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 Handbook of
Pharmaceutical Manufacturing Formulations
Second Edition
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:
Over-the-Counter Products

Volume 6
Handbook of Pharmaceutical Manufacturing Formulations:
Sterile Products
Informa Healthcare USA, Inc.
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C 2009 by Informa Healthcare USA, Inc.
Informa Healthcare is an Informa business

No claim to original U.S. Government works

Printed in the United States of America on acid-free paper
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Library of Congress Cataloging-in-Publication Data

Niazi, Sarfaraz, 1949–

Handbook of pharmaceutical manufacturing formulations /
Sarfaraz K. Niazi. – 2nd ed.
p. ; cm.
Includes bibliographical references and index.
ISBN-13: 978-1-4200-8106-0 (set) (hardcover : alk. paper)
ISBN-10: 1-4200-8106-3 (set) (hardcover : alk. paper)
ISBN-13: 978-1-4200-8116-9 (v. 1) (hardcover : alk. paper)
ISBN-10: 1-4200-8116-0 (v. 1) (hardcover : alk. paper)
[etc.]
1. Drugs–Dosage forms–Handbooks, manuals, etc. I. Title.
[DNLM: 1. Drug Compounding–Handbooks. 2. Dosage Forms–Handbooks.
3. Formularies as Topic–Handbooks. 4. Technology, Pharmaceutical–Handbooks.
QV 735 N577h 2009]
RS200.N53 2009
615 .19–dc22
2009009979

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to the memory of Takeru Higuchi
 Preface to the Series—Second Edition

The science and the art of pharmaceutical formulation keeps urged to make use of this information. Whereas this in-
evolving as new materials, methods, and machines become formation is provided free of charge, the process of ob-
readily available to produce more reliable, stable, and release- taining the information may be cumbersome, in which
controlled formulations. At the same time, globalization of case, commercial sources of these databases can prove
sourcing of raw and finished pharmaceuticals brings chal- useful, particularly for the non-U.S. companies.
lenges to regulatory authorities and results in more frequent 6. Also included are the new Good Manufacturing Guide-
revisions to the current good manufacturing practices, regu- lines (2007) with amendments (2008) for the United States
latory approval dossier requirements, and the growing need and similar updates for European Union and WHO; it is
for cost optimization. Since the publication of the first edition strongly urged that the companies discontinue using all
of this book, a lot has changed in all of these areas of impor- old documents as there are significant changes in the re-
tance to pharmaceutical manufacturers. The second edition vised form, and many of them are likely to reduce the
builds on the dynamic nature of the science and art of for- cost of GMP compliance.
mulations and provides an evermore useful handbook that 7. Details on design of clean rooms is a new entry that will
should be highly welcomed by the industry, the regulatory be of great use to sterile product manufacturers; whereas
authorities, as well as the teaching institutions. the design and flow of personnel and material flow is of
The first edition of this book was a great success as it critical nature, regulatory agencies view these differently
brought under one umbrella the myriad of choices available and the manufacturer is advised always to comply with
to formulators. The readers were very responsive and com- most stringent requirements.
municated with me frequently pointing out to the weaknesses 8. Addition of a self-auditing template in each volume of
as well as the strengths of the book. The second edition totally the series. While the cGMP compliance is a complex is-
revised attempts to achieve these by making major changes sue and the requirements diversified across the globe, the
to the text, some of which include: basic compliance remains universal. I have chosen the
European Union guidelines (as these are more in tune
1. Complete, revised errors corrected and subject matter with the ICH) to prepare a self-audit module that I rec-
reorganized for easy reference. Whereas this series has ommend that every manufacturer adopt as a routine to
six volumes differentiated on the basis of the type of assure GMP compliance. In most instances reading the
dosage form and a separate inclusion of the U.S. OTC template by those responsible for compliance with keep
products, ideally the entire collection is needed to ben- them sensitive to the needs of GMP.
efit from the myriad of topics relating to formulations, 9. OTC products cross-referenced in other volumes where
regulatory compliance, and dossier preparation. appropriate. This was necessary since the regulatory au-
2. Total number of pages is increased from 1684 to 2726. thorities worldwide define this class of drug differently.
3. Total number of formulations is expanded by about 30% It is important to iterate that regardless of the prescrip-
with many newly approved formulations. tion or the OTC status of a product, the requirements for
4. Novel formulations are now provided for a variety of compliance with the cGMP apply equally.
drugs; these data are collected from the massive intellec- 10. OTC monograph status is a new section added to the OTC
tual property data and suggest toward the future trend volume and this should allow manufacturers to chose ap-
of formulations. While some of these formulations may propriate formulations that may not require a filing with
not have been approved in the United States or Europe, the regulatory agencies; it is important to iterate that an
these do provide additional choices, particularly for the approved OTC monograph includes details of formula-
NDA preparation. As always, it is the responsibility of tion including the types and quantities of active drug and
the manufacturer to assure that the intellectual property excipients, labeling, and presentation. To qualify the ex-
rights are not violated. emption, the manufacturer must comply with the mono-
5. A significant change in this edition is the inclusion of graph in its entirety. However, subtle modifications that
commercial products; while most of this information are merely cosmetic in nature and where there is an evi-
is culled out from the open source such as the FOIA dence that the modification will not affect the safety and
(http://www.fda.gov/foi/default.htm), I have made at- efficacy of the products can be made but require prior
tempts to reconstruct the critical portions of it based approval of the regulatory agencies and generally these
on what I call the generally acceptable standards. The approvals are granted.
drug companies are advised to assure that any intellec- 11. Expanded discussion on critical factors in the manufac-
tual property rights are not violated and this applies to turing of formulations provided; from basic shortcuts
all information contained in this book. The freedom of to smart modifications now extend to all dosage forms.
information act (FOIA) is an extremely useful conduit Pharmaceutical compounding is one of the oldest pro-
for reliable information and manufacturers are strongly fessions and whereas the art of formulations has been

v
vi Preface to the Series—Second Edition

relegated to more objective parameters, the art neverthe- the rate and extent of absorption of the therapeutic ingre-
less remains. An experienced formulator, like an artist, dient [21 U.S.C. 355(j)(8); 21 CFR 320.1(e)]. BE studies are
would know what goes with what and why; he avoids undertaken in support of ANDA submissions with the
the pitfalls and stays with conservative choices. These goal of demonstrating BE between a proposed generic
sections of the book present advice that is time tested, drug product and its reference listed drug. The regu-
although it may appear random at times; this is intended lations governing BE are provided at 21 CFR in part
for experienced formulators. 320. The U.S. FDA has recently begun to promulgate
12. Expanded details on critical steps in the manufacturing individual bioequivalence requirements. To streamline
processes provided but to keep the size of the book man- the process for making guidance available to the pub-
ageable, and these are included for prototype formula- lic on how to design product-specific BE studies, the
tions. The reader is advised to browse through similar U.S. FDA will be issuing product-specific BE recommen-
formulations to gain more insight. Where multiple for- dations (www.fda.gov/cder/ogd/index.htm). To make
mulations are provided for the same drug, it intended to this vital information available, an appendix to each
show the variety of possibilities in formulating a drug volume includes a summary of all currently approved
and whereas it pertains to a single drug, the basic formu- products by the U.S. FDA where a recommendation on
lation practices can be extended to many drugs of same conducting bioequivalence studies is made available by
class or even of diversified classes. Readers have often the U.S. FDA. When filing an NDA or an ANDA, the
requested that more details be provided in the Manufac- filer is faced with the choice of defending the meth-
turing Direction sections. Whereas sufficient details are ods used to justify the bioavailability or bioequivalence
provided, this is restricted to prototype formulations to data. The U.S. FDA now allows application for waiver
keep the size of the book manageable and to reduce re- of bioequivalence requirement; a new chapter on this
dundancy. topic has been added along with details of the dis-
13. Addition of a listing of approved excipients and the level solution tests, where applicable, approved for various
allowed by regulatory authorities. This new section al- dosage forms.
lows formulators a clear choice on which excipients to 15. Dissolution testing requirements are included for all
choose; the excipients are reported in each volume per- dosage forms where this testing is required by the FDA.
taining to the formulation type covered. The listing is Surrogate testing to prove efficacy and compliance is get-
drawn from the FDA-approved entities. For the develop- ting more acceptance at regulatory agencies; in my expe-
ers of an ANDA, it is critical that the level of excipients be rience, a well-designed dissolution test is the best mea-
kept within the range generally approved to avoid large sure of continuous compliance. Coupled with chapters
expense in justifying any unapproved level. The only cat- on waivers of bioequivalence testing, this information on
egory for which the listing is not provided separately is dissolution testing should be great value to all manu-
the OTC volume since it contains many dosage forms and facturers; it is recommended that manufacturers develop
the reader is referred to dosage form–specific title of the their own in-house specifications, more stringent than
series. The choice of excipients forms keeps increasing those allowed in these listings and the USP.
with many new choices that can provide many special 16. Best-selling products (top 200 prescription products) are
release characteristics to the dosage forms. Choosing cor- identified with an asterisk and a brand name where ap-
rect excipients is thus a tedious exercise and requires so- plicable; in all instances, composition of these products is
phisticated multivariate statistical analysis. Whereas the provided and formulation of generic equivalents. Despite
formulator may choose any number of novel or classical the vast expansion of pharmaceutical sales and shifting
components, it is important to know the levels of excip- of categories of blockbuster drugs, basic drugs affecting
ients that are generally allowed in various formulations gastrointestinal tract, vascular system, and brain remain
to reduce the cost of redundant exercises; I have there- most widely prescribed.
fore included, as an appendix to each volume, a list of all 17. Updated list of approved coloring agents in the United
excipients that are currently approved by the U.S. FDA States, Canada, European Union, and Japan is included
along their appropriate levels. I suggest that a formula- to allow manufactures to design products for worldwide
tor consult this table before deciding on which level of distribution.
excipient to use; it does not mean that the excipient can- 18. Tablet-coating formulations that meet worldwide re-
not be used outside this range but it obviates the need quirements of color selection are included in the Volume
for a validation and lengthy justification studies in the 1 (compressed solids) and Volume 5 (OTC) because these
submission of NDAs. represent the products often coated.
14. Expanded section on bioequivalence submission was 19. Guidelines on preparing regulatory filings are now dis-
required to highlight the recent changes in these re- persed throughout the series depending on where these
quirements. New entries include a comprehensive listing guidelines are more crucial. However, the reader would,
of bioequivalence protocols in abbreviated form as ap- as before, need access to all volumes to benefit from the
proved by the U.S. FDA; these descriptions are provided advice and guidelines provided.
in each volume where pertinent. To receive approval
for an ANDA, an applicant must generally demonstrate, As always, comments and criticism from the readers are
among other things, equivalence of the active ingredi- welcomed and these can be sent to me at Niazi@pharmsci
ent, dosage form, strength, route of administration and .com or [email protected]. I would try to respond to any in-
conditions of use as the listed drug, and that the pro- quiries requiring clarification of the information enclosed in
posed drug product is bioequivalent to the reference these volumes.
listed drug [21 USC 355(j)(2)(A); 21 CFR 314.94(a)]. Bioe- I would like to express deep gratitude to Sherri R. Niziolek
quivalent drug products show no significant difference in and Michelle Schmitt-DeBonis at Informa, the publisher of
 Preface to the Series—Second Edition vii

