacturing Formulations:
Uncompressed Solid Products
Volume 3
Handbook of Pharmaceutical Manufacturing Formulations:
Liquid Products
Volume 4
Handbook of Pharmaceutical Manufacturing Formulations:
Semisolid Products
Volume 5
Handbook of Pharmaceutical Manufacturing Formulations:
V O L U M E 1
Over-the-Counter Products
Volume 6
Handbook of Pharmaceutical Manufacturing Formulations:
Sterile Products
© 2004 by CRC Press LLC
H A N D B O O K O F
Pharmaceutical
Manufacturing
Formulations
Sterile Products
V O L U M E 6
Sarfaraz K. Niazi
CRC PR ESS
Boca Raton London New York Washington, D.C.
© 2004 by CRC Press LLC
Library of Congress Cataloging-in-Publication Data
Niazi, Sarfaraz, 1949–
Handbook of pharmaceutical manufacturing formulations / Sarfaraz K. Niazi.
p. cm.
Includes bibliographical references and index.
Contents: — v.6. Sterile products.
ISBN 0-8493-1751-7 (alk. paper)
1. Drugs—Dosage forms—Handbooks, manuals, etc. I. Title
RS200.N53 2004
615'19—dc21
2003051451
This book contains information obtained from authentic and highly regarded sources. Reprinted material is quoted with permission, and
sources are indicated. A wide variety of references are listed. Reasonable efforts have been made to publish reliable data and information,
but the author and the publisher cannot assume responsibility for the validity of all materials or for the consequences of their use.
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 or retrieval system, without prior permission in writing from
the publisher.
The consent of CRC Press LLC does not extend to copying for general distribution, for promotion, for creating new works, or for resale.
Specific permission must be obtained in writing from CRC Press LLC for such copying.
Direct all inquiries to CRC Press LLC, 2000 N.W. Corporate Blvd., Boca Raton, Florida 33431.
Trademark Notice: Product or corporate names may be trademarks or registered trademarks, and are used only for identification and
explanation, without intent to infringe.
Visit the CRC Press Web site at www.crcpress.com
© 2004 by CRC Press LLC
No claim to original U.S. Government works
International Standard Book Number 0-8493-1751-7
Library of Congress Card Number 2003051451
Printed in the United States of America 1 2 3 4 5 6 7 8 9 0
Printed on acid-free paper
© 2004 by CRC Press LLC
Dedication
To Professor Shamsuz Zoha, my first pharmacy teacher, who inspired many
with his passion for the profession and for science
© 2004 by CRC Press LLC
Preface to the Series
No industry in the world is more highly regulated than dosage forms. These types of considerations have led to
the pharmaceutical industry because of potential threat to the classification of products into these six categories.
a patient’s life from the use of pharmaceutical products. Each volume includes a description of regulatory fil-
The cost of taking a new chemical entity (amortized over ing techniques for the formulations described. Also
the cost of all molecules racing) to final regulatory included are the current regulatory guidelines on cGMP
approval is a staggering $800 million, making the phar- compliance specific to the dosage form. Advice is offered
maceutical industry one of the most research-intensive on how to scale up the production batches.
industries in the world. In the year 2004, it is anticipated It is expected that formulation scientists will use this
that the industry will spend about $20 billion on research information to benchmark their internal development pro-
and development. The generic market of drugs as the new tocols and cut the race to file short by adopting formulae
entities come off patent is one of the fastest growing that have survived the test of time. Many of us who have
segments of the pharmaceutical industry, with every major worked in the pharmaceutical industry suffer from a close
multinational company having a significant presence in paradigm when it comes to selecting formulations — “not
this field. invented here” perhaps reigns in the mind of many sea-
Whereas many stages of new drug development are soned formulations scientists subconsciously when they
inherently constrained with time, the formulation of drugs prefer to choose only a certain platform for development.
into desirable dosage forms remains an area where expe- It is expected that with the quick review of possibilities
diency can be practiced with appropriate knowledge by available to formulate made available in this book, scien-
those who have mastered the skills of pharmaceutical for- tists will benefit from the experience of others.
mulations. The Handbook of Pharmaceutical Manufactur- For the teachers of formulation sciences, this series
ing Formulations is the first major attempt to consolidate offers a wealth of information. Whether it is a selection
the available knowledge about formulations in a compre- of a preservative system or the choice of a disintegrant,
hensive, and by nature a rather voluminous, presentation. the series offers a wide choice to study and rationalize.
