handbook of pharmaceutical manufacturing formulations second edition volume 3 liquid products

Introduction 79 Part I: Chapter 1: Quality Management 80 Principle 80 Quality Assurance 80 Good Manufacturing Practice for Medicinal Products GMP 80 Quality Control 81 Product Quality Re

S a r f a r a z K N i a z i

Pharmaceutical Scientist, Inc.

Deerfield, Illinois, USA

Handbook of

Pharmaceutical Manufacturing Formulations

Liquid Products

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

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Library of Congress Cataloging-in-Publication Data

Niazi, Sarfaraz, 1949–

Handbook of pharmaceutical manufacturing formulations / Sarfaraz K Niazi – 2nd ed.

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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

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2009009979

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to August P Lemberger

Preface to the Series—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 finished 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 first 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 first 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 hassix volumes differentiated on the basis of the type ofdosage form and a separate inclusion of the U.S OTCproducts, ideally the entire collection is needed to ben-efit 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 tual property data and suggest toward the future trend

intellec-of formulations While some intellec-of these formulations maynot have been approved in the United States or Europe,these do provide additional choices, particularly for theNDA preparation As always, it is the responsibility ofthe manufacturer to assure that the intellectual propertyrights are not violated

5 A significant 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 Thedrug companies are advised to assure that any intellec-tual property rights are not violated and this applies toall information contained in this book The freedom ofinformation act (FOIA) is an extremely useful conduitfor reliable information and manufacturers are strongly

urged to make use of this information Whereas this formation is provided free of charge, the process of ob-taining the information may be cumbersome, in whichcase, commercial sources of these databases can proveuseful, particularly for the non-U.S companies

in-6 Also included are the new Good Manufacturing lines (2007) with amendments (2008) for the United Statesand similar updates for European Union and WHO; it isstrongly urged that the companies discontinue using allold documents as there are significant changes in the re-vised form, and many of them are likely to reduce thecost of GMP compliance

Guide-7 Details on design of clean rooms is a new entry that will

be of great use to sterile product manufacturers; whereasthe design and flow of personnel and material flow is ofcritical nature, regulatory agencies view these differentlyand the manufacturer is advised always to comply withmost stringent requirements

8 Addition of a self-auditing template in each volume ofthe series While the cGMP compliance is a complex is-sue and the requirements diversified across the globe, thebasic compliance remains universal I have chosen theEuropean Union guidelines (as these are more in tunewith the ICH) to prepare a self-audit module that I rec-ommend that every manufacturer adopt as a routine toassure GMP compliance In most instances reading thetemplate by those responsible for compliance with keepthem sensitive to the needs of GMP

9 OTC products cross-referenced in other volumes whereappropriate This was necessary since the regulatory au-thorities worldwide define this class of drug differently

It is important to iterate that regardless of the tion or the OTC status of a product, the requirements forcompliance with the cGMP apply equally

prescrip-10 OTC monograph status is a new section added to the OTCvolume and this should allow manufacturers to chose ap-propriate formulations that may not require a filing withthe regulatory agencies; it is important to iterate that anapproved OTC monograph includes details of formula-tion including the types and quantities of active drug andexcipients, labeling, and presentation To qualify the ex-emption, the manufacturer must comply with the mono-graph in its entirety However, subtle modifications thatare merely cosmetic in nature and where there is an evi-dence that the modification will not affect the safety andefficacy of the products can be made but require priorapproval of the regulatory agencies and generally theseapprovals are granted

11 Expanded discussion on critical factors in the turing of formulations provided; from basic shortcuts

manufac-to smart modifications now extend manufac-to all dosage forms.Pharmaceutical compounding is one of the oldest pro-fessions and whereas the art of formulations has been

v

relegated to more objective parameters, the art less remains An experienced formulator, like an artist,would know what goes with what and why; he avoidsthe pitfalls and stays with conservative choices Thesesections of the book present advice that is time tested,although it may appear random at times; this is intendedfor experienced formulators.

neverthe-12 Expanded details on critical steps in the manufacturing

processes provided but to keep the size of the book ageable, and these are included for prototype formula-tions The reader is advised to browse through similarformulations to gain more insight Where multiple for-mulations are provided for the same drug, it intended toshow the variety of possibilities in formulating a drugand whereas it pertains to a single drug, the basic formu-lation practices can be extended to many drugs of sameclass or even of diversified classes Readers have oftenrequested that more details be provided in the Manufac-turing Direction sections Whereas sufficient details areprovided, this is restricted to prototype formulations tokeep the size of the book manageable and to reduce re-dundancy

man-13 Addition of a listing of approved excipients and the level

allowed by regulatory authorities This new section lows formulators a clear choice on which excipients tochoose; the excipients are reported in each volume per-taining to the formulation type covered The listing isdrawn from the FDA-approved entities For the develop-ers of an ANDA, it is critical that the level of excipients bekept within the range generally approved to avoid largeexpense in justifying any unapproved level The only cat-egory for which the listing is not provided separately isthe OTC volume since it contains many dosage forms andthe reader is referred to dosage form–specific title of theseries The choice of excipients forms keeps increasingwith many new choices that can provide many specialrelease characteristics to the dosage forms Choosing cor-rect excipients is thus a tedious exercise and requires so-phisticated multivariate statistical analysis Whereas theformulator may choose any number of novel or classicalcomponents, it is important to know the levels of excip-ients that are generally allowed in various formulations

al-to reduce the cost of redundant exercises; I have fore included, as an appendix to each volume, a list of allexcipients that are currently approved by the U.S FDAalong their appropriate levels I suggest that a formula-tor consult this table before deciding on which level ofexcipient to use; it does not mean that the excipient can-not be used outside this range but it obviates the needfor a validation and lengthy justification studies in thesubmission of NDAs

there-14 Expanded section on bioequivalence submission was

required to highlight the recent changes in these quirements New entries include a comprehensive listing

re-of bioequivalence protocols in abbreviated form as proved by the U.S FDA; these descriptions are provided

ap-in each volume where pertap-inent To receive approvalfor an ANDA, an applicant must generally demonstrate,among other things, equivalence of the active ingredi-ent, dosage form, strength, route of administration andconditions of use as the listed drug, and that the pro-posed drug product is bioequivalent to the referencelisted drug [21 USC 355(j)(2)(A); 21 CFR 314.94(a)] Bioe-quivalent drug products show no significant difference in

the rate and extent of absorption of the therapeutic dient [21 U.S.C 355(j)(8); 21 CFR 320.1(e)] BE studies areundertaken in support of ANDA submissions with thegoal of demonstrating BE between a proposed genericdrug product and its reference listed drug The regu-lations governing BE are provided at 21 CFR in part

ingre-320 The U.S FDA has recently begun to promulgateindividual bioequivalence requirements To streamlinethe process for making guidance available to the pub-lic on how to design product-specific BE studies, theU.S FDA will be issuing product-specific BE recommen-dations (www.fda.gov/cder/ogd/index.htm) To makethis vital information available, an appendix to eachvolume includes a summary of all currently approvedproducts by the U.S FDA where a recommendation onconducting bioequivalence studies is made available bythe U.S FDA When filing an NDA or an ANDA, thefiler is faced with the choice of defending the meth-ods used to justify the bioavailability or bioequivalencedata The U.S FDA now allows application for waiver

of bioequivalence requirement; a new chapter on thistopic has been added along with details of the dis-solution tests, where applicable, approved for variousdosage forms

15 Dissolution testing requirements are included for alldosage forms where this testing is required by the FDA.Surrogate testing to prove efficacy 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 ondissolution testing should be great value to all manu-facturers; it is recommended that manufacturers developtheir own in-house specifications, more stringent thanthose allowed in these listings and the USP

16 Best-selling products (top 200 prescription products) areidentified with an asterisk and a brand name where ap-plicable; in all instances, composition of these products isprovided and formulation of generic equivalents Despitethe vast expansion of pharmaceutical sales and shifting

of categories of blockbuster drugs, basic drugs affectinggastrointestinal tract, vascular system, and brain remainmost widely prescribed

17 Updated list of approved coloring agents in the UnitedStates, Canada, European Union, and Japan is included

to allow manufactures to design products for worldwidedistribution

18 Tablet-coating formulations that meet worldwide quirements of color selection are included in the Volume

re-1 (compressed solids) and Volume 5 (OTC) because theserepresent the products often coated

19 Guidelines on preparing regulatory filings are now persed throughout the series depending on where theseguidelines are more crucial However, the reader would,

dis-as before, need access to all volumes to benefit from theadvice and guidelines provided

As always, comments and criticism from the readers arewelcomed 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 clarification of the information enclosed inthese volumes

I would like to express deep gratitude to Sherri R Niziolekand 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

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

In the first edition, I had dedicated each volume to one of

my mentors; the second edition continues the dedication tothese great teachers

Sarfaraz K Niazi, Ph.D.

Deerfield, Illinois, U.S.A.

Preface to the Series—First Edition

No industry in the world is more highly regulated than the

pharmaceutical industry because of the potential threat to

a patient’s life from the use of pharmaceutical products

The cost of taking a new chemical entity to final

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 significant

presence in this field

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 first 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 five categories, OTC products are

considered separately to comply with the industry norms of

separate research divisions for OTC products Sterile ucts require skills related to sterilization of the product, and

prod-of less importance is the bioavailability issue, which is an herent problem of compressed dosage forms These types ofconsiderations have led to the classification of pharmaceuticalproducts into these six categories Each volume includes a de-scription of regulatory filing techniques for the formulationsdescribed Also included are regulatory guidelines on com-plying with current good manufacturing practices (cGMPs)specific to the dosage form and advice is offered on how toscale up the production batches

It is expected that formulation scientists will use this formation to benchmark their internal development protocolsand reduce the time required to file by adopting formulae thathave survived the test of time Many of us who have worked

in-in the pharmaceutical in-industry suffer from a fixed paradigmwhen it comes to selecting formulations: “Not invented here”perhaps is kept in the back of the minds of many seasonedformulations scientists when they prefer certain platformsfor development It is expected that with a quick review ofthe formulation possibilities that are made available in thisbook such scientists would benefit from the experience ofothers For teachers of formulation sciences, this series offers

a wealth of information Whether it is selection of a vative system or the choice of a disintegrant, the series offersmany choices to study and consider

preser-Sarfaraz K Niazi, Ph.D.

Deerfield, Illinois, U.S.A.

viii

Preface to the Volume—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 fluid

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 filling 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,

flavor-ing, appearance, and stability (chemical, physical, and

mi-crobiological), raw materials, equipment, the compounding

procedures (often the order of mixing), and finally 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 specific cGMP parameters but deals with the practical

as-pects as may arise during a U.S Food and Drug

Administra-tion (FDA) inspecAdministra-tion 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 official 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 theinnovator product The reason for this may lie in the improve-ments made since the innovator product was approved Forexample, if a better packaging material that imparts greatersafety and shelf life is available, the FDA would like this to

be used (not for the purpose of shelf life, but for the safetyfactors) 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 innovatorcontrols the proliferation of generic equivalents The originalpatents that pertain to synthesis or manufacturing of the ac-tive raw material may have been superseded by improvedprocesses that are not likely to be a part of a later patentapplication (to protect the trade secret because of double-patenting issues) The innovator often goes on to revise thespecifications of the active pharmaceutical ingredient to thedetriment of the generic manufacturer However, my experi-ence tells me that such changes are not necessarily binding onthe generic manufacturer, and as long as cGMP compliance

in the API is demonstrated and the impurities do not exceedthe reference standard (if one is available), there is no need

to be concerned about this aspect However, manufacturersare advised to seek a conference with the FDA should this

be a serious concern At times, the manufacturer changes thefinished product specification 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 tions include a tighter level of heavy metals, but a genericmanufacturer should have no problem if the original speci-fications are met because the product was approvable withthose specifications

specifica-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 andpackaging 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 ofthe product definition Whereas the industry is much attuned

to studies of the effects of the API and dosage formulationcomponents, the study of container or closure systems is of-ten left to the end of the study trials This is an imprudentpractice, as it might result in loss of valuable time The pack-aging industry generally undergoes faster changes than dothe chemical or pharmaceutical industries New materials,better tolerances, more environmentally friendly materials,and now, with the use of mechanical devices in many dosageforms, appropriate dosing systems emerge routinely As arule of thumb, the closure system for a product should be thefirst criterion selected before development of the dosage form.Switching between a glass and a plastic bottle at a later stagecan be a very expensive exercise Because many of these con-siderations are drawn by marketing teams, who may changetheir product positioning, the formulation team must beix

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 finished 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 “profiling” of companies and

list the requirements of Preapproval Inspections when an

ap-plication has been filed Whereas the emphasis in this

chap-ter is on “preapproval,” 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 finished 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

classifi-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 matterfor an experienced formulator to convert these formulationsinto quantitative Bills of Materials and then to benchmark itagainst similar formulations to come up with a working for-mula The problems incumbent in the formulation of liquidproducts are highlighted in chapter 5, but these are genericproblems, and the formulator should be aware of any spe-cific situations or problems that may arise from time to time

I would like to hear from the formulators about these lems so that they could be included in future editions of thisbook 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

prob-of the data provided herein is to allow the formulator to lect the ingredients that are reportedly compatible, avoidingneed for long-term studies to establish compatibilities

se-I am grateful to CRC Press for taking this lead in ing what is possibility the largest such work in the field ofpharmaceutical products It has been a distinct privilege toknow Mr Stephen Zollo, senior editor at CRC Press Stephenhas done more than any editor can do to encourage an authorinto 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 altogether mine I shall appre-ciate the readers bringing these to my attention for correction

publish-in future editions of this volume (niazi@pharmsci.com).This volume is dedicated to one of the great educatorsand a leader in the pharmaceutical profession, August P.Lemberger, who is truly a Wisconsin man At the Univer-sity of Wisconsin in Madison, he was an undergraduate andgraduate student He was then a professor, and twice Dean ofthe School of Pharmacy (1943–44, 1946–52, 1953–69, 1980–91).During the period between 1969 and 1980, he assumed theresponsibility of deanship at the University of Illinois, where

I was a graduate student In 1972, he offered me my firstteaching job, as an instructor of pharmacy at the University

of Illinois, while I was still in graduate school I was one of thegreatest beneficiaries of his kindness and attention Gus has

an unusual ability to put everyone at ease, respect everyonearound him, and in the end, come out as a group leader What-ever little I have accomplished in my life is mostly because

of Gus Many awards, recognitions, and salutations were fered to Gus during his celebrated career His research con-tributions included stability studies, suspension, emulsionstabilization, and later in his career, the various aspects ofpharmaceutical education I wish him many years of happyretirement and shuttling back and forth between his homes

of-in Arizona and Wisconsof-in Thanks, Gus

Sarfaraz K Niazi, Ph.D.