this work, for seeing an immediate value to the readers in In the first edition, I had dedicated each volume to one of
publishing the second edition of this book and allowing me my mentors; the second edition continues the dedication to
enough time to prepare this work. The diligent editing and these great teachers.
composing staff at Informa, particularly Joseph Stubenrauch,
Baljinder Kaur and others are highly appreciated. Regardless, Sarfaraz K. Niazi, Ph.D.
all errors and omissions remain altogether mine. Deerfield, Illinois, U.S.A.
 Preface to the Series—First Edition

No industry in the world is more highly regulated than the erations have led to the classification of products into these six
pharmaceutical industry because of potential threat to a pa- categories.
tient’s life from the use of pharmaceutical products. The cost Each volume includes a description of regulatory filing
of taking a new chemical entity (amortized over the cost of all techniques for the formulations described. Also included are
molecules racing) to final regulatory approval is a staggering the current regulatory guidelines on cGMP compliance spe-
$800 million, making the pharmaceutical industry one of the cific to the dosage form. Advice is offered on how to scale up
most research-intensive industries in the world. In the year the production batches.
2004, it is anticipated that the industry will spend about $20 It is expected that formulation scientists will use this in-
billion on research and development. The generic market of formation to benchmark their internal development protocols
drugs as the new entities come off patent is one of the fastest and cut the race to file short by adopting formulae that have
growing segments of the pharmaceutical industry, with every survived the test of time. Many of us who have worked in the
major multinational company having a significant presence pharmaceutical industry suffer from a close paradigm when
in this field. it comes to selecting formulations—”not invented here” per-
Whereas many stages of new drug development are in- haps reigns in the mind of many seasoned formulations scien-
herently constrained with time, the formulation of drugs into tists subconsciously when they prefer to choose only a certain
desirable dosage forms remains an area where expediency platform for development. It is expected that with the quick
can be practiced with appropriate knowledge by those who review of possibilities available to formulate made available
have mastered the skills of pharmaceutical formulations. The in this book, scientists will benefit from the experience of
Handbook of Pharmaceutical Manufacturing Formulations is the others.
first major attempt to consolidate the available knowledge For the teachers of formulation sciences, this series offers
about formulations in a comprehensive, and by nature a a wealth of information. Whether it is a selection of a preser-
rather voluminous, presentation. vative system or the choice of a disintegrant, the series offers
The book is divided into six volumes, based strictly on a wide choice to study and rationalize.
the type of formulation science involved in the development Many have assisted me in the development of this work
of these dosage forms: sterile products, compressed solids, that has taken years to compile, and I thank scores of my
uncompressed solids, liquid products, semisolid products, graduate students and colleagues for their help. A work of
and OTC products. The separation of OTC products, even this size cannot be produced without errors, although I hope
though they may easily fall into one of the other five cate- that these errors do not distract the reader from the utility
gories, is made to comply with the industry norms of sep- of the book. I would sincerely appreciate if readers point out
arate research divisions for OTC products. Sterile products these mistakes for corrections in future editions.
require skills related to sterilization of product, and of less
importance is the bioavailability issue, which is an inherent Sarfaraz K. Niazi, Ph.D.
problem of compressed dosage forms. These types of consid- Deerfield, Illinois, U.S.A.

viii
 Preface to the Volume—First Edition

Uncompressed solid products formulations comprise aggre- as small proteins, instantly liquefiable powders, and nanopar-
gates of powders, such as powders for topical application, ticles. Formulators are strongly urged to review the method-
for use as insufflations, and for extemporaneous suspensions, ologies described here to serve as a reference point for their
as well as hard gelatin capsules or any other form wherein own formulations. Some combination products or dosage
the final form is not compressed. The rationale for this clear forms are described that are not currently approved by the
demarcation of formulations based on their state of aggrega- FDA (i.e., not included in the Orange Book), and they may be
tion is important to understand. Whereas compressed solid in the development phase or in experimental phases. As is
products require formulation components to render them always the case, it is the responsibility of the manufacturer to
compressible while allowing free flow into compression cav- ensure that the formulations used in the production do not
ities, such considerations are of lesser importance for uncom- violate any intellectual property or proprietary practice laws.
pressed solid products. (The flow requirement, nevertheless, The most effective means of establishing this is through a
stays because the powders must be forced into capsule shells study of the Orange Book, which lists the exclusivities and un-
or poured into bottles or other packaging forms.) Uncom- expired patents. The patent numbers provided in the Orange
pressed solid products, on the other hand, offer their own set Book should then be searched for collateral patents, the FDA
of formulation problems related to segregation of powders freedom of information (FOI) database, and other literature
due to static charges, environmental contamination during to ensure that the intellectual or proprietary property rights
the filling process, and inevitable problems in wetting and are not violated.
dissolution, thus leading to possible bioavailability problems Whereas coating solutions are not as important as in the
in vivo. In the series of steps that determine the ultimate disso- case of compressed solids, nevertheless, some capsules are
lution of the product, however, uncompressed solid products coated and the granules that are filled in capsules for sus-
are one critical step ahead of compressed solid products— tained or timed release are coated, utilizing nonpareil sugar
disintegration. The formulator is advised to read chapter 4 beads most often. The coating solutions are described here,
of this volume, which discusses guidelines on the waiver of but the reader is further referred to Volume 1 for a detailed
bioavailability requirements. Substantial development costs description of coating solutions that can be easily adapted to
can be reduced when a drug undergoes fast dissolution, and the product intended for formulation into a sustained re-
these considerations must therefore be part of any new for- lease profile. Whereas some forms of powders are meant
mulation effort. The reader is also referred to Volume 1 of this to be sterile, the sterility considerations are discussed in
series where current and proposed bioavailability guidelines Volume 6.
are provided. The subject of powder technology is vast, with app-
Chapter 1 addresses the fundamental issues of good man- lications in many fields. The serious reader is referred
ufacturing practices (GMPs). The chapter provides access ad- to the journal Advanced Powder Technology (http://www.
dresses to all major guidelines around the world and also vsppub.com/journals/jn-AdvPowTec.html). Such advances
highlights the U.S. Food and Drug Administration (FDA) as inhalation insulin in a powder form and the new science of
guidelines. A discussion of the most recent changes in the nanoparticles open a new phase of pharmaceutical research
philosophy of establishing the GMP guidelines based on risk and development. Nanotechnology describes the ability to
assessment is addressed in this chapter as well. create new materials from building blocks the size of an atom
Chapter 2 presents a more recent discussion of how the cluster. Nanomaterials are powders and materials optimized
U.S. FDA inspectors are supposed to conduct inspections; this at the nanoscale (10−9 m or a billionth of a meter in size).
topic is of continuous importance to all drug manufacturers. Nanopowders consist of particles with dimensions that can
Although it is included in this volume, the guidelines apply be measured by X-ray crystallography to be a few hundred
to all dosage forms. atoms in diameter.
Chapter 3 discusses the topic of bioequivalence and The formulations are presented in this volume with a scale
bioavailability of solid products. Although this is discussed for each unit: per capsule or per unit dose of powder. Quan-
more thoroughly in Volume 1, the emphasis in chapter 3 is tities are expressed for 1000 units. Sometimes, however, a
placed on the guidelines to request a waiver of bioavailabil- different presentation is chosen for simplicity and clarity. It
ity/bioequivalence testing; this is something of great impor- is often customary for manufacturers to scale formulae for a
tance to both the innovator and the generic drug manufac- specific weight, such as 100 or 1000 kg to match the mixing
turer. vessel requirements. This can be done roughly by multiply-
Chapter 4 highlights the manufacturing aspects of uncom- ing the weight of each capsule or unit powder by the quantity
pressed drugs as well as various topics of general and specific desired to calculate the size of the batch. The reader should
interest. be aware that the actual yield may be different because of
Part II provides formulations for more than 400 pharma- differences in the scale and quantity due to differences in
ceutical products. Included in part are not only the currently the chemical form of drugs used, excesses added, and loss
approved products but also several innovative products such of moisture during manufacturing. Further, adjustment of

