/
`
`VOLUME THREE
`Second Edition
`
`Handbook of
`Pharmaceutical
`Manufacturing
`Formulations
`Liquid Products
`
`informa
`
`healthcare
`
`EXHIBIT
`
`Apotex (IPR2019-00400) Ex. 1041 p. 001
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`

`

`Pharmaceutical Scientist, Inc.
`Deerfield, Illinois, USA
`
`informa
`
`healthcare
`
`New York London
`
`Apotex (IPR2019-00400) Ex. 1041 p. 002
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`

`

`Handbook of
`Pharmaceutical Manufacturing Formulations
`Second Edition
`Volume Series
`Sarfaraz K. Niazi
`Volume 1
`
`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
`
`Apotex (IPR2019-00400) Ex. 1041 p. 003
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`

`

`Informa Healthcare USA, Inc.
`52 Vanderbilt Avenue
`New York, NY 10017
`
`© 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
`10987654321
`
`International Standard Book Number-10:1-4200-8116-0 (Volume 1; Hardcover)
`International Standard Book Number-13: 978-1-4200-8116-9 (Volume 1: Hardcover)
`International Standard Book Number-10:1-4200-8118-7 (Volume 2; Hardcover)
`International Standard Book Number-13: 978-1-4200-8118-3 (Volume 2; Hardcover)
`International Standard Book Number-10:1-4200-8123-3 (Volume 3; Hardcover)
`International Standard Book Number-13: 978-1-4200-8123-7 (Volume 3; Hardcover)
`International Standard Book Number-10:1-4200-8126-8 (Volume 4; Hardcover)
`International Standard Book Number-13: 978-1-4200-8126-8 (Volume 4; Hardcover)
`International Standard Book Number-10:1-4200-8128-4 (Volume 5; Hardcover)
`International Standard Book Number-13: 978-1-4200-8128-2 (Volume 5; Hardcover)
`International Standard Book Number-10:1-4200-8130-6 (Volume 6; Hardcover)
`International Standard Book Number-13: 978-1-4200-8130-5 (Volume 6; Hardcover)
`
`This book contains information obtained from authentic and highly regarded sources. Reprinted ma­
`terial 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 consequence of
`their use.
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`Library of Congress Cataloging-in-Publication Data
`
`Niazi, Sarfaraz, 1949p
`Handbook of pharmaceutical manufacturing formulations /
`Sarfaraz K. Niazi. p2nd 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. DrugspDosage formspHandbooks, manuals, etc. I. Title.
`[DNLM: 1. Drug CompoundingpHandbooks. 2. Dosage FormspHandbooks.
`3. Formularies as TopicpHandbooks. 4. Technology, PharmaceuticalpHandbooks.
`QV 735 N577h 2009]
`RS200.N53 2009
`615'.19pdc22
`
`2009009979
`
`For Corporate Sales and Reprint Permission call 212-520-2700 or write to: Sales Department,
`52 Vanderbilt Avenue, 16th oor. New York, NY 10017.
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`Visit the Informa Web site at
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`and the Informa Healthcare Web site at
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`Apotex (IPR2019-00400) Ex. 1041 p. 004
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`

`

`to August P. Lemberger
`
`Apotex (IPR2019-00400) Ex. 1041 p. 005
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`