Deerfield, Illinois, U.S.A.

About the Author

Sarfaraz K Niazihas 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 ofpharmaceutical formulation, biopharmaceutics, and pharmacokinetics of drugs He is also an inventorwith 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 fromthe 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 investigationalnew drugs (INDs) and new drug applications (NDAs) Dr Niazi advises the pharmaceutical industryinternationally on issues related to formulations, cGMP compliance, pharmacokinetics and bioequiva-lence evaluation, and intellectual property issues (http://www.pharmsci.com) He can be contacted atNiazi@pharmsci.com

xi

Preface to the Series—Second Edition v

Preface to the Series—First Edition viii

Preface to the Volume—First Edition ix

About the Author xi

PART I REGULATORY AND MANUFACTURING

IV Raw Materials 3

V Compounding 3

VI Microbiological Quality 3 VII Oral Suspensions 3 VIII Product Specifications 3

IX Process Validation 4

IV Raw Materials 5

V Compounding 5

VI Microbiological Quality 6 VII Oral Suspension Uniformity 6 VIII Product Specifications 6

IX Process Validation 6

V Components and Composition 22

VI Manufacturing Sites 22

A General Considerations 22

B Major Changes (Prior Approval

Supplement) 22

C Moderate Changes(Supplement—Changes

Contents xiii

C Moderate Changes(Supplement—Changes

Being Effected) 27

D Minor Changes (Annual Report) 27

XI Miscellaneous Changes 27

A Major Changes (Prior Approval

Supplement) 27

B Moderate Changes(Supplement—Changes

IX Physical Stability 31

X Raw Material 31

XI Manufacturing Equipment 32 XII Manufacturing Directions 32 XIII Packaging 32

XIV Particle Size and Shape 32

XV Suspensions 32 XVI Emulsions 32 XVII Powder for Reconstitution 33 XVIII Nasal Spray Products 33

A Inhalation Solutions and

Suspensions 33

B Inhalation Sprays 34

C Pump Delivery of Nasal Products 34

D Spray Content Uniformity for Nasal

6 Container Closure Systems 37

I Introduction 37

A Definitions 37

B Current Good Manufacturing Practice,the Consumer Product Safety

Commission, and Requirements on

Containers and Closures 37

D Inhalation Drug Products 41

E Injection and Ophthalmic Drug

2 Single-Unit Containers andUnit-Dose Containers for Capsulesand Tablets (USP<671>) 44

3 Multiple-Unit Containers forCapsules and Tablets(USP<671>) 44

H Other Dosage Forms 44 III Postapproval Packaging Changes 44

IV Type III Drug Master Files 44

V Bulk Containers 45 References 45

7 Material for Containers 47

for Parenteral Use 48

IV Nonplasticized Poly(Vinyl Chloride) forContainers for Dry Dosage Forms for Oral

IX Polypropylene for Containers andClosures for Parenteral Preparations and

XIII Rubber Closures for Containers forAqueous Parenteral Preparations,for Powders, and for Freeze-Dried

Powders 51 XIV Silicone Oil Used as a Lubricant 51

XV Silicone Elastomer for Closures

and Tubing 51

8 Stability Testing of New Drug Substances and

Products 52

I Introduction 52

A Objectives of the Guideline 52

B Scope of the Guideline 52

References 59

9 Stability Testing: Photostability Testing of New

Drug Substances and Products 60

A Presentation of Samples 61

B Analysis of Samples 62

C Judgement of Results 62

IV Annex 62

A Quinine Chemical Actinometry 62

10 Stability Testing for New Dosage Forms 63

I General 63

II New Dosage Forms 63 Glossary 63

Bibliography 63

11 Bracketing and Matrixing Designs for

Stability Testing of New Drug Substances

Room Temperature Storage 69

Storage Below Room Temperature 70

1 Drug Substances or ProductsIntended for Storage in a

Refrigerator 70

2 Drug Substances or ProductsIntended for Storage in

a Freezer 71

Appendix A: Decision Tree for Data Evaluation for

Retest Period or Shelf-Life Estimation for DrugSubstances or Products (Excluding Frozen

Products) 71

Appendix B: Examples of Statistical Approaches to

Stability Data Analysis 71 B.1 Data Analysis for a Single Batch 71

B.2 Data Analysis for One-Factor, Full-Design

Studies 71

B.2.1 Evaluating whether all batches support the

proposed retest period or shelf life 73 B.2.2 Testing for poolability of batches 74

B.2.2.1 Analysis of covariance 74

B.2.2.2 Other methods 74

B.3 Data Analysis for Multifactor, Full-Design

Studies 74

B.3.1 Evaluating whether all factor combinations

support the proposed shelf life 74 B.3.2 Testing for poolability 74

B.3.2.1 Testing for poolability of batch

factor only 74

B.3.2.2 Testing for poolability of all factors and factor

combinations 75 B.3.2.2.1 Analysis of covariance 75

B.3.2.2.2 Other methods 75

B.4 Data Analysis for Bracketing Design Studies 75

B.5 Data Analysis for Matrixing Design Studies 75

References 76

13 Stability Data Package for Registration

Applications in Climatic Zones III and IV 77

3 Tests at Elevated Temperature

and/or Extremes of Humidity 78

C Additional Considerations 78 References 78

14 EU Guidelines to Good Manufacturing

Practice Medicinal Products for Human

and Veterinary Use 79

I Introduction 79 Part I: Chapter 1: Quality Management 80

Principle 80

Quality Assurance 80

Good Manufacturing Practice for Medicinal

Products (GMP) 80 Quality Control 81

Product Quality Review 81 Quality Risk Management 81 Chapter 2: Personnel 81 Principle 81

General 82 Key Personnel 82 Training 82 Personnel Hygiene 83 Chapter 3: Premises and Equipment 83 Principle 83

Premises 83 Production Area 83 Storage Areas 84 Quality Control Areas 84 Ancillary Areas 84 Equipment 84 Chapter 4: Documentation 84 Principle 84

Manufacturing Formula and

Processing Instructions 85 Packaging Instructions 85 Batch Processing Records 86 Batch Packaging Records 86 Procedures and Records 86 Sampling 86

Testing 86 Other 87 Chapter 5: Production 87 Principle 87

General 87

Prevention of Cross-Contamination in

Production 87 Validation 88 Starting Materials 88 Packaging Materials 88 Packaging Operations 88 Finished Products 89 Rejected, Recovered, and Returned Materials 89 Chapter 6: Quality Control 89

Principle 89 General 89 Good Quality Control Laboratory Practice 90 Documentation 90

Sampling 90 Testing 90 Ongoing Stability Program 90

Chapter 7: Contract Manufacture and

Analysis 91 Principle 91 General 91 The Contract Giver 91 The Contract Acceptor 91 The Contract 92

Chapter 8: Complaints and Product Recall 92 Principle 92

Complaints 92 Recalls 92

15 EDQM Certification 93

I 2.3.S Drug Substance 93 A.2.3.S.1 General Information 93

1.2.3.S.1.1 Nomenclature 93

2.3.S.1.2 General Properties 94

2.3.S.2 Manufacture 94

2.3.S.2.1 Manufacturer(s) (Name, Manufacturer) and

Sites Involved in the Entire Process 94

2.3.S.2.2 Description of Manufacturing Process and

Process Controls 94 2.3.S.2.3 Control of Materials 94

2.3.S.2.4 Controls of Critical Steps

and Intermediates 94 2.3.S.2.5 Process Validation and/or Evaluation 94

2.3.S.5 Reference Standards or Materials 94

2.3.S.6 Container Closure System 95

2.3.S.7 Stability 95

2.3.S.7.1 Stability Summary and Conclusions 95

2.3.S.7.2 Postapproval Stability Protocol and Stability

C Solvents with Low Toxic Potential 98

D Solvents for Which No Adequate

Toxicological Data Was Found 98 Glossary 98

Appendix 1 List of Solvents Included in the

Guideline 99 Appendix 2 Additional Background 101

A2.1 Environmental Regulation of Organic Volatile

Solvents 101 A2.2 Residual Solvents in Pharmaceuticals 101

Appendix 3 Methods for Establishing Exposure

C Definition of Part 11 Records 106

D Approach to Specific Part 11

Requirements 106

E Copies of Records 107

F Record Retention 107 VII Establishing a Compliance Plan 107 VIII Software and Systems Support 109 Bibliography 111

18 GMP Audit Template, EU Guidelines 112

Glossary 131

19 Bioequivalence Testing Protocols 134

20 Dissolution Testing of Liquid

Dosage Forms 137

21 Approved Excipients in Liquid Forms 139

PART II MANUFACTURING FORMULATIONS

Acetaminophen Syrup 173 Acne Scrub 174

Acyclovir Oral Suspension (2%= 200 mg/

10 mL) 174 Acyclovir Oral Suspension 174 Acyclovir Oral Suspension 175 Adapalene Solution 175

Albendazole Oral Suspension 176 Albendazole Suspension 177 Albuterol Inhalation Solution 177 Albuterol Inhalation Solution 177

Alginic Acid+ Aluminium Hydroxide + MagnesiumSilicate Tablets (500 mg+ 100 mg + 25 mg) 178 Alpha-Bisabolol Aqueous Mouthwash Solution 178 Alpha-Bisabolol Buccal or Topical Solution 178

Contents xvii

Alpha-Bisabolol Ethanolic Mouthwash Solution 179

Alpha-Bisabolol Mouthwash Solution 179

Aluminium Hydroxide+ Magnesium Silicate

Chewable Tablets (120 mg+ 250 mg) 179 Aluminum Chloride Solution 180

Aluminum Hydroxide and Magnesium Carbonate

Aminolevulinic Acid HCl for Topical Solution

(20%) 190 Amoxicillin Powder for Suspension 190

Amoxicillin–Clavulanate Syrup 191

Amoxicillin–Clavulanate Syrup 191

Ampicillin Powder for Suspension 192

Ampicillin Powder for Suspension 192

Ampicillin and Cloxacillin Oily Suspension 193

Amprenavir Capsules 193

Amprenavir Capsules 193

Amprenavir Oral Solution 194

Anise Oil Solution 194

Antipyrine and Benzocaine Elixir 194

Antiseptic Wet Wipes 194

Apraclonidine Hydrochloride Ophthalmic

Solution 195 Ascorbic Acid Solution 195

Atovaquone Suspension 195

Atovaquone Suspension 195

Azelastine Hydrochloride Nasal Spray 196

Azelastine Hydrochloride Nasal Spray 196

Azithromycin Suspension 197

Azithromycin Suspension 197

Azulene Solution 198 Azulene Solution (1%) 198 Barium Sulfate Oral Suspension 198

Beclomethasone Dipropionate Inhalation

Benzethonium Chloride and Benzocaine Topical

Anesthetic 199 Benzocaine and Tetracaine Topical Solution 199 Benzyl Benzoate Solution 199

Beta-Estradiol Vaginal Solution 200 Betamethasone Syrup 200

Bismuth Carbonate Suspension 200 Bismuth Subsalicylate Suspension 201 Bromazepam Drops 201

Bromhexine Hydrochloride Syrup 202

Bromhexine Hydrochloride Syrup—Alcohol

Free 203 Bromhexine Hydrochloride Syrup 204 Budesonide Inhaler 204

Butamirate Citrate Syrup 205 Caffeine Citrate Oral Solution 205 Calcipotriene Solution 205 Calcitonin Nasal Spray 205 Calcitonin Nasal Spray 205 Calcium Carbonate and Guar Gum Suspension 206 Calcium Iodide and Ascorbic Acid Syrup 207 Carbamazepine Oral Suspension 2% 207

Carbetapentane Tannate and Chlorpheniramine

Suspension 208 Carnitine and Coenzyme Q Solution 208 Cefaclor Suspension 209

Cefadroxil Monohydrate Oral Suspension 209 Cefpodoxime Proxetil Oral Suspension 209 Cefpodoxime Proxetil Oral Suspension 209 Cefpodoxime Proxetil for Oral Suspension 210 Cefuroxime Axetil Suspension 210

Cetirizine Hydrochloride Syrup 210

Chlophedianol, Ipecac, Ephedrine, AmmoniumChloride, Carbinoxamine, and Balsam Tolu

Chloramphenicol Opthalmic Solution 213

Chloramphenicol Palmitate Oral or Topical

Emulsion 213 Chlorhexidine Gel 214 Chlorpheniramine Maleate Syrup 214 Chloroxylenol Surgical Scrub 215 Ciclopirox Topical Solution 215 Cimetidine Syrup 215