ix
x Preface to the Volume—First Edition

quantity based on potency of raw material, where pertinent, I am grateful to CRC Press I LLC for taking the lead in
changes the quantity requirements. Most of these products publishing what is possibly the largest such work in the field
are identified in this volume by a brief description before of pharmaceutical manufacturing. It has been a distinct priv-
the listing of the Bill of Materials, which may not necessarily ilege to have known Stephen Zollo, senior editor at CRC
represent the commercially available dosage form; the de- Press, for years. Stephen has done more than any editor I have
scription includes details of the commercial product. known to encourage me to complete this work on a timely ba-
A distinctive feature of this volume is the identification sis. The editorial assistance provided by the CRC Press staff
and inclusion of the most often approved capsules and pow- was indeed exemplary, particularly the assistance of Erika
ders in the United States. It is noteworthy that in the prepa- Dery, Samar Haddad, and others at CRC Press. Although
ration of an abbreviated new drug application (ANDA), it is much care has gone into correcting errors, any remaining er-
important for both regulatory and scientific reasons to keep rors are altogether mine. The reader is encouraged to bring
the selection of excipients as close as possible to the innova- any errors to my attention so that I may make corrections in
tor’s product. The listing provided here includes every excip- future editions of this volume ([email protected]).
ient used in the innovator listing and quantitative formulae This book is dedicated to Takeru Higuchi. Higuchi was
in several instances. Whereas, in most instances, sufficient a university regents distinguished professor of pharmaceu-
details are provided to assist in the formulation of a generic tical chemistry and chemistry at Kansas University, and the
equivalent with exact quantities of excipients and conditions founding chair of the department of pharmaceutical chem-
appropriate for processing, the examples provided for other istry. He was known for the first systematic application of
drugs of a similar type should be sufficient for an astute for- chemical principles to drug design, delivery, and analysis.
mulator to develop quickly these formulations. Should there His scientific accomplishments earned him the informal title
be a need for assistance in finalizing the formulations, how- of “father of physical pharmacy.” Higuchi died in 1987. A
ever, the reader is invited, without any obligation, to write to famous quote of Tak Higuchi is that “It is merely a matter
the author at [email protected]. It should be emphasized of orderly thinking . . . and a little organization.” One of his
that manufacturers frequently use colored capsule shells to admirers notes, “His uniqueness is that he can look into the
identify their products and often imprint them with logos or future and see things and imagine things that most of us can-
other identification marks. It is important to understand that not. Higuchi has the ability to identify what will be important
the coloring dyes are not universally approved and, in some in the future—that is his genius.” I met Tak several times dur-
instances, may form the basis for a trademark. The formulator ing my teaching career and heard a lot more about him from
is advised to investigate this aspect carefully; nevertheless, in my colleagues and teachers who worked with him directly. (It
most formulations, the dyes used are disclosed. was rumored that he wrote the entire logarithmic table when
Whereas the science and the art of formulations remain flying to Japan because he needed to solve an equation.) I
within the domain of experienced hands, the wide dissemi- learned much of my science by reading Tak’s papers, which
nation of information about drug formulation compositions are full of insight and fresh approaches to old problems. He
and problems related to them makes it easier for one to was also a good businessman and a wonderful role model
design excellent benchmarked formulations. The Web site for industry–academia partnership. His aura is inspiring and
of the U.S. FDA (http://www.fda.gov) remains one of the his presence overwhelming even though he is not among us
best sources of information. At times, however, commer- anymore. People like Tak Higuchi are rare in any profession;
cial sources of databases, particularly the details that come we were just lucky to have him.
under the Freedom of Information Act, can be more useful
(e.g., http://www.foiser-vices.com/). No endorsement is in- Sarfaraz K. Niazi, Ph.D.
tended here for any company or resource. Deerfield, Illinois, U.S.A.
 About the Author

Sarfaraz K. Niazi has been teaching and conducting research in the pharmaceutical industry for over
35 years. He has authored hundreds of scientific papers, textbooks, and presentations on the topics of
pharmaceutical formulation, biopharmaceutics, and pharmacokinetics of drugs. He is also an inventor
with scores of patents in the field of drug and dosage form delivery systems; he is also licensed to prac-
tice law before the U.S. Patent and Trademark Office. Having formulated hundreds of products from
the most popular consumer entries to complex biotechnology-derived products, he has accumulated
a wealth of knowledge in the science and art of formulating 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, cGMP compliance, pharmacokinetics and bioequiva-
lence evaluation, and intellectual property issues (http://www.pharmsci.com). He can be contacted at
[email protected]

xi
 Contents

Preface to the Series—Second Edition . . . . v 2.3.S.2 Manufacture (Name, Manufacturer) 55

Preface to the Series—First Edition . . . . viii 2.3.S.3 Characterization (Name, Manufacturer) 55
Preface to the Volume—First Edition . . . . ix For NCE: 55
About the Author . . . . xi For Biotech: 55
For NCE and Biotech: 55
PART I REGULATORY AND MANUFACTURING 2.3.S.4 Control of Drug Substance (Name,
GUIDELINES Manufacturer) 55
2.3.S.5 Reference Standards or Materials (Name,
1. U.S. FDA Good Manufacturing Practices 2 Manufacturer) 56
I. Introduction 2 2.3.S.6 Container Closure System (Name,
II. U.S. FDA cGMP Guidelines 2 Manufacturer) 56
A. General Provisions 4 2.3.S.7 Stability (Name, Manufacturer) 56
Part 210—cGMP in Manufacturing, 2.3.P Drug Product (Name, Dosage Form) 56
Processing, Packaging, or Holding of Drugs; 2.3.P.1 Description and Composition of the Drug
General 4 Product (Name, Dosage Form) 56
Part 211—cGMP for Finished 2.3.P.2 Pharmaceutical Development (Name, Dosage
Pharmaceuticals 5 Form) 56
III. Amendments to Part 211 18 2.3.P.3 Manufacture (Name, Dosage Form) 56
IV. U.S. FDA cGMP Overview Checklist 19 2.3.P.4 Control of Excipients (Name, Dosage
V. Drug Master Files and Certifications 23 Form) 56
A. Types of DMFs 23 2.3.P.5 Control of Drug Product (Name, Dosage
Glossary 23 Form) 56
2.3.P.6 Reference Standards or Materials (Name,
2. GMP Audit Template, EU Guidelines 27 Dosage Form) 56
2.3.P.7 Container Closure System (Name, Dosage
3. Guideline on the Common Technical Document Form) 56
for the Registration of Pharmaceuticals for 2.3.P.8 Stability (Name, Dosage Form) 56
Human Use 47 2.3.A Appendices 56
Background 47 2.3.A.1 Facilities and Equipment (Name,
Scope of the Guideline 47 Manufacturer) 56
General Principles 47 Biotech: 56
Organization of the Common Technical 2.3.A.2 Adventitious Agents Safety Evaluation (Name,
Document 47 Dosage Form, Manufacturer) 56
Organization of the Common Technical Document 2.3.A.3 Excipients 56
for the Registration of Pharmaceuticals for 2.3.R Regional Information 56
Human Use 48 Module 3: Quality 56
Granularity of Document 48 Scope of the Guideline 56
Definition of a Document 48 3.1 Table of Contents of Module 3 57
Document Pagination and Segregation 54 3.2 Body of Data 57
Section Numbering Within Documents 54 3.2.S Drug Substance (Name, Manufacturer) 57
Table of Contents Formatting 54 3.2.S.1 General Information (Name,
Module 2 54 Manufacturer) 57
Module 3 54 3.2.S.1.1 Nomenclature (Name, Manufacturer) 57
Module 4 54 3.2.S.1.2 Structure (Name, Manufacturer) 57
Module 5 54 NCE: 57
Organization of Module 3 55 Biotech: 57
Module 2: Common Technical Document 3.2.S.1.3 General Properties (Name,
Summaries 55 Manufacturer) 57
2.3: Quality Overall Summary 55 3.2.S.2 Manufacture (Name, Manufacturer) 57
Introduction 55 3.2.S.2.1 Manufacturer(s) (Name, Manufacturer) 57
2.3.S Drug Substance (Name, Manufacturer) 55 3.2.S.2.2 Description of Manufacturing Process and
2.3.S.1 General Information (Name, Process Controls (Name, Manufacturer) 57
Manufacturer) 55 NCE: 57