`

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

`vi
`
`Preface to the Series—Second Edition
`
`relegated to more objective parameters, the art neverthe­
`less remains. An experienced formulator, like an artist,
`would know what goes with what and why; he avoids
`the pitfalls and stays with conservative choices. These
`sections of the book present advice that is time tested,
`although it may appear random at times; this is intended
`for experienced formulators.
`12. Expanded details on critical steps in the manufacturing
`processes provided but to keep the size of the book man­
`ageable, and these are included for prototype formula­
`tions. The reader is advised to browse through similar
`formulations to gain more insight. Where multiple for­
`mulations are provided for the same drug, it intended to
`show the variety of possibilities in formulating a drug
`and whereas it pertains to a single drug, the basic formu­
`lation practices can be extended to many drugs of same
`class or even of diversi~ed classes. Readers have often
`requested that more details be provided in the Manufac­
`turing Direction sections. Whereas suf~cient details are
`provided, this is restricted to prototype formulations to
`keep the size of the book manageable and to reduce re­
`dundancy.
`13. Addition of a listing of approved excipients and the level
`allowed by regulatory authorities. This new section al­
`lows formulators a clear choice on which excipients to
`choose; the excipients are reported in each volume per­
`taining to the formulation type covered. The listing is
`drawn from the FDA-approved entities. For the develop­
`ers of an ANDA, it is critical that the level of excipients be
`kept within the range generally approved to avoid large
`expense in justifying any unapproved level. The only cat­
`egory for which the listing is not provided separately is
`the OTC volume since it contains many dosage forms and
`the reader is referred to dosage formpspeci~c title of the
`series. The choice of excipients forms keeps increasing
`with many new choices that can provide many special
`release characteristics to the dosage forms. Choosing cor­
`rect excipients is thus a tedious exercise and requires so­
`phisticated multivariate statistical analysis. Whereas the
`formulator may choose any number of novel or classical
`components, it is important to know the levels of excip­
`ients that are generally allowed in various formulations
`to reduce the cost of redundant exercises; I have there­
`fore included, as an appendix to each volume, a list of all
`excipients that are currently approved by the U.S. FDA
`along their appropriate levels. I suggest that a formula-
`tor consult this table before deciding on which level of
`excipient to use; it does not mean that the excipient can­
`not be used outside this range but it obviates the need
`for a validation and lengthy justi-cation studies in the
`submission of ND As.
`14. Expanded section on bioequivalence submission was
`required to highlight the recent changes in these re­
`quirements. New entries include a comprehensive listing
`of bioequivalence protocols in abbreviated form as ap­
`proved by the U.S. FDA; these descriptions are provided
`in each volume where pertinent. To receive approval
`for an ANDA, an applicant must generally demonstrate,
`among other things, equivalence of the active ingredi­
`ent, dosage form, strength, route of administration and
`conditions of use as the listed drug, and that the pro­
`posed drug product is bioequivalent to the reference
`listed drug [21 USC 355(j)(2)(A); 21 CFR 314.94(a)]. Bioe­
`quivalent drug products show no signi-cant difference in
`
`the rate and extent of absorption of the therapeutic ingre­
`dient [21 U.S.C. 355(j)(8); 21 CFR 320.1(e)]. BE studies are
`undertaken in support of ANDA submissions with the
`goal of demonstrating BE between a proposed generic
`drug product and its reference listed drug. The regu­
`lations governing BE are provided at 21 CFR in part
`320. The U.S. FDA has recently begun to promulgate
`individual bioequivalence requirements. To streamline
`the process for making guidance available to the pub­
`lic on how to design product-speci~c BE studies, the
`U.S. FDA will be issuing product-speci~c BE recommen­
`dations (www.fda.gov/cder/ogd/index.htm). To make
`this vital information available, an appendix to each
`volume includes a summary of all currently approved
`products by the U.S. FDA where a recommendation on
`conducting bioequivalence studies is made available by
`the U.S. FDA. When -ling an NDA or an ANDA, the
`-ler is faced with the choice of defending the meth­
`ods used to justify the bioavailability or bioequivalence
`data. The U.S. FDA now allows application for waiver
`of bioequivalence requirement; a new chapter on this
`topic has been added along with details of the dis­
`solution tests, where applicable, approved for various
`dosage forms.
`15. Dissolution testing requirements are included for all
`dosage forms where this testing is required by the FDA.
`Surrogate testing to prove ef~cacy and compliance is get­
`ting more acceptance at regulatory agencies; in my expe­
`rience, a well-designed dissolution test is the best mea­
`sure of continuous compliance. Coupled with chapters
`on waivers of bioequivalence testing, this information on
`dissolution testing should be great value to all manu­
`facturers; it is recommended that manufacturers develop
`their own in-house speci-cations, more stringent than
`those allowed in these listings and the USP.
`16. Best-selling products (top 200 prescription products) are
`identi~ed with an asterisk and a brand name where ap­
`plicable; in all instances, composition of these products is
`provided and formulation of generic equivalents. Despite
`the vast expansion of pharmaceutical sales and shifting
`of categories of blockbuster drugs, basic drugs affecting
`gastrointestinal tract, vascular system, and brain remain
`most widely prescribed.
`17. Updated list of approved coloring agents in the United
`States, Canada, European Union, and Japan is included
`to allow manufactures to design products for worldwide
`distribution.
`18. Tablet-coating formulations that meet worldwide re­
`quirements of color selection are included in the Volume
`1 (compressed solids) and Volume 5 (OTC) because these
`represent the products often coated.
`19. Guidelines on preparing regulatory -lings are now dis­
`persed throughout the series depending on where these
`guidelines are more crucial. However, the reader would,
`as before, need access to all volumes to bene~t from the
`advice and guidelines provided.
`
`As always, comments and criticism from the readers are
`welcomed and these can be sent to me at Niazi@pharmsci
`.com or Niazi@niazi.com. I would try to respond to any in­
`quiries requiring clari-cation of the information enclosed in
`these volumes.
`I would like to express deep gratitude to Sherri R. Niziolek
`and Michelle Schmitt-DeBonis at Informa, the publisher of
`
`Apotex (IPR2019-00400) Ex. 1041 p. 007
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`