Ciprofloxacin Hydrochloride and Hydrocortisone Otic

Suspension 216 Cisapride Suspension 217

Citalopram Hydrobromide Oral Solution 218

Clarithromycin Suspension 218

Clindamycin Phosphate Topical Solution 219

Clotrimazole Topical Solution 219

Clotrimazole Topical Solution (3%) 219

Codeine Phosphate and Acetaminophen

Elixir 219

Colistin Sulfate, Neomycin, Thonzonium Bromide,

and Hydrocortisone Otic Suspension 219 Cotrimoxazole Oral Suspension 220

Cromolyn Sodium Nasal Spray 221

Cromolyn Sodium Oral Concentrate 221

Crospovidone Oral Suspension (2000 mg/

10 mL) 221 Cyclosporin Oral Solution 221

Cyclosporine Soft Gelatin Capsules 221

Desmopressin Acetate Nasal Spray 221

Dexamethasone Elixir 221

Dextromethorphan and Chlorpheniramine Maleate

Solution 222

Dextromethorphan, Pseudoephedrine, and

Chlorpheniramine Maleate Syrup 222 Dextromethorphan Liquid 223

Dextromethorphan Liquid 223

Dextromethorphan, Pseudoephedrine, and

Chlorpheniramine Maleate Syrup 224 Dextromethorphan Solution 224

Dextrose, Levulose, and Phosphoric Acid

Solution 225 Diazepam Rectal Solution 225

Diclofenac Oral Solution 225

Didanosine for Oral Solution 226

Digoxin Capsules 226

Digoxin Elixir Pediatric 226

Dihydroergotamine Mesylate Drops 226

Diphenhydramine and Ammonium Chloride

Syrup 227 Diphenhydramine Hydrochloride Liquid 227

Dornase-Alpha Inhalation Solution 228

Doxercalciferol Capsules 228

Dyphylline, Guaifenesin Elixir 228

Electrolyte Lavage Solution 228

Eplerenone Solution 228

Erythromycin Drops 229

Erythromycin Topical Solution 229

Estradiol Nasal Spray 230

Ethchlorvynol Gelatin Capsule (200 mg) 230

Eucalyptus and Mint Emulsion 230

Eucalyptol Solution 231

Eucalyptol Solution (8%) 231

Fentanyl Citrate Nasal Spray 231

Ferrous Sulfate Oral Solution 231

Ferrous Sulfate Oral Syrup 232

Fluconazole Oral Suspension 232

Flunisolide Spray 232

Fluocinonide Topical Solution 232

Fluorouracil Solution 232

Fluorouracil Topical Solution 232

Fluticasone Suspension Spray 232

Furosemide Syrup 233

Ferrous Sulfate Oral Solution 233

Ferrous Sulfate Oral Syrup 234

Fir Needle Oil Solution 234

Guaifenesin, Pseudoephedrine, Carbinoxamine, and

Chlophedianol Drops 236

Guaifenesin Pseudoephedrine, Carbinoxamine, and

Chlophedianol Drops 237 Haloperidol Oral Liquid 238 Heparin Nasal Spray 238 Hydrocodone Bitartrate Elixir 238

Hydrocodone Polistirex Extended-Release

Suspension 238 Hydromorphone Hydrochloride Oral Liquid 238 Hydroxyzine Pamoate Oral Suspension 238 Hyoscine Butylbromide Syrup 239

Hyoscyamine Sulfate Elixir 239 Ibuprofen Topical Solution 239 Ibuprofen Pediatric Suspension 240 Iron Infant Drops 241

Iron Polystyrene and Vitamin C Syrup 242 Ibuprofen Pediatric Suspension 243 Ibuprofen Solution 243

Ibuprofen Suspension 244 Ibuprofen Suspension, Sugar Free 244

Ibuprofen and Domperidone Maleate

Suspension 244 Insulin Inhalation Spray 245 Ipratropium Bromide Inhalation Solution 245 Ipratropium Bromide Nasal Spray 245 Iron Polystyrene and Vitamin C Syrup 246

Isoproterenol Sulfate and Calcium Iodide

Syrup 247 Isotretinoin Capsules 247 Itraconazole Oral Solution 247

Kaolin, Pectin, and Aluminum Hydroxide

Suspension 248 Kaolin–Pectin Suspension 249 Kaolin–Pectin Suspension 250 Ketoprofen Topical Solution 250 Ketotifen Syrup 251

Lamivudine Oral Solution 251

Levalbuterol Hydrochloride Inhalation

Solution 251 Levocarnitine Oral Solution 251 Linezolid for Oral Suspension 251 Lithium Carbonate Solution 251 Lithium Citrate Syrup 251 Lomustine Nasal Spray 251 Loracarbef for Oral Suspension 251 Loratadine Syrup 252

Mafenide Acetate Topical Solution 252 Magaldrate Instant Powder for Dry Syrup 252 Magaldrate Suspension 253

Magaldrate with Simethicone Suspension 253 Magaldrate with Simethicone Suspension 254 Mebendazole Oral Suspension 255

Mebendazole Suspension 255 Megestrol Acetate Oral Suspension 256 Menthol and Benzocaine Solution 256 Menthol Mouthwash 257

Mesalamine Rectal Suspension Enema 257

Mint Oil Solution 263

Mint Oil Solution 264

Mometasone Furoate Nasal Spray 264

Monosulfiram Solution 264

Multivitamin and Calcium Syrup 265

Multivitamin and Mineral Syrup 266

Multivitamin Drops 267

Multivitamin Infant Drops 268

Multivitamin Infant Drops 269

Multivitamin Mineral Syrup 270

Multivitamin with Fluoride-Infant Drops 276

Nafarelin Acetate Nasal Solution 277

Ofloxacin Otic Solution 280

Ofloxacin Otic Solution 280

Oxycodone Hydrochloride Oral Concentrate

Oxymetazoline Nasal Solution 282

Oxymetazoline Nasal Spray 282

Oxymetazoline Sinus Nasal Spray 282

Peptide Topical Liquid 283

Pheniramine Maleate Syrup 283

Phenobarbital, Hyoscyamine Sulfate, Atropine

Sulfate, and Scopolamine Hydrobromide

Elixir 283

Phenylephrine Tannate and Chlorpheniramine

Tannate Pediatric Suspension 283

Phenylephrine Tannate and Pyrilamine

Pipenzolate Methyl Bromide and Phenobarbital

Drops 287 Podofilox Solution 288 Polidocanol Wound Spray 288 Polidocanol Wound Spray 288 Polyvinyl Pyrrolidone–Iodine Gargle Solution 289

Polyvinyl Pyrrolidone–Iodine Gargle Solution

Concentrate 289 Polyvinyl Pyrrolidone–Iodine Liquid Spray 289 Polyvinyl Pyrrolidone–Iodine Mouthwash 290

Polyvinyl Pyrrolidone–Iodine Mouthwash and Gargle

Solution Concentrate 290 Polyvinyl Pyrrolidone–Iodine Scrub 291 Polyvinyl Pyrrolidone–Iodine Solution 291 Polyvinyl Pyrrolidone–Iodine Solution 292 Polyvinyl Pyrrolidone–Iodine Solution 292 Polyvinyl Pyrrolidone–Iodine Solution 292 Polyvinyl Pyrrolidone–Iodine Solution 293 Polyvinyl Pyrrolidone–Iodine Surgical Scrub 293 Polyvinyl Pyrrolidone–Iodine Surgical Scrub 293

Polyvinyl Pyrrolidone–Iodine Vaginal Douche

Concentrate 294 Polyvinyl Pyrrolidone–Iodine Viscous Solution 294 Polyvinylpyrrolidone–Iodine Mouthwash 294

Povidone–Iodine Concentrates for Broilers and

Cattle 295 Povidone–Iodine Foam Spray 295 Povidone–Iodine Gargle 295 Povidone–Iodine Gargle Solution Concentrate 296 Povidone–Iodine Liquid Spray 296

Povidone–Iodine Mouthwash and Gargle Solution

Concentrate 296 Povidone–Iodine Powder Spray 297 Povidone–Iodine Pump Spray 297 Povidone–Iodine Shampoo 297 Povidone–Iodine Solution 298 Povidone–Iodine Solution 298 Povidone–Iodine Solution 299 Povidone–Iodine Solution 299 Povidone–Iodine Solution 299 Povidone–Iodine Scrub 300 Povidone–Iodine Surgical Scrub 300 Povidone–Iodine Surgical Scrub 301 Povidone–Iodine Vaginal Douche Concentrate 301 Povidone–Iodine Viscous Solution 301

Prednisone Oral Solution 302 Prednisolone Sodium Phosphate Oral Solution 302 Prednisolone Syrup 302

Progesterone Capsules 302 Promethazine and Codeine Syrup 302 Promethazine and Dextromethorphan Syrup 302 Promethazine Hydrochloride Syrup 302

Promethazine Hydrochloride Syrup 303 Promethazine Rectal Solution 303

Promethazine Rectal Solution 304 Pseudoephedrine Hydrochloride Syrup 304

Pseudoephedrine Hydrochloride, Carbinoxamine

Maleate Oral Drops 305

Pseudoephedrine Hydrochloride, Carbinoxamine

Maleate Oral Drops 306 Pseudoephedrine and Carbinoxamine Drops 307

Pseudoephedrine Hydrochloride Syrup 308

Ribavirin Inhalation Solution 308

Risperidone Oral Solution 308

Ritonavir Capsules 308

Ritonavir Oral Solution 308

Ritonavir and Lopinavir Oral Solution 308

Rivastigmine Tartarate Oral Solution 309

Salbutamol Aerosol 309

Salbutamol Syrup Sugar Free 310

Salbutamol Syrup 310

Salicylic Acid Collodion 311

Salmeterol Xinafoate Inhalation Aerosol 311

Salmeterol Xinafoate Inhalation Aerosol 311

Scopolamine Nasal Spray 312

Selenium Sulfide Shampoo with Conditioner 312

Sertraline Hydrochloride Oral Concentrate 313

Sertraline Hydrochloride Solution 313

Simethicone Drops 313

Sirolimus Solution 314

Sodium Chloride Nasal Drops 314

Stavudine for Oral Suspension 314

Sulfidoxine Solution 317

Sulfidoxine and Pyrimethamine Suspension 318

Sumatriptan Nasal Spray 318

Sumatriptan Nasal Spray 318

Terfenadine Oral Suspension 319

Terfenadine Suspension 319

Theophylline Sodium Glycinate Elixir 320

Thiabendazole Suspension 320

Thiothixene Oral Concentrate 320

Timolol Maleate Opthalmic Drops 320

Tolnaftate Foot Care Microemulsion 321

Tolu Balsam Cough Syrup 321

Tolu Balsam Cough Syrup 322

Tretinoin Solution (50 mg/100 g) 323

Tretinoin Solution 323

Triamcinolone Acetonide Nasal Spray 323

Triclosan Oral Solution 324

Triprolidine and Pseudoephedrine Hydrochloride

Syrup 324 Tulobuterol Syrup 325

Tolnaftate Foot Care Microemulsion 325

Triprolidine and Pseudoephedrine Hydrochloride

Syrup 326 Undecylenic Acid and Chloroxylenol Solution 327

Urea Peroxide Ear Drops 327

Valproic Acid Capsules 327

Valproic Acid Syrup 327 Vancomycin Hydrochloride Oral Solution 327 Vitamin A and Vitamin D Infant Drops 328 Vitamins A and D Infant Drops 329

Vitamin A and Vitamin D3Drops 329

Vitamin A and Vitamin D3Drops 330

Vitamin A and Vitamin D3Oral Solution 330

Vitamin A and Vitamin D3Oral Solution 330

Vitamin A and Vitamin D3Syrup 331

Vitamin A and Vitamin D3Syrup 331 Vitamin A and Vitamin E Drops 331 Vitamin A and Vitamin E Drops 332 Vitamin A and Vitamin E Drops 332 Vitamin A and Vitamin E Drops 332 Vitamin A Concentrate, Water-Miscible 333 Vitamin A Concentrate, Water-Miscible 333 Vitamin A Drops 333

Vitamin A Drops 334 Vitamin B Complex Syrup 334 Vitamin B Complex Syrup 335 Vitamin B Complex Syrup 336 Vitamin B Complex and Vitamin C Syrup 336

Vitamin B Complex (without B12) Syrup 337

Vitamin B Complex, A, C, D, and Calcium

Drops 338 Vitamin B Complex and Iron Syrup 339 Vitamin B Complex and Iron Syrup 340 Vitamin B Complex and Vitamin C Syrup 341 Vitamin B Complex and Vitamin C Syrup 342 Vitamin B Complex and Vitamin C Syrup 342 Vitamin B Complex, A, C, and D Syrup 343 Vitamin B Complex Syrup 344

Vitamin B Complex Syrup 345

Vitamin B Complex Syrup (without B12) 346

Vitamin B Complex, Vitamin A, Vitamin C, and

Vitamin D Syrup 347

Vitamin B Complex, Vitamin A, Vitamin C, Vitamin D,

and Calcium Drops 348

Vitamin B Complex, Vitamin A, Vitamin C, Vitamin D,

and Vitamin E Pediatric Drops 349 Vitamin B Complex, Vitamin C, and Iron Syrup 350

Vitamin B Complex, Vitamin C, and Iron

Syrup 351 Vitamin C Drops 352 Vitamin E and Benzocaine Solution 352 Vitamin E Concentrate, Water-Miscible 352 Vitamin E Drops 353

Vitamin E Soft Gel Capsules 353 Vitamin E Solution with Ethanol 353 Vitamin E and Benzocaine Solution 354 Vitamin E and Benzocaine Solution 354 Vitamin E Capsules 354

Vitamin E Drops 355 Vitamin E Drops 355 Vitamin E Solution with Ethanol 355 Vitamin E Solution with Ethanol 355 Xylometazoline Hydrochloride Nasal Solution 356 Xylometazoline Hydrochloride Nasal Solution 356

Xylometazoline Hydrochloride Children’s Nasal

Solution 356 Zinc Pyrithione Shampoo 357 Commercial Pharmaceutical Products 357 Index 365