xii
 Contents xiii

Biotech: 57 3.2.P.2.3 Manufacturing Process Development (Name,

Batch(es) and scale definition 57 Dosage Form) 60
Cell culture and harvest 57 3.2.P.2.4 Container Closure System (Name, Dosage
Purification and modification reactions 57 form) 60
Filling, storage, and transportation (shipping) 58 3.2.P.2.5 Microbiological Attributes (Name, Dosage
3.2.S.2.3 Control of Materials (Name, Form) 60
Manufacturer) 58 3.2.P.2.6 Compatibility (Name, Dosage Form) 60
Biotech: 58 3.2.P.3 Manufacture (Name, Dosage Form) 60
Control of source and starting materials of biological 3.2.P.3.1 Manufacturer(s) (Name, Dosage Form) 60
origin 58 3.2.P.3.2 Batch Formula (Name, Dosage Form) 60
Source, history, and generation of the cell 3.2.P.3.3 Description of Manufacturing Process and
substrate 58 Process Controls (Name, Dosage Form) 60
Cell banking system, characterization, and testing 58 3.2.P.3.4 Controls of Critical Steps and Intermediates
3.2.S.2.4 Controls of Critical Steps and Intermediates (Name, Dosage Form) 61
(Name, Manufacturer) 58 3.2.P.3.5 Process Validation and/or Evaluation (Name,
3.2.S.2.5 Process Validation and/or Evaluation (Name, Dosage Form) 61
Manufacturer) 58 3.2.P.4 Control of Excipients (Name, Dosage
Biotech: 58 Form) 61
3.2.S.2.6 Manufacturing Process Development (Name, 3.2.P.4.1 Specifications (Name, Dosage Form) 61
Manufacturer) 58 3.2.P.4.2 Analytical Procedures (Name, Dosage
NCE: 58 Form) 61
Biotech: 58 3.2.P.4.3 Validation of Analytical Procedures (Name,
3.2.S.3 Characterization (Name, Manufacturer) 59 Dosage Form) 61
3.2.S.3.1 Elucidation of Structure and Other 3.2.P.4.4 Justification of Specifications (Name, Dosage
Characteristics (Name, Manufacturer) 59 Form) 61
NCE: 59 3.2.P.4.5 Excipients of Human or Animal Origin
Biotech: 59 (Name, Dosage Form) 61
3.2.S.3.2 Impurities (Name, Manufacturer) 59 3.2.P.4.6 Novel Excipients (Name, Dosage Form) 61
3.2.S.4 Control of Drug Substance (Name, 3.2.P.5 Control of Drug Product (Name, Dosage
Manufacturer) 59 Form) 61
3.2.S.4.1 Specification (Name, Manufacturer) 59 3.2.P.5.1 Specification(s) (Name, Dosage Form) 61
3.2.S.4.2 Analytical Procedures (Name, 3.2.P.5.2 Analytical Procedures (Name, Dosage
Manufacturer) 59 Form) 61
3.2.S.4.3 Validation of Analytical Procedures (Name, 3.2.P.5.3 Validation of Analytical Procedures (Name,
Manufacturer) 59 Dosage Form) 61
3.2.S.4.4 Batch Analyses (Name, Manufacturer) 59 3.2.P.5.4 Batch Analyses (Name, Dosage Form) 61
3.2.S.4.5 Justification of Specification (Name, 3.2.P.5.5 Characterization of Impurities (Name,
Manufacturer) 59 Dosage Form) 61
3.2.S.5 Reference Standards or Materials (Name, 3.2.P.5.6 Justification of Specification(s) (Name,
Manufacturer) 59 Dosage Form) 61
3.2.S.6 Container Closure System (Name, 3.2.P.6 Reference Standards or Materials (Name,
Manufacturer) 59 Dosage Form) 61
3.2.S.7 Stability (Name, Manufacturer) 59 3.2.P.7 Container Closure System (Name, Dosage
3.2.S.7.1 Stability Summary and Conclusions (Name, Form) 61
Manufacturer) 59 3.2.P.8 Stability (Name, Dosage Form) 61
3.2.S.7.2 Postapproval Stability Protocol and Stability 3.2.P.8.1 Stability Summary and Conclusion (Name,
Commitment (Name, Manufacturer) 59 Dosage Form) 61
3.2.S.7.3 Stability Data (Name, Manufacturer) 59 3.2.P.8.2 Postapproval Stability Protocol and Stability
3.2.P Drug Product (Name, Dosage Form) 59 Commitment (name, dosage form) 62
3.2.P.1 Description and Composition of the Drug 3.2.P.8.3 Stability Data (Name, Dosage Form) 62
Product (name, dosage form) 59 3.2.A Appendices 62
3.2.P.2 Pharmaceutical Development (Name, Dosage 3.2.A.1 Facilities and Equipment (Name,
Form) 59 Manufacturer) 62
3.2.P.2.1 Components of the Drug Product (Name, Biotech: 62
Dosage Form) 60 3.2.A.2 Adventitious Agents Safety Evaluation (Name,
3.2.P.2.1.1 Drug substance (name, dosage form) 60 Dosage Form, Manufacturer) 62
3.2.P.2.1.2 Excipients (name, dosage form) 60 For nonviral adventitious agents: 62
3.2.P.2.2 Drug Product (Name, Dosage Form) 60 For viral adventitious agents: 62
3.2.P.2.2.1 Formulation development (name, dosage Materials of biological origin 62
form) 60 Testing at appropriate stages of production 62
3.2.P.2.2.2 Overages (name, dosage form) 60 Viral testing of unprocessed bulk 62
3.2.P.2.2.3 Physicochemical and biological properties Viral clearance studies 62
(name, dosage form) 60 3.2.A.3 Excipients 62
xiv Contents