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

`Preface to the Seriesq First Edition
`
`No industry in the world is more highly regulated than the
`pharmaceutical industry because of the potential threat to
`a patienhs life from the use of pharmaceutical products.
`The cost of taking a new chemical entity to ~nal regu­
`latory approval is a staggering $800 million, making the
`pharmaceutical industry one of the most research-intensive
`industries in the world. It is anticipated that the industry
`will spend about $20 billion on research and development
`in 2004. Because patent protection on a number of drugs is
`expiring, the generic drug market is becoming one of the
`fastest growing segments of the pharmaceutical industry
`with every major multinational company having a signi~cant
`presence in this -eld.
`Many stages of new drug development are inherently
`constrained by time, but the formulation of drugs into de­
`sirable dosage forms remains an area where expediency
`can be practiced by those who have mastered the skills of
`pharmaceutical formulations. The Handbook of Pharmaceu­
`tical Manufacturing Formulations is the -rst major attempt
`to consolidate the available knowledge about formulations
`into a comprehensive and, by nature, rather voluminous
`presentation.
`The book is divided into six volumes based strictly on the
`type of formulation science involved in the development of
`these dosage forms: sterile products, compressed solids, un­
`compressed solids, liquid products, semisolid products, and
`over-the-counter (OTC) products. Although they may easily
`fall into one of the other ~ve categories, OTC products are
`considered separately to comply with the industry norms of
`
`separate research divisions for OTC products. Sterile prod­
`ucts require skills related to sterilization of the product, and
`of less importance is the bioavailability issue, which is an in­
`herent problem of compressed dosage forms. These types of
`considerations have led to the classi-cation of pharmaceutical
`products into these six categories. Each volume includes a de­
`scription of regulatory -ling techniques for the formulations
`described. Also included are regulatory guidelines on com­
`plying with current good manufacturing practices (cGMPs)
`speci~c to the dosage form and advice is offered on how to
`scale up the production batches.
`It is expected that formulation scientists will use this in­
`formation to benchmark their internal development protocols
`and reduce the time required to ~le by adopting formulae that
`have survived the test of time. Many of us who have worked
`in the pharmaceutical industry suffer from a -xed paradigm
`when it comes to selecting formulations: rNot invented heres
`perhaps is kept in the back of the minds of many seasoned
`formulations scientists when they prefer certain platforms
`for development. It is expected that with a quick review of
`the formulation possibilities that are made available in this
`book such scientists would bene~t from the experience of
`others. For teachers of formulation sciences, this series offers
`a wealth of information. Whether it is selection of a preser­
`vative system or the choice of a disintegrant, the series offers
`many choices to study and consider.
`
`Sarfaraz K. Niazi, Ph.D.
`Deer-eld, Illinois, U.S.A.
`
`viii
`
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`