Part I

Regulatory and Manufacturing Guidance

Manufacturing Practice Considerations in Liquid Formulations

I INTRODUCTION

The manufacture and control of oral solutions and oral

sus-pensions presents some unusual problems not common to

other dosage forms Although bioequivalency concerns are

minimal (except for products in which dissolution is a

rate-limiting or absorption-determining step, as in phenytoin

sus-pension), other issues have frequently led to recalls of liquid

products These include microbiological, potency, and

stabil-ity problems In addition, because the population using these

oral dosage forms includes newborns, pediatrics, and

geri-atrics, who may not be able to take oral solid dosage forms

and who may have compromised drug metabolic or other

clearance function, defective dosage forms can pose a greater

risk if the absorption profiles are significantly altered from

the profiles used in the development of drug safety profiles

II FACILITIES

The designs of the facilities are largely dependent on the

type of products manufactured and the potential for

cross-contamination and microbiological cross-contamination For

ex-ample, the facilities used for the manufacture of

over-the-counter oral products might not require the isolation that a

steroid or sulfa product would require However, the concern

for contamination remains, and it is important to isolate

pro-cesses that generate dust (such as those propro-cesses occurring

before the addition of solvents) The HVAC (heating,

venti-lation, and air-conditioning) system should be validated just

as required for processing of potent drugs Should a

manu-facturer rely mainly on recirculation rather than filtration or

fresh air intake, efficiency of air filtration must be validated

by surface and air sampling It is advisable not to take any

shortcuts in the design of HVAC systems, as it is often very

difficult to properly validate a system that is prone to

break-down; in such instances a fully validated protocol would

need stress testing—something that may be more expensive

than establishing proper HVAC systems in the first place

However, it is also unnecessary to overdo it in designing the

facilities, as once the drug is present in a solution form,

cross-contamination to other products becomes a lesser problem

It is, nevertheless, important to protect the drug from other

powder sources (such as by maintaining appropriate pressure

differentials in various cubicles)

III EQUIPMENT

Equipment should be of sanitary design This includes

san-itary pumps, valves, flow meters, and other equipment that

can be easily sanitized Ball valves, the packing in pumps,

and pockets in flow meters have been identified as sources

of contamination Contamination is an extremely important

consideration, particularly for those sourcing

manufactur-ing equipment from less developed countries; manufacturers

of equipment often offer two grades of equipment: sanitaryequipment, and equipment not qualified as sanitary and of-fered at substantial savings All manufacturers intending toship any product subject to U.S Food and Drug Adminis-tration (FDA) inspection must insist on certification that theequipment is of sanitary design

To facilitate cleaning and sanitization, manufacturingand filling lines should be identified and detailed in drawingsand standard operating procedures Long delivery lines be-tween manufacturing areas and filling areas can be a source

of contamination Special attention should be paid to oping standard operating procedures that clearly establishvalidated limits for this purpose

devel-Equipment used for batching and mixing of oral lutions and suspensions is relatively basic These productsare generally formulated on a weight basis, with the batch-ing tank on load cells so that a final volume can be made byweight; if you have not done so already, consider convert-ing your systems to weight basis Volumetric means, such

so-as using a dipstick or a line on a tank, are not generally so-asaccurate and should be avoided where possible When vol-umetric means are chosen, make sure they are properly val-idated at different temperature conditions and other factorsthat might render this practice faulty In most cases, manu-facturers assay samples of the bulk solution or suspensionbefore filling A much greater variability is found with thosebatches that have been manufactured volumetrically ratherthan those that have been manufactured by weight Again,the rule of thumb is to avoid any additional validation ifpossible

The design of the batching tank with regard to the tion of the bottom discharge valve often presents problems.Ideally, the bottom discharge valve is flush with the bottom

loca-of the tank In some cases, valves—including undesirable ballvalves—are several inches to a foot below the bottom of thetank This is not acceptable It is possible that in this situa-tion the drug or preservative may not completely dissolveand may get trapped in the “dead leg” below the tank, withinitial samples turning out subpotent For the manufacture ofsuspensions, valves should be flush

Transfer lines are generally hard piped and are easilycleaned and sanitized In situations where manufacturers useflexible hoses to transfer product, it is not unusual to seethese hoses lying on the floor, thus significantly increasing thepotential for contamination Such contamination can occurthrough operators picking up or handling hoses, and possiblyeven through operators placing them in transfer or batchingtanks after the hoses had been lying on the floor It is a goodpractice to store hoses in a way that allows them to drain,rather than coiling them, which may allow moisture to collectand be a potential source of microbial contamination.Another common problem occurs when manifold orcommon connections are used, especially in water supply,premix, or raw material supply tanks Such common connec-tions can be a major source of contamination

2

Manufacturing Practice Considerations in Liquid Formulations 3

IV RAW MATERIALS

The physical characteristics, particularly the particle size of

the drug substance, are very important for suspensions As

with topical products in which the drug is suspended,

par-ticles are usually very fine to micronize (to<25 microns).

For syrup, elixir, or solution dosage forms in which there is

nothing suspended, particle size and physical characteristics

of raw materials are not that important However, they can

affect the rate of dissolution of such raw materials in the

man-ufacturing process Raw materials of a finer particle size may

dissolve faster than those of a larger particle size when the

product is compounded

Examples of a few oral suspensions in which a cific and well-defined particle-size specification for the drug

spe-substance is important include phenytoin suspension,

carba-mazepine suspension, trimethoprim and sulfamethoxazole

suspension, and hydrocortisone suspension It is therefore a

good idea to indicate particle size in the raw material

spec-ification, even though it is meant for dissolving in the

pro-cessing, to better validate the manufacturing process while

avoiding scale-up problems

V COMPOUNDING

In addition to a determination of the final volume (on weight

or volume basis) as previously discussed, there are

microbio-logical concerns, and these are well covered in other chapters

in this book

For oral suspensions there is the additional concern ofuniformity, particularly because of the potential for segrega-

tion during manufacture and storage of the bulk suspension,

during transfer to the filling line, and during filling It is

necessary to establish procedures and time limits for such

operations to address the potential for segregation or settling

as well as other unexpected effects that may be caused by

extended holding or stirring

For oral solutions and suspensions, the amount andcontrol of temperature is important from a microbiological as

well as a potency aspect For those products in which

temper-ature is identified as a critical part of the operation, the batch

records must demonstrate compliance using control charts

There are some processes in manufacturing in which heat is

used during compounding to control the microbiological

lev-els in the product For such products, the addition of purified

water to make up to final volume, the batch, and the

temper-atures during processing should be properly documented

In addition to drug substances, some additives such asthe most commonly used preservatives, parabens are diffi-

cult to dissolve, and require heat (often to 80◦C) The control

and verification of their dissolution during the compounding

stage should be established in the method validation From

a potency aspect, the storage of product at high

tempera-tures may increase the level of degradants Storage limitations

(time and temperature) should be justified

There are also some oral liquids that are sensitive tooxygen and that have been known to undergo degradation

This is particularly true of the phenothiazine class of drugs,

such as perphenazine and chlorpromazine The manufacture

of such products might require the removal of oxygen, as

by nitrogen purging In addition, such products might also

require storage in sealed tanks, rather than in those with

loose lids Manufacturing directions provided in this book

are particularly detailed about the purging steps, and these

should be closely observed

VI MICROBIOLOGICAL QUALITY

Microbiological contamination can present significant healthhazards in some oral liquids For example, some oral liq-uids, such as nystatin suspension, are used in infants andimmunocompromised patients, and microbiological contam-ination with organisms (such as Gram-negative organisms) isnot acceptable There are other oral liquid preparations such

as antacids in which Pseudomonas sp contamination is also

objectionable For other oral liquids such as cough

prepara-tions, contamination with Pseudomonas sp might not present

the same health hazard However, the presence of a specific

Pseudomonas sp may also indicate other plant or raw material

contamination and often points to defects in the water tems and environmental breaches; extensive investigationsare often required to trace the source of contamination Ob-viously, the contamination of any preparation with Gram-negative organisms is not desirable

sys-In addition to the specific contaminant being able, such contamination would be indicative of a deficientprocess as well as an inadequate preservative system For

objection-example, the presence of a Pseudomonas putida contaminant could also indicate that P aeruginosa, a similar source organ-

ism, is also present

Because FDA laboratories typically use more sensitivetest methods than industry, samples of oral liquids in whichmanufacturers report microbiological counts well within lim-its may be found unacceptable by the federal laborato-ries This result requires upgrading the sensitivity of testingprocedures

VII ORAL SUSPENSIONS

Liquid products in which the drug is suspended (not in tion) present some unique manufacturing and control prob-lems Depending on the viscosity, many suspensions requirecontinuous or periodic agitation during the filling process Ifdelivery lines are used between the bulk storage tank and thefilling equipment, some segregation may occur, particularly

solu-if the product is not viscous Procedures must therefore beestablished for filling and diagrams established for line setupprior to the filling equipment

Good manufacturing practice would warrant testingbottles from the beginning, middle, and end of a batch to en-sure that segregation has not occurred Such samples shouldnot be combined for the purpose of analysis In-process test-ing for suspensions might also include an assay of a samplefrom the bulk tank More important at this stage, however,may be testing for viscosity

VIII PRODUCT SPECIFICATIONS

Important specifications for the manufacture of all solutionsinclude assay and microbial limits Additional importantspecifications for suspensions include particle size of thesuspended drug, viscosity, pH, and in some cases, dissolu-tion Viscosity can be important, from a processing aspect,

to minimize segregation In addition, viscosity has also beenshown to be associated with bioequivalency pH may alsohave some meaning regarding effectiveness of preservativesystems and may even have an effect on the amount of drug

in solution With regard to dissolution, there are at leastthree products that have dissolution specifications These

products include phenytoin suspension, carbamazepine

sus-pension, and sulfamethoxazole and trimethoprim

suspen-sion Particle size is also important, and at this point it

would seem that any suspension should have some type

of particle-size specification As with other dosage forms,

the underlying data to support specifications should be

established

IX PROCESS VALIDATION

As with other products, the amount of data needed to support

the manufacturing process will vary from product to product

Development (data) should have identified critical phases

of the operation, including the predetermined specifications

that should be monitored during process validation

For example, for solutions, the key aspects that should

be addressed during validation include ensuring that the

drug substance and preservatives are dissolved Parameters

such as heat and time should be measured In-process assay

of the bulk solution during or after compounding according

to predetermined limits is also an important aspect of

pro-cess validation For solutions that are sensitive to oxygen or

light, dissolved oxygen levels would also be an important

test Again, the development data and the protocol should

provide limits

As discussed, the manufacture of suspensions presentsadditional problems, particularly in the area of uniformity

The development data should address the key compounding

and filling steps that ensure uniformity The protocol should

provide for the key in-process and finished product tests,

along with their specifications For oral solutions,

bioequiv-alency studies may not always be needed However, oral

suspensions, with the possible exception of some of the

over-the-counter antacids, usually require a bioequivalency or

clin-ical study to demonstrate their effectiveness Comparison of

product batches with the biobatch is an important part of

the validation process Make sure there are properly written

protocol and process validation reports and, if appropriate,

data for comparing full-scale batches with biobatch available

during FDA inspection

X STABILITY

One area that has presented a number of problems is ensuringthe stability of oral liquid products throughout their expiryperiod The presence of water or other solvents enhances allreaction rates: Because fluids can contain a certain amount

of oxygen, the oxidation reactions are also enhanced, as inthe case of vitamins and the phenothiazine class of drugs.Good practice for these classes of drug products should in-clude quantitation of both the active and primary degradant.There should be well-established specifications for the pri-mary degradant, including methods of quantitation of boththe active drug and degradant

Because interactions of products with closure systemsare possible, liquids and suspensions undergoing stabilitystudies should be stored on their side or inverted to determinewhether contact of the drug product with the closure systemaffects product integrity

Other problems associated with inadequate closuresystems are moisture losses that can cause the remain-ing contents to become superpotent and microbiologicalcontamination

XI PACKAGING

Problems in the packaging of oral liquids have included tency (fill) of unit dose products and accurate calibration ofmeasuring devices such as droppers, which are often pro-vided For unit dose solution products the label claim quan-tity within the limits described should be delivered

po-Another problem in the packaging of oral liquids is lack

of cleanliness of the containers before filling Fibers and eveninsects often appear as debris in containers, particularly inthe plastic containers used for many of these products Manymanufacturers receive containers shrink wrapped in plastic tominimize contamination from fiberboard cartons, and manymanufacturers use compressed air to clean the containers.Vapors, such as oil vapors, from the compressed air haveoccasionally been found to present problems, and it is a goodpractice to use compressed gas from oil-free compressors

Oral Solutions and Suspensions

I INTRODUCTION

The manufacture and control of oral solutions and oral

sus-pensions present unique problems to the industry While

bioequivalency concerns are minimal (except for antibiotic

suspensions, for example), other issues have led to recalls,

including microbiological, potency, and stability problems

Additionally, because the population using these oral dosage

forms includes newborn, pediatric, and geriatric patients who

may not be able to take oral solid dosage forms and may

be compromised, defective dosage forms can pose an even

greater risk than for other patients

II FACILITIES

The design of production facilities is largely dependent on

the type of products manufactured and the potential for

cross-contamination and microbiological cross-contamination For

exam-ple, facilities used for the manufacture of over-the-counter

(OTC) oral products might not require the isolation that a

steroid or sulfa product would require The manufacturer

must establish policies of isolation of processes to minimize

contamination It should be further established whether or

not particular drug substances and powdered excipients

gen-erate dust, given the method of manufacture used System

design and efficiency of dust removal system must be

con-sidered A firm’s HVAC system requires particular attention,

especially where potent or highly sensitizing drugs are

pro-cessed Some manufacturers recirculate air without adequate

filtration Where air is recirculated, a firm’s data must

demon-strate the efficiency of air filtration through surface and/or

air sampling

III EQUIPMENT

Equipment should be of a sanitary design and should include

sanitary pumps, valves, flow meters, and other equipment

that can be easily sanitized Ball valves, packing in pumps,

and pockets in flow meters have been identified as sources

of contamination In order to facilitate cleaning and

sanitiza-tion, manufacturing and filling lines should be identified and

detailed in drawings and standard operating procedures In

some cases, long delivery lines between manufacturing

ar-eas and filling arar-eas have been a source of contamination

The standard operating procedures of many manufacturers

have been found to be deficient, particularly with regard to

time limitations between batches and for cleaning

Equip-ment used for batching and mixing of oral solutions and

suspensions is relatively basic Generally, these products are

formulated on a weight basis with the batching tank on load

cells so that a final quantity sufficient (QS) can be made by

weight Volumetric means, such as using a dipstick or line

on a tank, have been found to be inaccurate In most cases,

manufacturers will assay samples of the bulk solution or pension prior to filling A much greater variability has beenfound with batches that have been manufactured volumetri-cally rather than by weight

sus-The design of the batching tank with regard to thelocation of the bottom discharge valve also presents prob-lems Ideally, the bottom discharge valve should be flush withthe bottom of the tank In some cases, valves (including un-desirable ball valves) are several inches below the bottom ofthe tank; in others, the drug or preservative is not completelydissolved and lies in the dead leg below the tank, with initialsamples being found to be subpotent For the manufacture ofsuspensions, valves should be flush