3.2.R Regional Information 62 4.2 Study Reports 67

3.3 Literature References 63 4.3 Literature References 68
Organization of Module 4 63 Appendix A 68
Nonclinical Overview and Nonclinical Summaries Tables and Figures for Written Summaries 68
of Module 2 Appendix B 68
Module 2: Common Technical Document The Nonclinical Tabulated Summaries—
Summaries 63 Templates 68
General Principles of Nonclinical Overview and The Nonclinical Tabulated Summaries—
Summaries 63 Templates 68
2.4 Nonclinical Overview 63 Module 5: Clinical Study Reports 68
General Aspects 63 Clinical Overview and Clinical Summary of
Content and Structural Format 63 Module 2 68
2.6 Nonclinical Written and Tabulated Summaries 64 Module 2: Common Technical Document
Nonclinical Written Summaries 64 Summaries 68
Introduction 64 2.5: Clinical Overview 68
General Presentation Issues 64 Preamble 68
Use of Tables and Figures 64 Detailed Discussion of Content of the Clinical
Content of Nonclinical Written and Tabulated Overview Sections 69
Summaries 64 2.5.1 Product Development Rationale 69
2.6.1 Introduction 64 2.5.2 Overview of Biopharmaceuticals 69
2.6.2 Pharmacology Written Summary 65 2.5.3 Overview of Clinical Pharmacology 69
2.6.2.1 Brief Summary 65 2.5.4 Overview of Efficacy 69
2.6.2.2 Primary Pharmacodynamics 65 2.5.5 Overview of Safety 70
2.6.2.3 Secondary Pharmacodynamics 65 2.5.6 Benefits and Risks Conclusions 70
2.6.2.4 Safety Pharmacology 65 2.5.7 Literature References 71
2.6.2.5 Pharmacodynamic Drug Interactions 65 2.7: Clinical Summary 71
2.6.2.6 Discussion and Conclusions 65 Preamble 71
2.6.2.7 Tables and Figures 65 Table of Contents 71
2.6.3 Pharmacology Tabulated Summary (See 2.7.1 Summary of Biopharmaceutical Studies and
Appendix B) 65 Associated Analytical Methods 71
2.6.4 Pharmacokinetics Written Summary 65 2.7.1.1 Background and Overview 71
2.6.4.1 Brief Summary 65 2.7.1.2 Summary of Results of Individual Studies 71
2.6.4.2 Methods of Analysis 65 2.7.1.3 Comparison and Analyses of Results across
2.6.4.3 Absorption 65 Studies 71
2.6.4.4 Distribution 65 2.7.1.4 Appendix 71
2.6.4.5 Metabolism (Interspecies Comparison) 65 2.7.2 Summary of Clinical Pharmacology Studies 72
2.6.4.6 Excretion 65 2.7.2.1 Background and Overview 72
2.6.4.7 Pharmacokinetic Drug Interactions 65 2.7.2.2 Summary of Results of Individual Studies 72
2.6.4.8 Other Pharmacokinetic Studies 65 2.7.2.3 Comparison and Analyses of Results across
2.6.4.9 Discussion and Conclusions 65 Studies 72
2.6.4.10 Tables and Figures 66 2.7.2.4 Special Studies 72
2.6.5 Pharmacokinetics Tabulated Summary (See Example 1: Immunogenicity 73
Appendix B) 66 Example 2: Clinical microbiology 73
2.6.6 Toxicology Written Summary 66 2.7.2.5 Appendix 73
2.6.6.1 Brief Summary 66 2.7.3 Summary of Clinical Efficacy 73
2.6.6.2 Single-Dose Toxicity 66 2.7.3.1 Background and Overview of Clinical
2.6.6.3 Repeat-Dose Toxicity (Including Supportive Efficacy 73
Toxicokinetics Evaluation) 66 2.7.3.2 Summary of Results of Individual Studies 73
2.6.6.4 Genotoxicity 66 2.7.3.3 Comparison and Analyses of Results across
2.6.6.5 Carcinogenicity (Including Supportive Studies 74
Toxicokinetics Evaluations) 66 2.7.3.3.1 Study Populations 74
2.6.6.6 Reproductive and Developmental Toxicity 2.7.3.3.2 Comparison of Efficacy Results of all
(Including Range-Finding Studies and Studies 74
Supportive Toxicokinetics Evaluations) 66 2.7.3.3.3 Comparison of Results in Subpopulations 74
2.6.6.7 Local Tolerance 66 2.7.3.4 Analysis of Clinical Information Relevant to
2.6.6.8 Other Toxicity Studies (If Available) 66 Dosing Recommendations 75
2.6.6.9 Discussion and Conclusions 67 2.7.3.5 Persistence of Efficacy and/or Tolerance
2.6.6.10 Tables and Figures 67 Effects 75
2.6.7 Toxicology Tabulated Summary (See 2.7.3.6 Appendix 75
Appendix B) 67 2.7.4 Summary of Clinical Safety 75
Nonclinical Tabulated Summaries 67 2.7.4.1 Exposure to the Drug 76
Module 4: Nonclinical Study Reports 67 2.7.4.1.1 Overall Safety Evaluation Plan and
4.1 Table of Contents of Module 4 67 Narratives of Safety Studies 76
 Contents xv

2.7.4.1.2 Overall Extent of Exposure 76 5.3.4.1 Healthy Subject PD and PK/PD Study
2.7.4.1.3 Demographic and Other Characteristics of Reports 82
Study Population 76 5.3.4.2 Patient PD and PK/PD Study Reports 82
2.7.4.2 Adverse Events 76 5.3.5 Reports of Efficacy and Safety Studies 82
2.7.4.2.1 Analysis of Adverse Events 76 5.3.5.1 Study Reports of Controlled Clinical Studies
2.7.4.2.1.1 Common Adverse Events 77 Pertinent to the Claimed Indication 83
2.7.4.2.1.2 Deaths 78 5.3.5.2 Study Reports of Uncontrolled Clinical
2.7.4.2.1.3 Other Serious Adverse Events 78 Studies 83
2.7.4.2.1.4 Other Significant Adverse Events 78 5.3.5.3 Reports of Analyses of Data from More than
2.7.4.2.1.5 Analysis of Adverse Events by Organ One Study 83
System or Syndrome 78 5.3.5.4 Other Study Reports 83
2.7.4.2.2 Narratives 78 5.3.6 Reports of PostMarketing Experience 83
2.7.4.3 Clinical Laboratory Evaluations 78 5.3.7 Case Report Forms and Individual Patient
2.7.4.4 Vital Signs, Physical Findings, and Other Listings 83
Observations Related to Safety 79 5.4 Literature References 83
2.7.4.5 Safety in Special Groups and Situations 79 1. General Questions 83
2.7.4.5.1 Intrinsic Factors 79 Format or Content? 83
2.7.4.5.2 Extrinsic Factors 79 CTD training 85
2.7.4.5.3 Drug Interactions 79 2. Questions Regarding Location Issues 85
2.7.4.5.4 Use in Pregnancy and Lactation 79 General Issues 85
2.7.4.5.5 Overdose 79 3. Associated Information Located in Different
2.7.4.5.6 Drug Abuse 79 Sections 86
2.7.4.5.7 Withdrawal and Rebound 79 3.1 Polymorphism 86
2.7.4.5.8 Effects on Ability to Drive or Operate 3.2 Particle Size 86
Machinery or Impairment of Mental Ability 79 3.3 Impurities 86
2.7.4.6 Postmarketing Data 80 3.4 New Location of Quality Information for
2.7.4.7 Appendix 80 Investigational Formulations 87
2.7.5 Literature References 80 3.5 Where Would the Information Related to
2.7.6 Synopses of Individual Studies 80 Nonviral Adventitious Agents be Placed Within
Summary of Bioavailability Studies 80 Module 3.2? 87
Summary of In vitro Dissolution Studies 80 6. Safety 94
Summary of Drug–Drug Interaction PK 7. Efficacy 94
Studies 80 ISS/ISE 95
Module 5: Clinical Study Reports 80
Preamble 80
Detailed Organization of Clinical Study Reports and 4. Process Validation: General Principles and
Related Information in Module 5 80 Practices 98
5.1 Table of Contents of Module 5 80 I. Introduction 98
5.2 Tabular Listing of All Clinical Studies 81 II. Background 98
5.3 Clinical Study Reports 81 III. Statutory and Regulatory Requirements for
5.3.1 Reports of Biopharmaceutical Studies 81 Process Validation 99
5.3.1.1 Bioavailability (BA) Study Reports 81 IV. Recommendations 99
5.3.1.2 Comparative BA and BE Study Reports 81 A. General Considerations for Process
5.3.1.3 In Vitro –In Vivo Correlation Study Reports 81 Validation 99
5.3.1.4 Reports of Bioanalytical and Analytical B. Specific Stages and Activities of Process
Methods for Human Studies 81 Validation in the Product Lifecycle 99
5.3.2 Reports of Studies Pertinent to Pharmacokinetics 1. Stage 1—Process Design 100
Using Human Biomaterials 81 2. Stage 2—Process Qualification 100
5.3.2.1 Plasma Protein Binding Study Reports 81 3. Stage 3—Continued Process
5.3.2.2 Reports of Hepatic Metabolism and Drug Verification 102
Interaction Studies 81 V. Concurrent Release of Performance
5.3.2.3 Reports of Studies Using Other Human Qualification Batches 103
Biomaterials 81 VI. Documentation 103
5.3.3 Reports of Human PK Studies 81 VII. Analytical Methodology 103
5.3.3.1 Healthy Subject PK and Initial Tolerability References 103
Study Reports 82
5.3.3.2 Patient PK and Initial Tolerability Study
Reports 82 5. Bioequivalence Regulatory Compliance 104
5.3.3.3 Intrinsic Factor PK Study Reports 82 I. Background 104
5.3.3.4 Extrinsic Factor PK Study Reports 82 II. Regulatory Aspects 105
5.3.3.5 Population PK Study Reports 82 III. Equivalence Documentation for Marketing
5.3.4 Reports of Human Pharmacodynamic (PD) Authorization 105
Studies 82 IV. Therapeutic Classification 106
xvi Contents