`

`Preface to the Volumeq First Edition
`
`Liquid products, for the purpose of inclusion in this volume,
`include nonsterile drugs administered by any route in the
`form of solutions (monomeric and multimeric), suspensions
`(powder and liquid), drops, extracts, elixirs, tinctures, paints,
`sprays, colloidons, emulsions, aerosols, and other uid prepa­
`rations. Sterile liquid products are presented in another vol­
`ume. Whereas liquid drugs do not share the compression
`problems of solid dosage forms, the ~lling problems of pow­
`der dosage forms, and the consistency problems of semisolid
`dosage forms, they do have their own set of considerations
`in the formulation and manufacturing stages. The considera­
`tions of prime importance for liquid drugs include solubility
`of active drugs, preservation, taste masking, viscosity, avor-
`ing, appearance, and stability (chemical, physical, and mi­
`crobiological), raw materials, equipment, the compounding
`procedures (often the order of mixing), and -nally the packag­
`ing (to allow a stable product to reach patients). Suspensions
`present a special situation in which even the powder for re­
`constitution needs to be formulated such that it can be stable
`after reconstitution; therefore, limited examples are included
`here.
`Chapter 1 in section I (Regulatory and Manufacturing
`Guidance) describes the practical details in complying with
`the current good manufacturing practice (cGMP) require­
`ments in liquid manufacturing. This chapter does not address
`the speci~c cGMP parameters but deals with the practical as­
`pects as may arise during a U.S. Food and Drug Administra­
`tion (FDA) inspection. This includes what an FDA inspector
`would be looking into when auditing a liquid manufacturing
`facility.
`Chapter 2 describes the stability testing of new drugs and
`dosage forms. Drawn from the most current international
`conference on harmonization (ICH) guidelines, this chapter
`describes in detail the protocols used for stability testing not
`only for new drugs but also for new dosage forms. The chap­
`ter is placed in this volume because stability studies are of
`greater concern in liquid dosage forms; however, keeping in
`mind the overall perspective of the series of this title, this
`chapter would apply to all dosage forms. Again, emphasis
`is placed on the practical aspects, and the reader is referred
`to of~cial guidelines for the development of complete testing
`protocols. It is noteworthy that the ICH guidelines divide the
`world into four zones; the discussion given in this chapter
`mainly refers to the U.S. and European regions, and again the
`formulator is referred to the original guideline for full guid­
`ance. Stability studies constitute one of the most expensive
`phases of product development because of their essential time
`investment. As a result, formulators often prepare a matrix
`of formulations to condense the development phase, partic­
`ularly where there are known issues in compatibility, drug
`interactions, and packaging interactions. The FDA is always
`very helpful in this phase of study protocols, particularly
`where a generic drug is involved. It is also a good idea to
`benchmark the product against the innovator product. How­
`ever, one should understand clearly that the FDA is not bound
`
`to accept stability data even though it might match that of the
`innovator product. The reason for this may lie in the improve­
`ments made since the innovator product was approved. For
`example, if a better packaging material that imparts greater
`safety and shelf life is available, the FDA would like this to
`be used (not for the purpose of shelf life, but for the safety
`factors). In recent years, the FDA has placed greater empha­
`sis on the control of active pharmaceutical ingredient (API),
`particularly if it is sourced from a new manufacturer with
`a fresh DMF. Obviously, this is one way how the innovator
`controls the proliferation of generic equivalents. The original
`patents that pertain to synthesis or manufacturing of the ac­
`tive raw material may have been superseded by improved
`processes that are not likely to be a part of a later patent
`application (to protect the trade secret because of double­
`patenting issues). The innovator often goes on to revise the
`speci-cations of the active pharmaceutical ingredient to the
`detriment of the generic manufacturer. However, my experi­
`ence tells me that such changes are not necessarily binding on
`the generic manufacturer, and as long as cGMP compliance
`in the API is demonstrated and the impurities do not exceed
`the reference standard (if one is available), there is no need
`to be concerned about this aspect. However, manufacturers
`are advised to seek a conference with the FDA should this
`be a serious concern. At times, the manufacturer changes the
`-nished product speci-cation as the patents expire or refor­
`mulates the product under a new patent. A good example
`of this practice was the reformulation of calcitriol injection
`by Abbott as its patent came to expiry. The new speci-ca­
`tions include a tighter level of heavy metals, but a generic
`manufacturer should have no problem if the original speci-
`-cations are met because the product was approvable with
`those speci-cations.
`Chapter 3 describes the container closure systems; again,
`this discussion would apply to all dosage forms. It is note­
`worthy that the regulatory agencies consider containers and
`packaging systems, all those components that come in con­
`tact with the product, protect the product from environment,
`or are instrumental in the delivery of the product as part of
`the product de~nition. Whereas the industry is much attuned
`to studies of the effects of the API and dosage formulation
`components, the study of container or closure systems is of­
`ten left to the end of the study trials. This is an imprudent
`practice, as it might result in loss of valuable time. The pack­
`aging industry generally undergoes faster changes than do
`the chemical or pharmaceutical industries. New materials,
`better tolerances, more environmentally friendly materials,
`and now, with the use of mechanical devices in many dosage
`forms, appropriate dosing systems emerge routinely. As a
`rule of thumb, the closure system for a product should be the
`-rst criterion selected before development of the dosage form.
`Switching between a glass and a plastic bottle at a later stage
`can be a very expensive exercise. Because many of these con­
`siderations are drawn by marketing teams, who may change
`their product positioning, the formulation team must be
`
`Apotex (IPR2019-00400) Ex. 1041 p. 010
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`