With regard to transfer lines, they are generally hardpiped and easily cleaned and sanitized In some cases, man-ufacturers have used flexible hoses to transfer product, but

it is not unusual to find flexible hoses on the floor, thus nificantly increasing the potential for contamination Suchcontamination can occur when operators pick up or handlethe hoses, possibly even placing them in transfer or batch-ing tanks after picking them up from the floor It is also agood practice to store hoses in a way that allows them todrain rather than coiling them, which may allow moisture tocollect and be a potential source of microbial contamination.Another common problem occurs when a manifold orcommon connection is used, especially in water supply, pre-mix, or raw material supply tanks Such common connectionshave been shown to be a source of contamination

sig-IV RAW MATERIALS

Physical characteristics, particularly the particle size of thedrug substance, are very important for suspensions As withtopical products in which the drug is suspended, particles areusually very fine to micronize (less than 25␮m) For syrups,elixirs, or solution dosage forms in which nothing is sus-pended, the particle size and physical characteristics of theraw materials are not that important; however, they can af-fect the rate of dissolution of such raw materials during themanufacturing process Raw materials of a finer particle sizemay dissolve faster than those of a larger particle size whenthe product is compounded

V COMPOUNDING

In addition to a determination of the final volume (QS) aspreviously discussed, microbiological concerns also exist.For oral suspensions, an additional concern is uniformity,particularly because of the potential for segregation duringthe manufacture and storage of the bulk suspension, dur-ing transfer to the filling line, and during filling A man-ufacturer’s data should support storage times and transferoperations Procedures and time limits for such operations5

should be established to address the potential for segregation

or settling, as well as other unexpected effects that may be

caused by extended holding or stirring

For oral solutions and suspensions, the amount andcontrol of temperature are important from a microbiological

as well as a potency aspect For those products in which

tem-perature is identified as a critical part of the operation, the

manufacturer should maintain documentation of

tempera-ture, such as by control charts

Some manufacturers rely on heat during ing to control the microbiological levels in product For such

compound-products, the addition of purified water to a final QS, the

batch, and the temperatures during processing should be

doc-umented and available for review

In addition to drug substances, some additives, such asparaben, are difficult to dissolve and require heat The control

and monitoring of their dissolution during the

compound-ing stage should be documented From a potency aspect, the

storage of product at high temperatures may increase the

level of degradants Storage limitations (time and

tempera-ture) should be justified by manufacturers and are likely to

be evaluated during an inspection

Some oral liquids are sensitive to oxygen and have beenknown to undergo degradation This is particularly true of

the phenothiazine class of drugs, such as perphenazine and

chlorpromazine The manufacture of such products might

re-quire the removal of oxygen such as by nitrogen purging

Ad-ditionally, such products might also require storage in sealed

tanks, rather than in tanks with loose lids In the OTC

cate-gory, the entire line of vitamins is subject to degradation if

they are not properly protected against oxidation,

particu-larly those products that contain minerals (which might

con-tain highly active trace elements that catalyze degradation of

vitamins)

VI MICROBIOLOGICAL QUALITY

Microbiological contamination of some oral liquids can

present significant health hazards For example, some oral

liquids, such as nystatin suspension, are used for infants and

immunocompromised patients, and microbiological

contam-ination with organisms such as Gram-negative organisms

is objectionable For other oral liquid preparations, such as

antacids, Pseudomonas sp contamination is also

objection-able; however, for some oral liquids, such as cough

prepara-tions, contamination with Pseudomonas sp might not present

the same health hazard Obviously, the contamination of any

preparation with Gram-negative organisms is not desirable

In addition to the specific contaminant being tionable, such contamination would be indicative of a de-

objec-ficient process as well as an inadequate preservative system

The presence of a specific Pseudomonas sp may also indicate

that other plant or raw material contaminants could survive

the process For example, the fact that a Pseudomonas putida

contaminant is present could also indicate that Pseudomonas

aeruginosa, a similar source organism, could also be present.

VII ORAL SUSPENSION UNIFORMITY

Liquid products in which the drug is suspended (and not in

solution) present manufacturer control problems

Depend-ing upon the viscosity, many suspensions require continuous

or periodic agitation during the filling process If delivery

lines are used between the bulk storage tank and the ing equipment, some segregation may occur, particularly ifthe product is not viscous Inspectors will review a manu-facturer’s procedures for filling and diagrams for line setupprior to the filling equipment Good manufacturing practicewould warrant testing bottles from the beginning, middle,and end to assure that segregation has not occurred Suchsamples should not be composited or pooled In-process test-ing for suspensions might also include an assay of a samplefrom the bulk tank More important, however, may be testingfor viscosity

fill-VIII PRODUCT SPECIFICATIONS

Important specifications for the manufacture of all solutionsinclude assay and microbial limits Additional importantspecifications for suspensions include particle size of the sus-pended drug, viscosity, pH, and in some cases, dissolution.Maintaining an appropriate viscosity is important from a pro-cessing perspective to minimize segregation Additionally,viscosity has also been shown to be associated with bioe-quivalency The pH may also have some meaning regardingeffectiveness of preservative systems and may even have aneffect on the amount of drug in solution With regard to dis-solution, at least several products have dissolution specifica-tions listed in their U.S Pharmacopeia (USP) monographs.Particle size is also important, and at this point it would seemthat any suspension should have some type of particle-sizespecification

IX PROCESS VALIDATION

As with other products, the amount of data required to port the manufacturing process will vary from product toproduct Development (data) should identify critical phases

sup-of the operation, including the predetermined specificationsthat should be monitored during process validation For ex-ample, for solutions the key aspects that should be addressedduring validation include assurance that the drug substanceand preservatives are dissolved Parameters such as heat andtime should be measured In-process assay of the bulk solu-tion during and/or after compounding according to prede-termined limits is also an important aspect of process valida-tion For solutions that are sensitive to oxygen and/or light,dissolved oxygen levels would also be an important test.Again, the development data and the protocol should pro-vide limits The manufacture of suspensions presents addi-tional problems, particularly in the area of uniformity Again,development data should address the key compounding andfilling steps that ensure uniformity The protocol should pro-vide for the key in-process and finished product tests, alongwith their specifications For oral solutions, bioequivalencystudies may not always be needed; however, oral suspen-sions, with the possible exception of some antacids and OTCproducts, usually require a bioequivalency or clinical study todemonstrate effectiveness As with oral solid dosage forms,comparison to the biobatch is an important part of validatingthe process

X STABILITY

One area that has presented a number of problems includesmaintaining the stability of oral liquid products throughout

Oral Solutions and Suspensions 7

their expiry period Vitamins with fluoride oral liquid

prod-ucts have had a number of recalls because of vitamin

degrada-tion Drugs in the phenothiazine class, such as perphenazine,

chlorpromazine, and promethazine, have also shown

evi-dence of instability Good practice for this class of drug

products would include quantitation of both the active

and primary degradant Dosage form manufacturers should

know and have specifications for the primary degradant

These manufacturers’ data and validation data for methods

used to quantitate both the active drug and degradant are

likely to be reviewed during an inspection Because

inter-actions of products with closure systems are possible,

liq-uids and suspensions undergoing stability studies should be

stored on their side or inverted in order to determine whether

contact of the drug product with the closure system affects

product integrity Moisture losses that can cause the

remain-ing contents to become superpotent and microbiological

con-tamination are other problems associated with inadequate

closure systems

XI PACKAGING

Problems in the packaging of oral liquids have included tency (fill) of unit dose products and accurate calibration ofmeasuring devices such as droppers that are often provided.The USP does not provide for dose uniformity testing for oralsolutions Thus, unit-dose solution products should deliverlabel claims within the limits described in the USP Inspectorswill review a manufacturer’s data to ensure uniformity of filland test procedures to ascertain that unit-dose samples arebeing tested Another problem in the packaging of oral liq-uids is a lack of cleanliness of containers prior to filling Fibersand even insects have been identified as debris in containers,particularly plastic containers used for these products Manymanufacturers receive containers shrink wrapped in plastic tominimize contamination from fiberboard cartons Some man-ufacturers may utilize compressed air to clean containers, inwhich case vapors (such as oil vapors) from the compressedair have occasionally been found to present problems

The FDA Drug Product Surveillance Program

I BACKGROUND

A primary mission of the Food and Drug Administration

(FDA) is to conduct comprehensive regulatory coverage of

all aspects of production and distribution of drugs and drug

products to assure that such products meet the 501(a)(2)(B)

requirements of the Food, Drugs, and Cosmetics Act The

FDA has developed two basic strategies:

1 Evaluating through factory inspections, including the

col-lection and analysis of associated samples, the conditions

and practices under which drugs and drug products are

manufactured, packed, tested, and held

2 Monitoring the quality of drugs and drug products

through surveillance activities such as sampling and

ana-lyzing products in distribution

This compliance program is designed to provide ance for implementing the first strategy Products from

guid-production and distribution facilities covered under this

pro-gram are consistently of acceptable quality if the firm is

operating in a state of control The Drug Product

Surveil-lance Program (CP 7356.008) provides guidance for the latter

strategy

II IMPLEMENTATION

A Objectives

The goal of this program’s activities is to minimize

con-sumer’s exposure to adulterated drug products Under this

program, inspections and investigations, sample collections

and analyses, and regulatory or administrative follow-up are

made:

r To determine whether inspected firms are operating in

compliance with applicable current Good Manufacturing

Practices (cGMPs) requirements and, if not, to provide the

evidence for actions to prevent adulterated products from

entering the market; and, as appropriate, to remove

adul-terated products from the market and to take action against

persons responsible as appropriate

r To provide cGMP assessment, which may be used in

ef-ficient determination of acceptability of the firm in the

preapproval review of a facility for new drug applications

r To provide input to firms during inspections to improve

their compliance with regulations

r To continue the FDA’s unique expertise in drug

manufac-turing in determining the adequacy of cGMP requirements,

FDA cGMP regulatory policy, and guidance documents

B Strategy

1 Biennial Inspection of Manufacturing Sites

Drugs and drug products are manufactured using many

physical operations to bring together components,

contain-ers, and closures into a product that is released for bution Activities found in drug firms can be organized intosystems that are sets of operations and related activities Con-trol of all systems helps to ensure that the firm will producedrugs that are safe, have the identity and strength, and meetthe quality and purity characteristics as intended

distri-Biennial inspections (every 2 years) of manufacturingsites, which include repackaging, contract labs, etc., help to

r reduce the risk that adulterated products are reaching themarketplace,

r increase communication between the industry and theAgency,

r provide for timely evaluation of new manufacturing ations in the firm, and

oper-r provide for regular feedback from the Agency to vidual firms on the continuing status of the firm’s GMPcompliance

indi-This program applies to all drug manufacturing ations Currently, not enough FDA resources are available toaudit every aspect of cGMP in every manufacturing facilityduring every inspection visit Profile classes generalize in-spection coverage from a small number of specific products

oper-to all the products in that class This program establishes asystems approach to further generalize inspection coveragefrom a small number of profile classes to an overall evalua-tion of the firm Reporting coverage for every profile class asdefined in Field Accomplishment and Compliance TrackingSystem (FACTS), in each biennial inspection, provides themost broadly resource-efficient approach Biennial updating

of all profile classes will allow for cGMP acceptability minations to be made without delays resulting from revisit-ing the firm This will speed the review process, in response

deter-to compressed time frames for application decisions and inresponse to provisions of the FDA Modernization Act of

1997 (FDAMA) This will allow for Preapproval Inspections/Investigations Program inspections and Postapproval AuditInspections to focus on the specific issues related to a givenapplication or the firm’s ability to keep applications current.The inspection is defined as audit coverage of two ormore systems, with mandatory coverage of the Quality Sys-tem (see the system definitions in section II.B.3.) Inspectionoptions include different numbers of systems to be covereddepending on the purpose of the inspection Inspecting theminimum number of systems, or more systems as deemednecessary by the regional District of the FDA, will providethe basis for an overall cGMP decision

2 Inspection of Systems

Inspections of drug manufacturers should be made and ported using the system definitions and organization in thiscompliance program Focusing on systems instead of on pro-file classes will increase efficiency in conducting inspectionsbecause the systems are often applicable to multiple profile8

re-The FDA Drug Product Surveillance Program 9

classes One biennial inspection visit will result in a

determi-nation of acceptability/nonacceptability for all profile classes

Inspection coverage should be representative of all the

pro-file classes manufactured by the firm The efficiency will be

realized, because multiple visits to a firm will not be needed

to cover all profile classes; delays in approval decisions will

be avoided because up-to-date profile class information will

be available at all times

Coverage of a system should be sufficiently detailed,with specific examples selected, so that the system inspection

outcome reflects the state of control in that system for

ev-ery profile class If a particular system is adequate, it should

be adequate for all profile classes manufactured by the firm

For example, the way a firm handles “materials” (i.e.,

re-ceipt, sampling, testing, acceptance, etc.) should be the same

for all profile classes The investigator should not have to

inspect the Material System for each profile class Likewise,

the Production System includes general requirements such as

standard operating procedure (SOP) use, charge-in of

com-ponents, equipment identification, and in-process sampling

and testing, which can be evaluated through selection of

ex-ample products in various profile classes Under each system,

there may be something unique for a particular profile class

(e.g., under the Materials System, the production of Water for

Injection USP (US Pharmacopeia) for use in manufacturing.