V. Topics Related to Regulatory Compliance G. Dose Selection 117

106 H. Multiple Strengths of Solid Oral Dosage
A. Is a BE Study Required? 106 Forms 117
B. Prior Review 109 I. Manufacturing of Pilot Batch
VI. Record Maintenance 109 (“Biobatch”) 118
VII. Clarification on Requirements 110 J. Dosing by Labeled Concentration 118
A. In Which Cases Is It Allowed to Use a K. Single Dose vs. Multiple Dose
Wider Acceptance Range for the Ratio of Studies 118
Cmax? 110 L. Guidelines on the Design of a
B. When Can Subjects Classified as Outliers Single-Dose Study 118
Be Excluded from the Analysis in BE M. Guidelines for Multiple-Dose
Studies? 110 Study 118
C. If One Side of the 90% CI of a PK N. Fed vs. Fasted State 119
Variable for Testing BE Lies on 0.80 or O. Pharmacological End-Point Studies 119
1.25, Can We Conclude that the Products P. Clinical End-Point Studies 119
Are Bioequivalent? 111 Q. Analytical Methods 120
D. In Which Cases May a Nonparametric 1. Assay Consideration 120
Statistical Model Be Used? 111 Concentration range and
E. When Should Metabolite Data Be Used linearity 120
to Establish BE? 111 Limit of detection 120
F. When Using Metabolite Data to Establish Limit of quantitation 120
BE, May One Use the Same Justification Specificity 120
for Widening the Cmax Acceptance Accuracy (Recovery) 120
Criteria as in the Case of the Parent Precision 120
Compound? 111 Analyte stability 120
G. What is a “Highly Variable Drug or Drug Analytical system stability 120
Product”? 111 QC samples 121
H. What Are the Conditions for Using Replicate and repeat analyses 121
Urinary PK Data for BE Assessment? Summary of samples to be run with
112 each analysis 121
I. Standardization of BE Studies with R. Sampling Time Considerations 121
Regard to Food Intake. How Strictly S. Protein Binding 121
Should the Guideline Be Interpreted? T. Subject Number 121
112 U. Crossover and Parallel Design
J. Worldwide Considerations 112 Considerations 121
VIII. Postapproval Changes 113 V. Duration of Washout Time for Crossover
A. NDAs: BA and BE Studies 113 Study 122
B. Waivers of In Vivo BE Studies W. Fed BE Studies 122
(Biowaivers): NDAs and aNDAs 113 X. Food Effects on Drug Products 122
1. Beaded Capsules—Lower Y. Recommendations for
Strength 113 Immediate-Release Drugs: 122
2. Tablets—Lower Strength 113 Z. Recommendations For Modified-Release
C. Risk-Based BE 113 Products 122
D. Typical Examples of Complex BE 115 1. Study Design 123
1. Digoxin 115 2. General Design 123
2. Levothyroxine 115 3. Subject Selection 123
3. Warfarin Sodium 115 4. Dosage Strength 123
4. Albuterol Metered-Dose Inhalers 116 5. Test Meal 123
E. General PK Study Design and Data 6. Administration 123
Handling 116 7. Sample Collection 123
1. Study Conduct 116 8. Data Analysis and Labeling 123
2. Sample Collection and Sampling Parent Drug vs. Metabolites 124
Times 117 Enantiomers vs. Racemates 124
3. Subjects with Predose Plasma Drug Products with Complex
Concentrations 117 Mixtures as the Active
4. Data Deletion due to Vomiting 117 Ingredients 124
5. PK Information Recommended for Long Half-Life Drugs 124
Submission 117 First-Point Cmax 124
6. BE Demonstration Measures 117 Orally Administered Drugs Intended
7. CI Values 117 for Local Action 125
8. Statistical Information for AUC0-T, Sprinkles 125
AUC0-◦ , and Cmax 117 Special Vehicles 125
F. Measurement Indices 117 Locally Acting GI Drugs 125
 Contents xvii

Animal Drug BE Testing 125 4.4. Containment 145

Reference Product 126 4.5. Lighting 145
Reference 126 4.6. Sewage and Refuse 145
4.7. Sanitation and Maintenance 146
6. Bioequivalence Regulatory Review Process and 5. Process Equipment 146
Audit 127 5.1. Design and Construction 146
Background 127 5.2. Equipment Maintenance and
Protocols 127 Cleaning 146
Productivity Documentation 127 5.3. Calibration 146
Methods Validation for Abbreviated 5.4. Computerized Systems 146
New Drug Applications 128 6. Documentation and Records 147
Good Laboratory Practices 128 6.1. Documentation System and
Types of Inspections 129 Specifications 147
Inspections 129 6.2. Equipment Cleaning and Use
FDA Audit Plans 133 Record 147
PART I—Background 133 6.3. Records of Raw Materials,
PART II—Implementation 134 Intermediates, API Labeling, and
Objective 134 Packaging Materials 147
Program Management Instructions 134 6.4. Master Production Instructions (Master
PART III—Inspectional 134 Production and Control Records) 147
Operations 134 6.5. Batch Production Records (Batch
PART IV—Analytical 135 Production and Control Records) 148
PART V—Regulatory/Administrative Strategy 135 6.6. Laboratory Control Records 148
Clinical Testing 135 6.7. Batch Production Record Review 148
Analytical Testing 135 7. Materials Management 149
Bioequivalence Inspection Report 136 7.1. General Controls 149
PART I—Facilities and Procedures (Clinical 7.2. Receipt and Quarantine 149
and Analytical) 136 7.3. Sampling and Testing of Incoming
Electronic Records and Signatures 136 Production Materials 149
Clinical Data and Operations 137 7.4. Storage 149
General 137 7.5. Reevaluation 149
Inspection Procedures 137 8. Production and In-Process Controls 149
Study Responsibility and Administration 137 8.1. Production Operations 149
Protocol 137 8.2. Time Limits 150
Subjects’ Records 137 8.3. In-Process Sampling and Controls 150
Other Study Records 138 8.4. Blending Batches of Intermediates or
Consent of Human Subjects 138 APIs 150
Institutional Review Board 138 8.5. Contamination Control 150
Sponsor 138 9. Packaging and Identification Labeling of APIs
Test Article Accountability 138 and Intermediates 151
Records Retention 138 9.1. General 151
Abbreviated Report Format 138 9.2. Packaging Materials 151
I. Analytical Data and Operations 139 9.3. Label Issuance and Control 151
References 141 9.4. Packaging and Labeling
Operations 151
7. EU Guidelines to Good Manufacturing 10. Storage and Distribution 151
Practice 142 10.1. Warehousing Procedures 151
1.1. Objective 142 10.2. Distribution Procedures 151
1.2. Scope 142 11. Laboratory Controls 152
2. Quality Management 143 11.1. General Controls 152
2.1. Principles 143 11.2. Testing of Intermediates and APIs 152
2.2. Responsibilities of the Quality 11.3. Validation of Analytical
Unit(s) 143 Procedures—See section 12. 152
2.3. Responsibility for Production 11.4. Certificates of Analysis 152
Activities 144 11.5. Stability Monitoring of APIs 153
2.4. Internal Audits (Self-Inspection) 144 11.6. Expiry and Retest Dating 153
3. Personnel 144 11.7. Reserve/Retention Samples 153
3.1. Personnel Qualifications 144 12. Validation 153
3.2. Consultants 144 12.1. Validation Policy 153
4. Buildings and Facilities 145 12.2. Validation Documentation 153
4.1. Design and Construction 145 12.3. Qualification 153
4.2. Utilities 145 12.4. Approaches to Process Validation 154
4.3. Water 145 12.5. Process Validation Program 154
xviii Contents