The book is divided into six volumes, based strictly Many have assisted me in the development of this
on the type of formulation science involved in the devel- work that has taken years to compile, and I thank scores
opment of these dosage forms: sterile products, com- of my graduate students and colleagues for their help. A
pressed solids, uncompressed solids, liquid products, work of this size cannot be produced without errors,
semisolid products, and OTC products. The separation of although I hope that these errors do not distract the reader
OTC products even though they may easily fall into one from the utility of the book. I would sincerely appreciate
of the other five categories is made to comply with the if readers point out these mistakes for corrections in future
industry norms of separate research divisions for OTC editions.
products. Sterile products require skills related to steril-
ization of product, and of less importance is the bioavail- Sarfaraz K. Niazi, Ph.D.
ability issue, which is an inherent problem of compressed Deerfield, Illinois
© 2004 by CRC Press LLC
Preface to the Volume
The Handbook of Pharmaceutical Manufacturing Formu- manufacturing directions are provided. This type is further
lations: Sterile Products (HPMF/SP) is written for the composed of two types, wherein greater detail is provided
pharmaceutical scientist and others involved in the regu- for some products. This differentiation is intentional
latory filing and manufacturing of new sterile products. because the common details are often omitted in subse-
No other area of regulatory compliance receives more quent presentations. The second type of formulations is
attention and scrutiny by regulatory authorities than the provided with bill of materials only. This may include
regulation of sterile products, for obvious reasons. With products for which the manufacturing directions are obvi-
the increasing number of potent products, particularly the ous to a prospective manufacturer, particularly in light of
new line of small protein products, joining the long list the details already provided for similar products elsewhere
of proven sterile products — mainly parenteral and oph- in the book, and also those products for which such infor-
thalmic products — the technology of manufacturing ster- mation is not readily available. The third category of for-
ile products has evolved into a very sophisticated industry. mulations includes experimental formulations, which may
The entry barrier to this technology is much higher com- not yet have been commercialized or received regulatory
pared with those for other dosage forms. Consequently, approvals. These formulations are included to show to the
the cost of production remains high as well. In recent formulation scientist unique opportunities that exist for
years, regulatory agencies around the world have taken the chemical entity in question.
very serious notice of the deficiencies in the manufactur- Formulations of biotechnology-derived drugs are
ing specifications of the active raw material intended for provided with some additional details and remain
parenteral administration. New guidelines for the API and restricted to declaration of composition, yet they provide
aseptic processing of sterile products are the main issues a good overview of the complexities involved in such
of concern today for manufacturers. This volume of formulations.
HPMF/SP does not delve into details related to starting In consolidating the details of formulations, efforts
material issues. Of interest in this issue are formulations have been made to present them in as unified a form as
of sterile dosage forms, regulatory filing requirements of possible; nevertheless, some nonuniformities exist
sterile preparations, and cGMP compliance, all of which because of the large variety of presentations possible for
are tied together in the final preparation of the Chemistry, the wide diversity of formulations presented in the book.
Manufacturing, and Control (CMC) sections of regulatory A limited number of products intended for veterinary use
applications. are also included. These products are subject to cGMP
Chapter 1 describes the specifications of a manufac- compliance similar to that for human products.
turing facility to manufacture compliant sterile products. The formulations provided here meet the 4S
Chapter 2 outlines the New Drug Application (NDA) or requirements:
ANDA (Abbreviated New Drug Application) filing
requirements of sterile products. Chapter 3 describes in • Safety. This is an important issue for parenteral
detail the layout of formulations provided in the book. products; the choice of excipients is limited by
This chapter must be thoroughly examined to make the this consideration. In most of the formulations,
best use of this book. Because the intent of the information the ingredients are fully approved by the regu-
provided in this book is to help the formulator develop a latory authorities; in some formulations, the
product for regulatory filing, boilerplate details are left active drug moiety may have been banned in
out. Chapter 3 provides these details and also makes strong some countries, for example, dipyrone.
recommendations on how the formulator can benefit from • Sterility. The compositions presented are fully
the information available from suppliers of components sterilizable either by terminal treatment or by
and chemicals used in the formulation. aseptic processing; where preservatives are
These three chapters are followed by the body of the added, these are in sufficient quantity to fulfill
book, which provides an alphabetical presentation of for- the dedicated function.
mulations of pharmaceutical products based on their • Stability. Besides the rigor of treatment in ren-
generic names. There are three types of formulation dering a product sterile, incompatibility issues
entries. In the first type, both the bill of materials and may render a sterile product prone to instability.