Selecting unique functions within a system will be at the

dis-cretion of the lead investigator) Any given inspection need

not cover every system (see section III)

Complete inspection of one system may necessitatefurther follow-up of some items within the activities of an-

other/other system(s) to fully document the findings

How-ever, this coverage neither constitute nor require complete

coverage of these other systems

3 A Scheme of Systems for the Manufacture of Drugs

and Drug Products

A general scheme of systems for auditing the manufacture of

drugs and drug products consists of the following:

1 Quality System—This system assures overall compliance

with cGMPs and internal procedures and specifications

The system includes the quality control unit and all its

re-view and approval duties (e.g., change control,

reprocess-ing, batch release, annual record review, validation

proto-cols, and reports) It includes all product defect evaluations

and evaluation of returned and salvaged drug products

(See the cGMP regulation, 21 CFR 211 subparts B, E, F, G,

I, J, and K.)

2 Facilities and Equipment System—This system includes the

measures and activities that provide an appropriate

phys-ical environment and the resources used in the production

of the drugs or drug products It includes the following:

a Buildings and facilities along with maintenance

b Equipment qualifications (installation and operation);

equipment calibration and preventative maintenance;

and cleaning and validation of cleaning processes asappropriate process performance qualification will beevaluated as part of the inspection of the overall processvalidation that is done within the system where theprocess is employed

c Utilities not intended for incorporation into the

prod-uct such as heating, ventilating, and air conditioning(HVAC), compressed gases, steam, and water systems

(See the cGMP regulation, 21 CFR 211 subparts B, C, D,and J.)

3 Materials System—This system includes measures and

ac-tivities to control finished products, components, ing water or gases that are incorporated into the product,containers, and closures It includes validation of comput-erized inventory control processes, drug storage, distribu-tion controls, and records (See the cGMP regulation, 21CFR 211 subparts B, E, H, and J.)

includ-4 Production System—This system includes measures and

activities to control the manufacture of drugs and drugproducts including batch compounding, dosage form pro-duction, in-process sampling and testing, and processvalidation It also includes establishing, following, anddocumenting performance of approved manufacturingprocedures (See the cGMP regulation, 21 CFR 211 sub-parts B, F, and J.)

5 Packaging and Labeling System—This system includes

mea-sures and activities that control the packaging and ing of drugs and drug products It includes written pro-cedures, label examination and usage, label storage andissuance, packaging and labeling operations controls, andvalidation of these operations (See the cGMP regulation,

label-21 CFR label-211 subparts B, G, and J.)

6 Laboratory Control System—This system includes measures

and activities related to laboratory procedures, testing, alytical methods development and validation or verifica-tion, and the stability program (See the cGMP regulation,

an-21 CFR an-211 subparts B, I, J, and K.)The overall theme in devising this scheme of systemswas the subchapter structure of the cGMP regulation Everyeffort was made to group whole subchapters together in a ra-tional set of six systems that incorporates the general scheme

of pharmaceutical manufacturing operations

The organization and personnel, including appropriatequalifications and training, employed in any given system, isevaluated as part of that system’s operation Production, con-trol, or distribution records required to be maintained by thecGMP regulation and selected for review should be includedfor inspection audit within the context of each of the previ-ously described systems Inspections of contract companiesshould be within the systems for which the products or ser-vices are contracted as well as their quality systems

III PROGRAM MANAGEMENT INSTRUCTIONS

A Definitions

1 Surveillance Inspections

a The Full Inspection Option

The Full Inspection Option is a surveillance or compliance spection that is meant to provide a broad and deep evaluation

in-of the firm’s cGMP This is done when little or no tion is known about a firm’s cGMP compliance (e.g., for newfirms); or for firms where doubt exists about the cGMP com-pliance in the firm (e.g., a firm with a history of documentedshort-lived compliance and recidivism); or follow-up to pre-vious regulatory actions Based on findings of objectionableconditions (as listed in section V) in one or more systems—aminimum of two systems must be completed—a Full Inspec-tion may revert to the Abbreviated Inspection Option, withDistrict concurrence (see section III.B.1.) During the course

informa-of a Full Inspection, verification informa-of Quality System activitiesmay require limited coverage in other systems The Full In-spection Option normally includes an inspection audit of atleast four of the systems, one of which must be the Quality

System (the system that includes the responsibility for the

annual product reviews)

b The Abbreviated Inspection Option

The Abbreviated Inspection Option is a surveillance or

com-pliance inspection that is meant to provide an efficient update

evaluation of a firm’s cGMP The abbreviated inspection

pro-vides documentation for continuing a firm in a satisfactory

cGMP compliance status Generally, this is done when a firm

has a record of satisfactory cGMP compliance, with no

sig-nificant recall or product defect or alert incidents, or with

little shift in the manufacturing profiles of the firm within

the previous two years (see section III.B.2) A full inspection

may revert to an abbreviated inspection based on findings

of objectionable conditions as listed in section V in one or

more systems The Abbreviated Inspection Option normally

includes an inspection audit of at least two of the systems,

one of which must be the Quality System (the system which

includes the responsibility for the annual product reviews)

The District drug program managers should ensure that the

optional systems are rotated in successive abbreviated

in-spections During the course of an abbreviated inspection,

verification of quality system activities may require limited

coverage in other systems Some firms participate in a

lim-ited part of the production of a drug or drug product (e.g.,

a contract laboratory) Such firms may employ only two of

the systems defined In these cases, the inspection of the two

systems comprises inspection of the entire firm; this is

con-sidered as the Full Inspection Option

c Selecting Systems for Coverage

The selection of the system(s) for coverage will be made by

the FDA’s Regional District Office based on such factors as a

given firm’s specific operation, history of previous coverage,

history of compliance, or other priorities determined by the

District Office

2 Compliance Inspections

Compliance inspections are inspections conducted to

evalu-ate or verify compliance corrective actions after a regulatory

action has been taken First, the coverage given in

compli-ance inspections must be related to the deficient areas and

subjected to corrective actions

In addition, coverage must be given to systems because

a determination must be made on the overall compliance

sta-tus of the firm after the corrective actions are taken The firm

is expected to address all its operations in its corrective action

plan after a previously violative inspection, not just the

de-ficiencies noted in the FDA-483 (inspectional observations)

The Full Inspection Option should be used for a compliance

inspection, especially if the Abbreviated Inspection Option

was used during the violative inspection

Compliance Inspections include “For Cause tions.” For Cause Inspections are compliance inspections that

Inspec-are conducted to investigate a specific problem that has come

to the attention of some level of the agency The problems

may be indicated in Field Alert Reports (FARs), industry

complaints, recalls, indicators of defective products, etc

Cov-erage of these areas may be assigned under other compliance

programs; however, expansion of the coverage to a GMP

in-spection must be reported under this program For Cause

Inspections may be assigned under this program as the need

arises

3 State of Control

A drug firm is considered to be operating in a “state of trol” when it employs conditions and practices that assurecompliance with the intent of sections 501(a)(2)(B) of the Actand portions of the cGMP regulations that pertain to theirsystems A firm in a state of control produces finished drugproducts for which there is an adequate level of assurance

con-of quality, strength, identity, and purity A firm is “out con-ofcontrol” if any one system is out of control A system is out

of control if the quality, identity, strength, and purity of theproducts resulting from that (those) system(s) cannot be ade-quately assured Documented cGMP deficiencies provide theevidence for concluding that a system is not operating in astate of control See section V, “Regulatory/AdministrativeStrategy,” for a discussion of compliance actions based on in-spection findings demonstrating out of control systems/firm

5 Drug Manufacturing Inspection

A Drug Manufacturing Inspection is a factory inspection inwhich evaluation of two or more systems, including the Qual-ity System, is done to determine if manufacturing is occurring

in a state of control

B Inspection Planning

The Field Office will conduct drug manufacturing inspectionsand maintain profiles or other monitoring systems, whichensures that each drug firm receives biennial inspectionalcoverage, as provided for in the strategy

The District Office is responsible for determining thedepth of coverage given to each drug firm cGMP inspectionalcoverage shall be sufficient to assess the state of compliancefor each firm

The frequency and depth of inspection should be termined by the statutory obligation, the firm’s compliancehistory, the technology employed, and the characteristics ofthe products When a system is inspected, the inspection ofthat system may be considered applicable to all products thatuse it Investigators should select an adequate number andtype of products to accomplish coverage of the system Se-lection of products should be made so that coverage is repre-sentative of the firm’s overall abilities to manufacture withincGMP requirements

de-Review of new drug application/anticipated new drugapplication (NDA/ANDA) files may assist in selecting sig-nificant drug processes for coverage in the various systems.Significant drug processes are those that utilize all the systems

in the firm very broadly and contain steps with unique or ficult manipulation in the performance of a step Productsposing special manufacturing features (e.g., low-dose prod-ucts, narrow therapeutic range drugs, combination drugs,modified release products, etc.) and new products made un-der an approved drug application should be considered first

dif-in selectdif-ing products for coverage

The health significance of certain cGMP deviations may

be lower when the drug product involved has no major temic effect or no dosage limitations, such as in productslike calamine lotion or over-the-counter (OTC) medicated

sys-The FDA Drug Product Surveillance Program 11

shampoos Such products should be given inspection

cov-erage with appropriate priority

Inspections for this compliance program may be formed during visits to a firm when operations are being

per-performed for other compliance programs or other

investi-gations

C Profiles

The inspection findings will be used as the basis for updating

all profile classes in the profile screen of the FACTS EIR

cov-ersheet that is used to record profile/class determinations

Normally, an inspection under this systems approach will

result in the update of all profile classes

IV INSPECTIONAL OBSERVATIONS

A Investigational Operations

1 General

Review and use the cGMPs for Finished Pharmaceuticals (21

CFR 210 and 211) to evaluate manufacturing processes Use

the Guides to Inspection published by the Office of Regional

Operations for information on technical applications in

vari-ous manufacturing systems

The investigator should conduct inspections according

to the “Strategy” section in part II of this compliance program

Recognizing that drug firms vary greatly in size and scope,

and manufacturing systems are more or less sophisticated,

the approach to inspecting each firm should be carefully

planned For example, it may be more appropriate to review

the Quality System thoroughly before entering production

ar-eas in some firms; in others, the Quality System review should

take place concurrently with inspection of another system or

systems selected for coverage The complexity and

variabil-ity necessitate a flexible inspection approach—one that not

only allows the investigator to choose the inspection focus

and depth appropriate for a specific firm, but also directs

the performance and reporting on the inspection within a

framework that will provide for a uniform level of cGMP

assessment Furthermore, this inspection approach provides

for fast communication and evaluation of findings

Inspectional Observations noting cGMP deficienciesshould be related to a requirement Requirements for the

manufacture of drug products (dosage forms) are in the

cGMP regulation and are amplified by policy in the

Compli-ance Policy Guides or case precedents cGMP requirements

apply to the manufacture of distributed prescription drug

products, OTC drug products, approved products, and

prod-ucts not requiring approval, as well as drug prodprod-ucts used

in clinical trials The cGMP regulations are not direct

require-ments for manufacture of active pharmaceutical ingredients

(APIs); the regulations should not be referenced as the basis

for a GMP deficiency in the manufacture of APIs, but they

are guidance for cGMP in API manufacture

Guidance documents do not establish requirements;

they state examples of ways to meet requirements Guidance

documents are not to be referred to as the justification for

an inspectional observation The justification comes from the

cGMPs Current Guides to Inspection and Guidance to

In-dustry documents provide interpretations of requirements,

which may assist in the evaluation of the adequacy of cGMP

in this program List observations in order of importancewithin each system Where repeated or similar observationsare made, they should be consolidated under a unified obser-vation For those Districts utilizing Turbo EIR, a limited num-ber of observations can be common to more than one system(e.g., organization and personnel including appropriate qual-ifications and training) In these instances, put the observation

in the first system reported on the FDA-483 and in the text

of the EIR, reference the applicability to other systems whereappropriate This should be done to accommodate the struc-ture of Turbo EIR, which allows individual citation once perFDA-483 Refrain from using unsubstantiated conclusions

Do not use the term “inadequate” without explaining whyand how Refer to the policy in the IOM, chapter 5, section

512 and Field Management Directive 120 for further guidance

on the content of Inspectional Observations

Specific specialized inspectional guidance may be vided as attachments to this program, or in requests for in-spection, assignments, etc

pro-2 Inspection Approaches

This program provides two surveillance inspectional options:Abbreviated Inspection Option and Full Inspection Option(see the definitions of the inspection options in part II of thiscompliance program)

1 Selecting the Full Inspection Option—The Full Inspection

Option will include inspection of at least four of the tems as listed in part II “Strategy,” one of which must bethe Quality System

sys-a Select the Full Inspection Option for an initial FDAinspection of a facility A full inspection may revert to

the Abbreviated Inspection Option, with District rence, based on the finding of objectionable conditions

concur-as listed in part V in one or more systems (a minimum

of two systems must be completed)

b Select the Full Inspection Option when the firm has ahistory of fluctuating into and out of compliance Todetermine if the firm meets this criterion, the Districtshould utilize all information at its disposal, such as, in-spection results, results of sample analyses, complaints,drug quality reporting system (DQRS) reports, recalls,etc., and the compliance actions resulting from them

or from past inspections A Full Inspection may revert

to the Abbreviated Inspection Option, with District currence, based on findings of objectionable conditions

con-as listed in part V in one or more systems (a minimum

of two systems must be completed)

c Evaluate if important changes have occurred by paring current operations against the EIR for the previ-ous full inspection The following types of changes aretypical of those that warrant the Full Inspection Option:

com-r New potential for cross-contamination arisingthrough change in process or product line

r Use of new technology requiring new expertise, nificant new equipment, or new facilities

sig-d A Full Inspection may also be conducted on a lance basis at the District’s discretion

surveil-e The Full Inspection Option will satisfy the biennial spection requirement

in-f Follow-up to a Warning Letter or other significant ulatory actions should require a Full Inspection Option

reg-2 Selecting the Abbreviated Inspection Option—The

Abbrevi-ated Inspection Option normally will include inspection

audit of at least two systems, one of which must be the

Quality System During the course of an abbreviated

in-spection, verification of quality system activities may

re-quire limited coverage in other systems

a This option involves an inspection of the

manufac-turer to maintain surveillance over the firm’s activitiesand to provide input to the firm on maintaining andimproving the GMP level of assurance of quality of itsproducts

b A full inspection may revert to the Abbreviated

Inspec-tion OpInspec-tion, with District concurrence, based on findings

of objectionable conditions as listed in part V in one

or more systems (a minimum of two systems must becompleted)

c An abbreviated inspection is adequate for routine

coverage and will satisfy the biennial inspectionalrequirement

a Comprehensive Inspection Coverage

It is not anticipated that full inspections will be conducted

every two years They may be conducted at less frequent

intervals, perhaps at every third or fourth inspection cycle

Districts should consider selecting different optional systems

for inspection coverage as a cycle of Abbreviated inspections

are carried out to build comprehensive information on the

firm’s total manufacturing activities

3 System Inspection Coverage

a Quality System

Assessment of the Quality System is two-phased:

1 The first phase evaluates whether the Quality Control

Unit has fulfilled the responsibility to review and approve

all procedures related to production, quality control, and

quality assurance and assure the procedures are adequate

for their intended use This also includes the associated

record-keeping systems

2 The second phase assesses the data collected to identify

quality problems and may link to other major systems for

inspectional coverage

For each of the following, the firm should have ten and approved procedures and documentation resulting

writ-therefrom The firm’s adherence to written procedures should

be verified through observation whenever possible These

ar-eas are not limited to finished products, but may also

incorpo-rate components and in-process materials These areas may

indicate deficiencies not only in this system, but also in other

major systems that would warrant expansion of coverage

All areas under this system should be covered; however, the

depth of coverage may vary depending upon inspectional

findings:

r Product reviews—at least annually; should include

infor-mation from areas listed below as appropriate; batches

re-viewed for each product are representative of all batches

manufactured; trends are identified [refer to 21 CFR

211.180(e)]

r Complaint reviews (quality and medical)—documented;

eval-uated; investigated in a timely manner; includes corrective

action where appropriate

r Discrepancy and failure investigations related to

manufactur-ing and testmanufactur-ing—documented; evaluated; investigated in a

timely manner; includes corrective action where priate

appro-r Change control—documented; evaluated; approved; needfor revalidation assessed

r Product improvement projects—for marketed products

r Reprocess/rework—evaluation, review, and approval; pact on validation and stability

im-r Returns/salvages—assessment; investigation expandedwhere warranted; disposition

r Rejects—investigation expanded where warranted; tive action where appropriate

correc-r Stability failures—investigation expanded where ranted; need for field alerts evaluated; disposition

war-r Quarantine products

r Validation—status of required validation/revalidation(e.g., computer, manufacturing process, laboratory meth-ods)

r Training/qualification of employees in quality control unitfunctions

b Facilities and Equipment System

For each of the following, the firm should have written andapproved procedures and documentation resulting there-from The firm’s adherence to written procedures should beverified through observation whenever possible These areasmay indicate deficiencies not only in this system but also

in other systems that would warrant expansion of age When this system is selected for coverage in addition

cover-to the Quality System, all areas listed next should be covered;however, the depth of coverage may vary depending uponinspectional findings:

1 Facilities

r Cleaning and maintenance

r Facility layout and air handling systems for prevention

of cross-contamination (e.g., penicillin, beta-lactams,steroids, hormones, cytotoxics, etc.)

r Specifically designed areas for the manufacturing ations performed by the firm to prevent contamination

oper-or mix-ups

r General air handling systems

r Control system for implementing changes in the ing

build-r Lighting, potable water, washing and toilet facilities,sewage and refuse disposal

r Sanitation of the building, use of rodenticides, cides, insecticides, and cleaning and sanitizing agents

fungi-2 Equipment

r Equipment installation and operational qualificationwhere appropriate

r Adequacy of equipment design, size, and location

r Equipment surfaces should not be reactive, additive, orabsorptive

r Appropriate use of equipment operations substances(lubricants, coolants, refrigerants, etc.), contacting prod-ucts, containers, etc

r Cleaning procedures and cleaning validation

r Controls to prevent contamination, particularly withany pesticides or any other toxic materials, or other drug

or nondrug chemicals

r Qualification, calibration, and maintenance of storageequipment, such as refrigerators and freezers for en-suring that standards, raw materials, and reagents arestored at the proper temperatures

The FDA Drug Product Surveillance Program 13

r Equipment qualification, calibration, and maintenance,

including computer qualification/validation and rity

secu-r Control system for implementing changes in the

equipment

r Equipment identification practices (where appropriate)

r Documented investigation into any unexpected

discrepancy

c Materials System

For each of the following, the firm should have written and

approved procedures and documentation resulting

there-from The firm’s adherence to written procedures should

be verified through observation whenever possible These

areas are not limited to finished products, but may also

incorporate components and in-process materials These

ar-eas may indicate deficiencies not only in this system, but

also in other systems that would warrant expansion of

cov-erage When this system is selected for coverage in addition

to the Quality System, all areas listed next should be covered;

however, the depth of coverage may vary depending upon

inspectional findings:

r Training/qualification of personnel

r Identification of components, containers, and closures

r Inventory of components, containers, and closures

r Storage conditions

r Storage under quarantine until tested or examined and

released

r Representative samples collected, tested, or examined

us-ing appropriate means

r At least one specific identity test is conducted on each lot

of each component

r A visual identification is conducted on each lot of

contain-ers and closures

r Testing or validation of supplier’s test results for

compo-nents, containers, and closures

r Rejection of any component, container, or closure not

meet-ing acceptance requirements

r Investigate fully the firm’s procedures for verification of

the source of components

r Appropriate retesting/reexamination of components,

con-tainers, and closures

r First in–first out use of components, containers, and

clo-sures

r Quarantine of rejected materials

r Water and process gas supply, design, maintenance,

vali-dation, and operation

r Containers and closures should not be additive, reactive,

or absorptive to the drug product

r Control system for implementing changes in the materials

handling operations

r Qualification/validation and security of computerized or

automated processes

r Finished product distribution records by lot

r Documented investigation into any unexpected

discrep-ancy

d Production System

For each of the following, the firm should have written and

approved procedures and documentation resulting

there-from The firm’s adherence to written procedures should be

verified through observation whenever possible These areas

are not limited to finished products, but may also

incorpo-rate components and in-process materials These areas mayindicate deficiencies not only in this system, but also in othersystems that would warrant expansion of coverage Whenthis system is selected for coverage in addition to the QualitySystem, all areas listed next should be covered; however, thedepth of coverage may vary depending upon inspectionalfindings:

r Training/qualification of personnel

r Control system for implementing changes in processes

r Adequate procedure and practice for charge-in of nents

compo-r Formulation/manufacturing at not less than 100%

r Identification of equipment with contents, and, where propriate, phase of manufacturing or status

ap-r Validation and verification of cleaning/sterilization/depyrogenation of containers and closures

r Calculation and documentation of actual yields and centage of theoretical yields

per-r Contemporaneous and complete batch production mentation

docu-r Establishing time limits for completion of phases of duction

pro-r Implementation and documentation of in-process controls,tests, and examinations (e.g., pH, adequacy of mix, weightvariation, clarity)

r Justification and consistency of in-process specificationsand drug product final specifications

r Prevention of objectionable microorganisms in unsteriledrug products

r Adherence to preprocessing procedures (e.g., setup, lineclearance, etc.)

r Equipment cleaning and use logs

r Master production and control records

r Batch production and control records

r Process validation, including validation and security ofcomputerized or automated processes

r Change control; the need for revalidation evaluated

r Documented investigation into any unexpected ancy

discrep-e Packaging and Labeling System

For each of the following, the firm should have written andapproved procedures and documentation resulting there-from The firm’s adherence to written procedures should beverified through observation whenever possible These areasare not limited only to finished products, but may also incor-porate components and in-process materials These areas mayindicate deficiencies not only in this system, but also in othersystems that would warrant expansion of coverage Whenthis system is selected for coverage in addition to the QualitySystem, all areas listed next should be covered; however, thedepth of coverage may vary depending upon inspectionalfindings:

r Finished product cut labels for immediate containers that

are similar in appearance without some type of 100%

elec-tronic or visual verification system or the use of dedicated

lines

r Labels are not gang printed unless they are differentiated

by size, shape, or color

r Control of filled unlabeled containers that are later labeled

under multiple private labels

r Adequate packaging records that will include specimens

of all labels used

r Control of issuance of labeling, examination of issued

la-bels, and reconciliation of used labels

r Examination of the labeled finished product

r Adequate inspection (proofing) of incoming labeling

r Use of lot numbers and the destruction of excess labeling

bearing lot/control numbers

r Physical/spatial separation between different labeling and

packaging lines

r Monitoring of printing devices associated with

manufac-turing lines

r Line clearance, inspection, and documentation

r Adequate expiration dates on the label

r Conformance to tamper-evident packaging (TEP)

require-ments (see 21CFR 211.132 and Compliance Policy Guide,

7132a.17)

r Validation of packaging and labeling operations, including

validation and security of computerized processes

r Documented investigation into any unexpected

discrep-ancy

f Laboratory Control System

For each of the following, the firm should have written and

approved procedures and documentation resulting

there-from The firm’s adherence to written procedures should be

verified through observation whenever possible These areas

are not limited only to finished products, but may also

incor-porate components and in-process materials These areas may

indicate deficiencies not only in this system, but also in other

systems that would warrant expansion of coverage When

this system is selected for coverage in addition to the Quality

System, all areas listed next should be covered; however, the

depth of coverage may vary depending upon inspectional

findings:

r Training/qualification of personnel

r Adequacy of staffing for laboratory operations

r Adequacy of equipment and facility for intended use

r Calibration and maintenance programs for analytical

in-struments and equipment

r Validation and security of computerized or automated

processes

r Reference standards: source, purity and assay, and tests

to establish equivalency to current official reference

stan-dards as appropriate

r System suitability checks on chromatographic systems

[e.g., gas chromatography (GC) or high pressure liquid

chromatography (HPLC)]

r Specifications, standards, and representative sampling

plans

r Adherence to the written methods of analysis

r Validation/verification of analytical methods

r Control system for implementing changes in laboratory

operations

r Required testing is performed on the correct samples

r Documented investigation into any unexpecteddiscrepancy

r Complete analytical records from all tests and summaries

defi-When a large number of products have been producedunder deficient controls, collect physical or documentarysamples of products that have the greatest therapeutic sig-nificance, narrow range of toxicity, or low dosage strength.Include samples of products of minimal therapeutic signifi-cance only when they illustrate highly significant cGMP de-ficiencies

5 Inspection Teams

An inspection team (see IOM 502.4) composed of experts fromwithin the District, other Districts, or Headquarters is en-couraged when it provides needed expertise and experience.Contact the ORO/Division of Field Investigations if technicalassistance is needed (see also FMD 142) Participation of ananalyst (chemist or microbiologist) on an inspection team isalso encouraged, especially where laboratory issues are ex-tensive or complex Contact your Drug Servicing Laboratory

or ORO/Division of Field Science

6 Reporting

The investigator utilizes Subchapter 590 of the IOM for ance in reporting of inspectional findings The Summary ofFindings should identify systems covered The body of the re-port should identify and explain the rationale for inspectingthe profile classes covered Any adverse findings by systemsunder separate captions should be reported and discussed infull Additional information should be provided as needed ordesired, for example, a description of any significant changesthat have occurred since previous inspections

guid-Reports with specific, specialized information requiredshould be prepared as instructed within the individual as-signment/attachment

The FDA Drug Product Surveillance Program 15

Region Examining Laboratory

3 Other microbiological examinations—NRL (for the CE

Region), SRL, SAN, and DEN; Salmonella Serotyping

Lab—ARL

4 Chemical cross-contamination analyses by mass

spec-trometry (MS)—NRL, SRL, DEN, PRL/NW, and PHI

Non–mass-spectrometry laboratories should call one oftheir own regional MS-capable laboratories or Division

of Field Science (HFC-140) to determine the most priate lab for the determinations to be performed

appro-5 Chemical cross-contamination analyses by nuclear

mag-netic resonance (NMR) spectroscopy—NRL Non-NMRlaboratories should call one of their own regional labsequipped with NMR or Division of Field Science (HFC-140) to determine the most appropriate lab for the deter-minations to be performed

6 Dissolution testing—NRL, KAN, SRL, SJN, DET, PHI,

DEN, PRL/SW, and PRL-NW Districts without tion testing capability should use one of their own re-gional labs for dissolution testing Otherwise, call DFS

dissolu-7 Antibiotic analyses: ORA Examining Laboratory,

Denver District Lab (HFR-SW260): Tetracyclines, thromycins

ery-Northeast Regional Lab (HFR-NE500): Penicillins,cephalosporins

CDER Examining Laboratory, Office of Testing and search, Division of Pharmaceutical Analysis (HFD-473): All other antibiotics

Re-8 Bioassays—Division of Testing and Applied Analytical

Research, Drug Bioanalysis Branch(HFN-471)

9 Particulate Matter in Injectables—NRL, SRL

10 Pyrogen/LAL Testing— SRL

B Analysis

1 Samples must be examined for compliance with applicable

specifications as they relate to deficiencies noted during

the inspection The official method should be used for

check analyses or, when no official method exists, by other

validated procedures

2 The presence of cross-contamination must be confirmed

by a second method Spectroscopic methods, such as MS,

NMR, ultraviolet (UV)-Visible, or infrared (IR) are

pre-ferred A second confirmatory method should be

em-ployed by different mechanisms than the initial analysis

(i.e., ion-pairing vs conventional reverse phase HPLC)

3 Check Analysis for dissolution rate must be performed by

a second dissolution-testing laboratory

4 Sterility testing methods should be based on current

edi-tions of USP and the Sterility Analytical Manual Other

mi-crobiological examinations should be based on

appropri-ate sections of USP and BAM

VI REGULATORY/ADMINISTRATIVE STRATEGY

Inspection findings that demonstrate that a firm is not

oper-ating in a state of control may be used as evidence for taking

appropriate advisory, administrative, or judicial actions

When the management of the firm is unwilling or able to provide adequate corrective actions in an appropriatetime frame, formal agency regulatory actions will be recom-mended that are designed to meet the situation encountered.When deciding the type of action to recommend, theinitial decision should be based on the seriousness of theproblem and the most effective way to protect consumers

un-Outstanding instructions in the Regulatory Procedures Manual (RPM) should be followed.