12.6. Periodic Review of Validated D. Strategies for Preinspection 166

Systems 154 E. International Inspection 168
12.7. Cleaning Validation 154 F. Product Stability Data 169
12.8. Validation of Analytical Methods 155 G. Validation of Processes 170
13. Change Control 155 H. Change Control 172
14. Rejection and Reuse of Materials 155 1. Cleaning Validation 172
14.1. Rejection 155 2. Analytical Methods Validation 173
14.2. Reprocessing 155 3. Computer System Validation 173
14.3. Reworking 155 PART 11—Electronic Records;
14.4. Recovery of Materials and Solvents 155 Electronic Signatures 173
14.5. Returns 156 Subpart A—General
15. Complaints and Recalls 156 Provisions 173
16. Contract Manufacturers (including Sec. 11.1 Scope. 173
Laboratories) 156 Sec. 11.2 Implementation. 173
17. Agents, Brokers, Traders, Distributors, Sec. 11.3 Definitions. 174
Repackers, and Relabellers 156 Subpart B—Electronic Records 174
17.1. Applicability 156 Sec. 11.10 Controls for closed
17.2. Quality Management 156 systems. 174
17.3. Repackaging, Relabeling and Holding of Sec. 11.30 Controls for open
APIs and Intermediates 156 systems. 174
17.4. Stability 157 Sec. 11.50 Signature
17.5. Transfer of Information 157 manifestations. 175
17.6. Handling of Returns 157 Sec. 11.70 Signature/record
18. General 157 linking. 175
18.1. Cell Bank Maintenance and Record Subpart C—Electronic
Keeping 158 Signatures 175
18.2. Cell Culture/Fermentation 158 Sec. 11.100 General
18.3. Harvesting, Isolation, and requirements. 175
Purification 158 Sec. 11.200 Electronic signature
18.4. Viral Removal/Inactivation steps 158 components and controls. 175
19. APIs for Use in Clinical Trials 158 Sec. 11.300 Controls for
19.1. General 158 identification codes/
19.2. Quality 159 passwords. 175
19.3. Equipment and Facilities 159 I. Documentation Standards 176
19.4. Control of Raw Materials 159 1. Development History Report 176
19.5. Production 159 2. Deviation Records 176
19.6. Validation 159 3. Installation, Operational, and
19.7. Changes 159 Performance Qualification 177
19.8. Laboratory Controls 159 4. Organizational Chart 177
19.9. Documentation 159 5. Products List 177
Glossary 159 6. Drawings 177
7. Stability Data 177
8. Preapproval Inspections 163 8. SOPs 177
I. Introduction 163 9. Training Records 177
A. Background 163 10. Validation Records 177
B. Objective 163 11. Technology Transfer and
C. Triggering of Inspections 164 Scale-Up 177
D. Inspections/Audits 165 12. Quality Policy 178
1. Manufacturing Process 165 13. Vendor Approval 178
i. Drug Product (Dosage Form) 165 14. Outside Contractors 178
ii. Drug Substance (Bulk Drug
Chemical) 165 9. Formulation Factors in Uncompressed Dosage
2. Reprocessing 165 Forms 179
3. Laboratory 165 I. Relative Humidity 179
4. Components 165 II. Surface Area 179
5. Building and Facilities 165 III. Sieve Analysis 179
6. Equipment 165 IV. Particle Size Distribution 179
7. Packaging and Labeling Controls V. Powder Flow Properties 180
165 VI. Real, Tapped, and Bulk Density 180
II. Regulatory/Administrative Strategy 165 VII. Solid Handling 180
A. General 165 VIII. Mixing of Powders 181
B. Process Validation 166 IX. Oral Powders 181
C. Key Elements 166 X. Capsules 181
 Contents xix

XI. FDA Classification of Capsule Types 181 Amoxicillin and Bromhexine Hydrochloride
XII. FDA Classification of Powders 182 Capsules 238
XIII. Inhalers and Lung Delivery 182 Amoxicillin and Clavulanic Acid Powder for
XIV. Problems in Powder Handling 182 Suspension, 125 mg and 31.25 mg per 5 mL
XV. Capsulation Equipment 183 (Amoxil) 239
XVI. Capsule Finishing 183 Amoxicillin and Clavulanic Acid Powder for
XVII. Modified-Release Products 183 Suspension 239
XVIII. Clinical Test Supplies and Placebos 183 Amoxicillin and Clavulanate Potassium for
XIX. Coated Particles 183 Suspension 240
XX. Mixing Mechanisms 183 Amoxicillin and Clavulanate Potassium for
XXI. Segregation Mechanisms 183 Suspension 240
XXII. Mixing Equipment 183 Amoxicillin Powder for Suspension (125 and
XXIII. Milling 184 250 mg) 241
References 184 Amoxicillin Trihydrate Capsules (250 and
500 mg) 241
10. Bioequivalence Testing Protocols 185 Ampicillin Dry Syrup (5% = 500 mg/10 mL) 242
Ampicillin Powder for Suspension 242
Ampicillin Trihydrate Capsules 242
11. Dissolution Testing of Uncompressed Solid
Ampicillin Trihydrate Capsules for Suspension 243
Dosage Forms 197
Ampicillin Trihydrate Powder for Suspension 243
Antibacterial and Bacterial Culture Capsules 244
12. Approved Excipients in Uncompressed Solid Antifungal Foot Powder 244
Dosage Forms 204 Antioxidant Eye Nutrition Supplement Capsules 245
Aspartame Granules in Sachets 245
Aspartame Powder in Sachets 245
PART II MANUFACTURING FORMULATIONS
Aspirin and Chlorpheniramine Powder 245
Uncompressed Solids Formulations 229 Aspirin-Coated Crystals 245
Acebutolol Hydrochloride Capsules 229 Aspirin and Phenylpropanolamine Powder 246
Aceclofenac Instant Granules 229 Aspirin Microencapsulated Sustained-Release
Acetaminophen and Diphenhydramine Capsules 246
Hydrochloride Hot Therapy Sachets 230 Aspirin, Salicylamide, and Caffeine Powder 246
Acetaminophen Capsules (500 mg) 230 Azithromycin Suspension 246
Acetaminophen, Doxylamine, and Caffeine Azithromycin Capsules 247
Effervescent 231 Azithromycin Capsules 247
Acetaminophen Instant Granules 231 Azithromycin Capsules 247
Acetaminophen Instant Granules 232 Azithromycin Capsules and Oral Suspension 248
Acetaminophen Instant Granules 232 Azithromycin for Oral Suspension 248
Acetaminophen, Pseudoephedrine Hydrochloride, Azithromycin for Oral Suspension 249
Chlorpheniramine Hot Therapy Sachet 233 Azithromycin Sachets for Oral Suspension 249
Acetaminophen, Pseudoephedrine Hydrochloride Balsalazide Disodium Capsules 250
Hot Therapy Sachet 233 Benazepril Hydrochloride and Amlodipine Besylate
Acetaminophen Swallow Capsules 234 Capsules 250
Acetazolamide Sustained-Release Capsules 234 Benazepril Hydrochloride and Amlodipine Besylate
Acetylcysteine Sachets 234 Capsules 250
Acitretin Capsules 235 Bisacodyl Colonic Delivery Capsules 251
Acrivastine and Pseudoephedrine Hydrochloride Brompheniramine and Pseudoephedrine
Capsules 235 Capsules 251
Acrivastine and Pseudoephedrine Hydrochloride Budesonide Capsules 252
Capsules 235 Budesonide Inhalation Powder 252
Acyclovir Capsules 235 Butalbital and Acetaminophen Capsules 252
Acyclovir Capsules 235 Calcitonin (Salmon) Capsules 253
Adenosine Monophosphate Topical Powder 236 Calcitriol Capsules 254
Aluminum Acetate Powder 236 Calcium Carbonate Microencapsulated
Aluminum Hydroxide and Magnesium Carbonate Sustained-Release Capsules 254
Dry Syrup 236 Camptothecin Capsules 254
Aminosalicylic Acid Granules 236 Carbamazepine Extended-Release Capsules 255
Amlodipine Besylate and Benazepril Hydrochloride Cefaclor Capsules 256
Capsules 237 Cefdinir Capsules and Oral Suspension 256
Amlodipine Besylate and Benazepril Hydrochloride Cefixime for Oral Suspension 256
Capsules 237 Cefpodoxime Proxetil for Oral Suspension 256
Amlodipine Besylate Capsules 237 Cefprozil for Oral Suspension 256
Amlodipine Free Base Capsules 238 Ceftibuten Capsules and Oral Suspension 257
Amlodipine Maleate Capsules 238 Ceftibuten for Oral Suspension 257
xx Contents