© 2004 by CRC Press LLC
The formulations included here have been fully validated parts of a CMC package for submission to reg-
validated to provide sufficient shelf-life, ulatory authorities is a long one; nevertheless, working
depending on the product. with these formulations will reduce the risk of prolonged
• Scalability. Whereas the batch formulation is experimentation, and for generic formulation develop-
presented for a 1-l batch, these formulations are ment, it will expedite entrance to the market. Some sci-
linearly scalable. Manufacturing losses have entists may find this information useful in improving their
been included and these formulations can be products for any of the 4S considerations. More informa-
readily scaled up to any size; of course, the tion is available on the website of Pharmaceutical Scien-
requirements of size change in the validation tist, Inc. (http://www.pharmsci.com), wherein scientists
protocol should be considered. can find updated information on regulatory compliance
and additional tools for writing the CMC portions of the
One of the best utilities of the database included in this ANDA and NDA filings. The readers are encouraged to
book is to benchmark the products intended for develop- consult this website.
ment. A large number of formulation possibilities exist Although I have tried to sift through the large data-
for any drug; though with the 4S limitations, the choice bases in both the formative and proofreading stages of the
of ingredients (excipients) narrows rather rapidly. Multi- handbook, it is possible that errors remain. I would appre-
vitamin formulations are one such example wherein ciate it if readers point these out to me by e-mailing me
extreme instability and cost considerations have resulted at [email protected].
in a variety of formulations. A study of many possibilities I am grateful to CRC Press for taking this lead in
tells us about the problems we can anticipate while for- publishing what is possibly the largest such work in the
mulating these products. In some instances, only compo- field of pharmaceutical sciences. It has been a distinct
sition details are provided, along with raw material man- privilege to know Mr. Stephen Zollo, senior editor at CRC
ufacturing details, because they are often an integral part Press. Stephen has done more than what any editor can
of the formulation, such as in the case of biotechnology- do to encourage an author into conceiving, planning, draft-
derived products. Whereas this information may be at best ing, and finally, despite many reasons why it could not be
cursory, it is useful to provide a study of these product done, completing the work on a timely basis. I am greatly
formulations. indebted to him. The editorial assistance provided by CRC
The information contained in this book has been Press staff was indeed exemplary, particularly the help
obtained mainly from sources open to the public. It has given by Erika Dery, Gail Renard, Sara Kreisman, and
taken years to accumulate this database and no warranties others at CRC Press. Although the editors and proofread-
are provided that these formulation compositions will not ers have pored over this book diligently, any mistakes
infringe on any proprietary product or intellectual prop- remaining are altogether mine.
erty. The formulators must consider this before using the
information. Also, as with all scientific experimental data, Sarfaraz K. Niazi, Ph.D.
it should be understood that replication is subject to many Pharmaceutical Scientist, Inc.
factors, including type of equipment used, grade of mate- 20 Riverside Drive
rial employed, and other processing techniques imple- Deerfield, Illinois 60015
mented. The road to converting these formulations to
© 2004 by CRC Press LLC
About the Author
Dr. Sarfaraz K. Niazi has been teaching and conducting research in the pharma-
ceutical industry for over 30 years. He has authored hundreds of scientific papers,
textbooks, and presentations on the topics of pharmaceutical formulation, biophar-
maceutics, and pharmacokinetics of drugs. He is also an inventor with scores of
patents and is licensed to practice law before the U.S. Patent and Trademark Office.
Having formulated hundreds of products from consumer products to complex bio-
technology-derived products, he has accumulated a wealth of knowledge in the
science of formulations and regulatory filings of Investigational New Drugs (INDs)
and New Drug Applications (NDAs). Dr. Niazi advises the pharmaceutical industry
internationally on issues related to formulations, pharmacokinetics and bioequivalence
evaluation, and intellectual property issues (http://www.pharmsci.com).
© 2004 by CRC Press LLC
Table of Contents
Part I
Sterile Manufacturing Practice
Chapter 1
Inspection of Sterile Product Manufacturing Facilities
I. Introduction
II. cGMP Compliance Basics
A. Personnel
B. Buildings
C. Air
D. Environmental Controls
E. Equipment
F. Water for Injection
G. Containers and Closures
H. Sterilization
1. Methods
2. Indicators
3. Filled Containers
I. Personnel Practices
J. Laboratory Controls
1. Retesting for Sterility
2. Retesting for Pyrogens
3. Particulate Matter Testing
4. Production Records
III. Aseptic Processing
A. Introduction
B. Buildings and Facilities
1. Critical Area (Class 100)
2. Supporting Clean Areas
3. Clean Area Separation
4. Air Filtration
5. Design
C. Personnel Training, Qualification, and Monitoring
1. Manufacturing Personnel
2. Laboratory Personnel
3. Monitoring Program
D. Components and Containers/Closures
1. Components
2. Containers/Closures
E. Endotoxin Control
F. Time Limitations
G. Process Validation and Equipment Qualification
1. Process Simulations
2. Filtration Efficacy
3. Sterilization of Equipment and Containers/Closures
© 2004 by CRC Press LLC