`

`X
`
`Preface to the Volume—First Edition
`
`appropriately represented in marketing decision conferences.
`Once a decision has been made about the presentation of a
`product, the product development team should prepare sev­
`eral alternatives, based on the ease of formulation and the
`cost of the -nished product involved. It should be empha­
`sized at all stages of development that packaging scale-ups
`require just as much work as does a formulation scale-up
`or changes. As a result, the FDA provides the scale-up and
`postapproval change (SUPAC) guidelines for packaging com­
`ponents. Changes in the dimensions of a bottle may expose
`a large surface of liquid to the gaseous phase in the bottle
`and thus require a new stability testing exercise. This chapter
`forms an important reminder to formulators on the need to
`give consideration to every aspect of the container closure
`system as part of routine development.
`Chapter 4 introduces the area of Preapproval Inspections,
`a process initiated by the FDA in the wake of the grand scan­
`dals in the generic pharmaceutical industry a few years ago.
`The FDA guidelines now allow r pro-lings of companies and
`list the requirements of Preapproval Inspections when an ap­
`plication has been -led. Whereas the emphasis in this chap­
`ter is on rpreapproval,s the advice provided here applies
`to all regulatory inspections. A regulatory inspection can be
`an arduous exercise if the company has not prepared for it
`continuously. Preparedness for inspection is not something
`that can be achieved through a last-minute crash program.
`This chapter goes into considerable detail on how to create
`a cGMP culture, how to examine the documentary needs,
`assignment of responsibility, preparation of validation plan,
`and above all, the art of presenting the data to the FDA. Also
`discussed are the analyses of the outcome of inspection. Ad­
`vice is provided on how to respond to Form 483 issued by the
`FDA, and the manufacturer is warned of the consequences of
`failing an inspection. Insight is also provided for foreign man­
`ufacturers, for whom a different set of rules may be applied
`because of the physical constraints of inspection. The inspec­
`tion guidelines provided apply to both the manufacturers of
`API as well as to the -nished products.
`Chapter 5 includes highlights of topics of importance in
`the formulation of liquid products. However, this chapter
`is not an all-inclusive guide to formulation. Only highlights
`of points of concern are presented here, and the formula-
`tor is referred to several excellent treatises available on the
`subject.
`Section II contains formulations of liquid products and
`lists a wide range of products that fall under this classi—
`cation, as interpreted in the volume. There are three levels
`at which these formulations are described. First, the Bill of
`Materials is accompanied by detailed manufacturing direc­
`tions; second, the manufacturing directions are abbreviated
`because they are already described in another product of sim­
`ilar nature; and third, only the composition is provided as
`supplied by the manufacturer. With the wide range of formu­
`
`lations included in this volume, it should be a simple matter
`for an experienced formulator to convert these formulations
`into quantitative Bills of Materials and then to benchmark it
`against similar formulations to come up with a working for­
`mula. The problems incumbent in the formulation of liquid
`products are highlighted in chapter 5, but these are generic
`problems, and the formulator should be aware of any spe-
`ci~c situations or problems that may arise from time to time.
`I would like to hear from the formulators about these prob­
`lems so that they could be included in future editions of this
`book. Again, the emphasis in this series is on a practical reso­
`lution of problems; the theoretical teachings are left to other,
`more comprehensive works on this topic. The key application
`of the data provided herein is to allow the formulator to se­
`lect the ingredients that are reportedly compatible, avoiding
`need for long-term studies to establish compatibilities.
`I am grateful to CRC Press for taking this lead in publish­
`ing what is possibility the largest such work in the -eld of
`pharmaceutical products. It has been a distinct privilege to
`know Mr. Stephen Zollo, senior editor at CRC Press. Stephen
`has done more than any editor can do to encourage an author
`into completing this work on a timely basis. The editorial as­
`sistance provided by CRC Press staff was indeed exemplary,
`particularly the help given by Erika Dery, Amy Rodriguez,
`and others. Although much care has gone into correcting er­
`rors, any errors remaining are