Cefuroxime for Oral Suspension 257 Erythromycin Delayed-Release Capsules 276

Celecoxib Capsules 258 Erythromycin Delayed-Release Capsules 276
Celecoxib Tablets Celebrex 258 Erythromycin Ethylsuccinate for Oral
Cellulose Triacetate Liquefiable Topical Suspension 276
Powder 258 Erythromycin Ethylsuccinate for Oral Suspension
Cephalexin Capsules 259 (200 mg/5 mL) 277
Cephalexin Powder for Oral Suspension 259 Erythromycin Stearate for Oral Suspension 278
Cephradine Capsules 259 Erythromycin Stearate for Oral Suspension 279
Cephradine Powder for Suspension 260 Erythropoietin Capsules 280
Cevimeline Capsules 260 Esomeprazole Magnesium Capsules 281
Cevimeline Capsules 260 Estramustine Phosphate Capsules 281
Chlordiazepoxide Hydrochloride Capsules 261 Ethosuximide Capsules 281
Chlordiazepoxide Hydrochloride Capsules 261 Etodolac Capsules 281
Chloroxylenol and Chlorhexidine Topical Felbamate for Oral Suspension 281
Powder 261 Fenofibrate Capsules 281
Chlorpromazine Sustained-Release Capsules 262 Fenofibrate Capsules 281
Cimetidine Microencapsulated Sustained-Release Fenofibrate Capsules 282
Capsules 262 Fexofenadine Hydrochloride Capsules 282
Citrate Effervescent Powder 262 Fexofenadine Hydrochloride Capsules 282
Clindamycin Capsules 263 Fluconazole for Oral Suspension 283
Clindamycin Capsules (150 mg) 263 Flucytosine Capsules 283
Clofibrate Capsules 263 Fluoxetine Capsules 283
Clonidine Sustained-Release Capsules 263 Fluoxetine Hydrochloride Capsules 283
Clorazepate Dipotassium Capsules 264 Fluoxetine Hydrochloride Instant and Weekly
Coated Spheroids 264 Capsules 284
Crospovidone Water-Dispersible Tablets 265 Flutamide Capsules 284
Cyanocobalamin Tablets 265 Fluticasone Propionate and Salmeterol Xinafoate
Cyclosporin A Capsules 265 Inhalation Powder 284
Dantrolene Sodium Capsules 266 Fluvastatin Sodium Capsules 284
Dextroamphetamine Sulfate Capsules 266 Fluvastatin Sodium Capsules 284
Diclofenac and Misoprostol Capsules 266 Formoterol Fumarate Inhalation Powder 285
Diclofenac Spheronized Pellets for Sustained-Release Formoterol Fumarate Inhaler Capsules 285
Coating (30%) 266 Fosfomycin Tromethamine Sachets 285
Diclofenac Sustained-Release Capsules 266 Gabapentin Capsules 285
Diclofenac Granules 267 Gabapentin Capsules 285
Didanosine Delayed-Release Capsules 268 Ganciclovir Capsules 285
Didanosine Delayed-Release Capsules Enteric-Coated Ganciclovir Capsules 285
Beadlets 268 Gemfibrozil Capsules 286
Didanosine for Oral Suspension 268 Glycoprotein IIa/IIb Capsules 286
Diethyl Toluamide Topical Powder 268 Guaifenesin Sustained-Release Capsules 287
Difluoromethylornithine-Alpha Capsules 269 Herbal AIDS Treatment Capsules 287
Diltiazem Hydrochloride Extended-Release Histidine Capsules 287
Capsules 270 Human Growth Hormone Capsules 288
Diphenhydramine Hydrochloride Capsules 271 Hydrochlorothiazide and Triamterene Capsules 289
Dipyridamole and Aspirin Extended-Release Hydrochlorothiazide Capsules 289
Capsules 271 Hydroxyzine Pamoate Capsules and Oral
Divalproex Sodium Capsules 271 Suspension 289
Divalproex Sodium Coated Particle Capsules 271 Hyoscyamine Sulfate Capsules 289
Dofetilide Capsules 271 Ibuprofen Microencapsulated Sustained-Release
Doxepin Hydrochloride Capsules 271 Capsules 289
Doxycycline Capsules 271 Ibuprofen and Domperidone Maleate Capsules 290
Doxycycline Hyclate Capsules 272 Ibuprofen and Domperidone Maleate Effervescent
Doxycycline Hyclate Capsules 272 Granules 290
Doxycycline Hydrochloride Capsules and Oral Ibuprofen Sustained-Release Capsules 290
Suspension 272 Ifosfamide Capsules 292
Efavirenz Capsules 272 Imatinib Mesylate Capsules 292
Enalapril Maleate Capsules 272 Indinavir Sulfate Capsules 292
Enalapril Maleate Capsules 272 Indinavir Sulfate Capsules 292
Eplerenone Capsules 273 Indomethacin Capsules 292
Erythromycin and Bromhexine Powder for Indomethacin Capsules 293
Suspension 274 Indomethacin Capsules 293
Erythromycin and Sulfisoxazole Granules for Indomethacin Capsules (25 mg) 294
Suspension 275 Indomethacin Capsules (50 mg) 294
 Contents xxi

Indomethacin Powder for Hard Gelatin Capsules Nizatidine Capsules 313

(160 mg) 295 Nizatidine Capsules 313
Indomethacin Microencapsulated Sustained-Release Nystatin Powder 313
Capsules 295 Omeprazole and Piroxicam Capsules 313
Indomethacin Sustained-Release Capsules 296 Omeprazole Capsules 314
Insulin Capsules 297 Omeprazole Capsules 314
Iron–Polysaccharide Complex Capsules 298 Omeprazole Delayed-Release Capsules 315
Isometheptene Mucate, Dichloralphenazone, and Oral Rehydration Salt (45 mEq) 315
Acetaminophen Capsules 298 Orlistat Capsules 316
Isosorbide Mononitrate Capsules (20 mg) 298 Orlistat Capsules 316
Isradipine Capsules 299 Oseltamivir Phosphate Capsules and Oral
Itraconazole Capsules 299 Suspension 316
Itraconazole Capsules 299 Oxcarbazepine Oral Suspension 316
Ketoprofen and Misoprostol Capsules 299 Oxycodone Hydrochloride and Acetaminophen
Ketoprofen Capsules 300 Capsules 316
Lansoprazole Capsules 300 Oxytetracycline Hydrochloride Capsules 317
Lansoprazole Delayed-Release Capsules 300 Oxytetracycline Hydrochloride, Sulfamethizole, and
Lincomycin Capsules 300 Phenazopyridine Hydrochloride Capsules 317
Linezolid Oral Suspension 301 Pancrelipase Capsules 317
Lipase, Amylase, and Protease Capsules 301 Pancrelipase Capsules Enteric-Coated
Lithium Carbonate Capsules 301 Microspheres 317
Loperamide and Trimebutine Capsules 301 Penicillamine Capsules 317
Lopinavir–Ritonavir Capsules 301 Pentosan Polysulfate Sodium Capsules 317
Loracarbef Capsules and Oral Suspension 301 Pentostatin Capsules 318
Loxapine Succinate Capsules 302 pH-Sensitive Coated Spheroids 318
Magaldrate Instant Powder or Dry Syrup 302 Phenobarbital and Hyoscyamine Sulfate
Magaldrate Instant Powder or Dry Syrup 302 Capsules 319
Magnesium Oxide Capsules 302 Phenoxybenzamine Hydrochloride Capsules 319
Mefenamic Acid Capsules 302 Phentermine Capsules 319
Mesalamine Capsules 303 Phentermine Hydrochloride Capsules 319
Mesalamine Colonic Delivery Capsules 303 Phenytoin Sodium Extended-Release Capsules 319
Methsuximide Capsules 303 Piroxicam and Beta-Cyclodextrin Topical
Methylphenidate Capsules 303 Powder 319
Methylphenidate Capsules 303 Piroxicam Capsules 320
Methylphenidate Immediate- and Extended-Release Piroxicam Capsules 320
Capsules 304 Piroxicam Capsules 320
Methyltestosterone Capsules 304 Polyethylene Glycol 3350 Powder for
Metoclopramide Hydrochloride Sustained-Release Reconstitution 321
Capsules 304 Polythiazide Capsules 321
Metyrosine Capsules 305 Potassium Chloride Extended-Release Capsules 321
Miconazole Nitrate Foot and Itch Powder 305 Potassium Chloride for Oral Solution 321
Midodrine Capsules 305 Potassium Chloride Microencapsulated
Mineral Powder for Topical Herpes Simplex 306 Sustained-Release Capsules 321
Minocycline Hydrochloride Capsules 306 Potassium Chloride Powder (20 mEq) 322
Mixed Amphetamine Salt Capsules 306 Prazosin and Polythiazide Capsules 322
Mixed Amphetamine Salts Enteric-Release Capsules Prednisolone Targeted-Release Capsules 322
306 Procarbazine Hydrochloride Capsules 323
Morphine Sulfate Capsules 307 Prochlorperazine Sustained-Release Capsules 323
Morphine Sulfate Controlled-Release Propoxyphene Hydrochloride, Caffeine, and Aspirin
Capsules 307 Capsules 323
Morphine Sulfate Sustained-Release Capsules 308 Propoxyphene Hydrochloride Capsules 323
Multivitamin Effervescent Granules 308 Propranolol Hydrochloride and Hydrochlorothiazide
Multivitamin Effervescent Granules 309 Capsules 323
Multivitamin Instant Granules 310 Propranolol Hydrochloride Long-Acting
Multivitamin Instant Granules 311 Capsules 323
Mycophenolate Mofetil Capsules and Oral Propranolol Hydrochloride Multiple Bead
Suspension 311 Capsules 323
Nanoparticle Polymer Particle Powders 311 Propranolol Hydrochloride Sustained-Release
Nelfinavir Mesylate Oral Powder 312 Capsules 324
Nelfinavir Mesylate Oral Powder 312 Propranolol Timed- and Sustained-Release
Nilvadipine Capsules 312 Capsules 325
Nitrofurantoin Capsules 312 Proton Pump Inhibitor Powder for Reconstitution for
Nitrofurantoin Sustained-Release Capsules 312 Oral Use 325
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