The endorsement to the inspection report should pointout the actions that have been taken or will be taken andwhen All deficiencies noted in inspections/audits under thisprogram must be addressed by stating the firm’s correctiveactions, accomplished or projected, for each as established inthe discussion with management at the close of the inspection.All corrective action approaches in domestic firmsare monitored and managed by the District Offices Theapproaches may range from shutdown of operations, re-call of products, conducting testing programs, develop-ment of new procedures, modifications of plants andequipment, to simple immediate corrections of conditions.CDER/DMPQ/CMGB/HFD-325 will assist District Offices

as requested

An inspection report that documents that one or moresystems is/are out of control should be classified as OAI Dis-trict Offices may issue Warning Letters per RPM to warn firms

of violations, to solicit voluntary corrections, and to providefor the initial phase of formal agency regulatory actions.Issuance of a Warning Letter or taking other regulatoryactions pursuant to a surveillance inspection (other than aFor Cause Inspection) should result in the classification ofall profile classes as unacceptable Also, the inspection find-ings will be used as the basis for updating profile classes inFACTS

The FDA laboratory tests that demonstrate the effects ofabsent or inadequate cGMPs are strong evidence for support-ing regulatory actions Such evidence development should beconsidered as an inspection progresses and deficiencies are

found; however, the lack of violative physical samples is not a

barrier to pursuing regulatory or administrative action, vided that cGMP deficiencies have been well documented

pro-Likewise, physical samples found to be in compliance are not

a barrier to pursuing action under cGMP charges

Evidence to support significant deficiencies or a trend

of deficiencies within a system covered could demonstratethe failure of a system and should result in consideration ofthe issuance of a Warning Letter or other regulatory action

by the District When deciding the type of action to mend, the initial decision should be based on the seriousness

recom-or the frequency of the problem Examples include the lowing:

fol-Quality System

1 Pattern of failure to review/approve procedures

2 Pattern of failure to document execution of operations

as required

3 Pattern of failure to review documentation

4 Pattern of failure to conduct investigations and resolvediscrepancies/failures/deviations/complaints

5 Pattern of failure to assess other systems to assure pliance with GMP and SOPs

com-Facilities and Equipment

1 Contamination with filth, objectionable isms, toxic chemicals or other drug chemicals, or a rea-sonable potential for contamination, with demonstrated

microorgan-avenues of contamination, such as airborne or throughunclean equipment

2 Pattern of failure to validate cleaning procedures for

nondedicated equipment; lack of demonstration of fectiveness of cleaning for dedicated equipment

ef-3 Pattern of failure to document investigation of

discrep-ancies

4 Pattern of failure to establish/follow a control system

for implementing changes in the equipment

5 Pattern of failure to qualify equipment, including

com-putersMaterials System

1 Release of materials for use or distribution that do not

conform to established specifications

2 Pattern of failure to conduct one specific identity test

for components

3 Pattern of failure to document investigation of

discrep-ancies

4 Pattern of failure to establish/follow a control system

for implementing changes in the materials handling erations

op-5 Lack of validation of water systems as required

depend-ing upon the intended use of the water

6 Lack of validation of computerized processes

Production System

1 Pattern of failure to establish/follow a control system

for implementing changes in the production system erations

op-2 Pattern of failure to document investigation of

discrep-ancies

3 Lack of process validation

4 Lack of validation of computerized processes

5 Pattern of incomplete or missing batch production

records

6 Pattern of nonconformance to established in-process

controls, tests, and specificationsPackaging and Labeling

1 Pattern of failure to establish/follow a control system

for implementing changes in the packaging or labelingoperations

2 Pattern of failure to document investigation of

discrep-ancies

3 Lack of validation of computerized processes

4 Lack of control of packaging and labeling operations

that may introduce a potential for mislabeling

5 Lack of packaging validation

Laboratory Control System

1 Pattern of failure to establish/follow a control system

for implementing changes in the laboratory operations

2 Pattern of failure to document investigation of

discrep-ancies

3 Lack of validation of computerized and/or automated

processes

4 Pattern of inadequate sampling practices

5 Lack of validated analytical methods

6 Pattern of failure to follow approved analytical

proce-dures

7 Pattern of failure to follow an adequate OOS procedure

8 Pattern of failure to retain raw data

9 Lack of stability indicating methods

10 Pattern of failure to follow stability programs

Follow-up to a Warning Letter or other significant ulatory action because of an abbreviated inspection should

reg-warrant full inspection coverage as defined in this program

GLOSSARY

Acceptance Criteria—Numerical limits, ranges, or other able measures for acceptance of test results

suit-Active Pharmaceutical Ingredient (API) (or Drug

in-tended to be used in the manufacture of a drug inal) product and that, when used in the production of

(medic-a drug, becomes (medic-an (medic-active ingredient of the drug uct Such substances are intended to furnish pharma-cological activity or other direct effect in the diagnosis,cure, mitigation, treatment, or prevention of disease or

prod-to affect the structure and function of the body

Airlock—An enclosed space with two or more doors, which

is interposed between two or more rooms, for example,

of differing classes of cleanliness, for the purpose ofcontrolling the airflow between those rooms when theyneed to be entered An airlock is designed for use either

by people or for goods and/or equipment

API Starting Material—A raw material, intermediate, or anAPI that is used in the production of an API and that

is incorporated as a significant structural fragment intothe structure of the API An API Starting Material can

be an article of commerce, a material purchased fromone or more suppliers under contract or commercialagreement, or produced in-house API Starting Mate-rials are normally of defined chemical properties andstructure

Authorized person—The person recognized by the nationalregulatory authority as having the responsibility forensuring that each batch of finished product has beenmanufactured, tested, and approved for release in com-pliance with the laws and regulations in force in thatcountry

Batch (or Lot)—A specific quantity of material produced in

a process or series of processes so that it is expected

to be homogeneous within specified limits In the case

of continuous production, a batch may correspond to

a defined fraction of the production The batch sizecan be defined either by a fixed quantity or by theamount produced in a fixed time interval A definedquantity of starting material, packaging material, orproduct processed in a single process or series of pro-cesses so that it is expected to be homogeneous It maysometimes be necessary to divide a batch into a num-ber of sub-batches, which are later brought together toform a final homogeneous batch In the case of termi-nal sterilization, the batch size is determined by thecapacity of the autoclave In continuous manufacture,the batch must correspond to a defined fraction of theproduction, characterized by its intended homogene-ity The batch size can be defined either as a fixedquantity or as the amount produced in a fixed timeinterval

Batch Number (or Lot Number)—A unique combination ofnumbers, letters, and/or symbols that identifies a batch(or lot) and from which the production and distributionhistory can be determined A distinctive combination

of numbers and/or letters which uniquely identifies abatch on the labels, its batch records and correspondingcertificates of analysis, etc

Batch Records—All documents associated with the facture of a batch of bulk product or finished product.They provide a history of each batch of product and

manu-The FDA Drug Product Surveillance Program 17

of all circumstances pertinent to the quality of the finalproduct

Bioburden—The level and type (e.g., objectionable or not) of

micro-organisms that can be present in raw materials,API starting materials, intermediates or APIs Biobur-den should not be considered contamination unless thelevels have been exceeded or defined objectionable or-ganisms have been detected

Bulk Product—Any product that has completed all

process-ing stages up to, but not includprocess-ing, final packagprocess-ing

Calibration—The demonstration that a particular instrument

or device produces results within specified limits bycomparison with those produced by a reference ortraceable standard over an appropriate range of mea-surements The set of operations that establish, underspecified conditions, the relationship between valuesindicated by an instrument or system for measuring(especially weighing), recording, and controlling, or thevalues represented by a material measure, and the cor-responding known values of a reference standard Lim-its for acceptance of the results of measuring should beestablished

Clean Area—An area with defined environmental control of

particulate and microbial contamination, constructedand used in such a way as to reduce the introduction,generation, and retention of contaminants within thearea

Computer System—A group of hardware components and

associated software, designed and assembled to form a specific function or group of functions A pro-cess or operation integrated with a computer system

per-Consignment (or Delivery)—The quantity of a

pharmaceu-tical(s), made by one manufacturer and supplied at onetime in response to a particular request or order A con-signment may comprise one or more packages or con-tainers and may include material belonging to morethan one batch

Contamination—The undesired introduction of impurities of

a chemical or microbiological nature, or of foreign ter, into or onto a raw material, intermediate, or APIduring production, sampling, packaging or repackag-ing, storage, or transport

mat-Contract Manufacturer—A manufacturer performing some

aspect of manufacturing on behalf of the original ufacturer

man-Critical—Describes a process step, process condition, test

re-quirement, or other relevant parameter or item thatmust be controlled within predetermined criteria to en-sure that the API meets its specification

Critical Operation—An operation in the manufacturing

pro-cess that may cause variation in the quality of the maceutical product

phar-Cross-Contamination—Contamination of a material or

prod-uct with another material or prodprod-uct Contamination of

a starting material, intermediate product, or finishedproduct with another starting material or product dur-ing production

Deviation—Departure from an approved instruction or

es-tablished standard

Drug (Medicinal) Product—The dosage form in the final

im-mediate packaging intended for marketing (ReferenceQ1A)

Drug Substance—See Active Pharmaceutical Ingredient

Expiry Date (or Expiration Date)—The date placed on the

container/labels of an API designating the time during

which the API is expected to remain within establishedshelf life specifications if stored under defined condi-tions, and after which it should not be used

Fnished Product—A finished dosage form that has gone all stages of manufacture, including packaging inits final container and labeling

under-Impurity—Any component present in the intermediate orAPI that is not the desired entity

Impurity Profile—A description of the identified and tified impurities present in an API

uniden-In-Process Control—Checks performed during production

in order to monitor and, if necessary, to adjust the cess to ensure that the product conforms to its spec-ifications The control of the environment or equip-ment may also be regarded as a part of in-processcontrol

pro-Intermediate—A material produced during steps of the cessing of an API that undergoes further molecularchange or purification before it becomes an API In-termediates may or may not be isolated Partly pro-cessed product that must undergo further manufactur-ing steps before it becomes a bulk product

pro-Large-Volume Parenterals—Sterile solutions intended forparenteral application with a volume of 100 mL or more

in one container of the finished dosage form

Lot—See Batch

Lot Number—see Batch Number

Manufacture—All operations of receipt of materials, duction, packaging, repackaging, labeling, relabeling,quality control, release, storage, and distribution ofAPIs and related controls

pro-Manufacturer—A company that carries out operations such

as production, packaging, repackaging, labeling, andrelabeling of pharmaceuticals

Marketing Authorization (Product License, Registration Certificate)—A legal document issued by the com-petent drug regulatory authority that establishes thedetailed composition and formulation of the productand the pharmacopoeial or other recognized specifi-cations of its ingredients and of the final product it-self, and includes details of packaging, labeling, andshelf-life

Master Formula—A document or set of documents fying the starting materials with their quantities andthe packaging materials, together with a description

speci-of the procedures and precautions required to produce

a specified quantity of a finished product as well asthe processing instructions, including the in-processcontrols

Master Record—A document or set of documents that serve

as a basis for the batch documentation (blank batchrecord)

Material—A general term used to denote raw materials(starting materials, reagents, solvents), process aids,intermediates, APIs and packaging and labeling ma-terials

Mother Liquor—The residual liquid which remains after thecrystallization or isolation processes A mother liquormay contain unreacted materials, intermediates, levels

of the API, and/or impurities It may be used for furtherprocessing

Packaging—All operations, including filling and labeling,that a bulk product has to undergo in order to be-come a finished product Filling of a sterile productunder aseptic conditions or a product intended to be

terminally sterilized, would not normally be regarded

as part of packaging

Packaging Material—Any material intended to protect an

intermediate or API during storage and transport Anymaterial, including printed material, employed in thepackaging of a pharmaceutical, but excluding any outerpackaging used for transportation or shipment Pack-aging materials are referred to as primary or secondaryaccording to whether or not they are intended to be indirect contact with the product

Pharmaceutical Product—Any material or product intended

for human or veterinary use presented in its finisheddosage form or as a starting material for use in such

a dosage form, that is subject to control by ceutical legislation in the exporting state and/or theimporting state

pharma-Procedure—A documented description of the operations to

be performed, the precautions to be taken, and sures to be applied directly or indirectly related to themanufacture of an intermediate or API

mea-Process Aids—Materials, excluding solvents, used as an

aid in the manufacture of an intermediate or APIthat do not themselves participate in a chemical orbiological reaction (e.g., filter aid, activated carbon,etc)

Process Control—See In-Process Control

Production—All operations involved in the preparation of

a pharmaceutical product, from receipt of materials,through processing, packaging and repackaging, la-beling and relabeling, to completion of the finishedproduct

Qualification—Action of proving and documenting that

equipment or ancillary systems are properly installed,work correctly, and actually lead to the expected re-sults Qualification is part of validation, but the individ-ual qualification steps alone do not constitute processvalidation

Quality Assurance (QA)—The sum total of the organized

arrangements made with the object of ensuring that allAPIs are of the quality required for their intended useand that quality systems are maintained

Quality Control (QC)—Checking or testing that

specifica-tions are met

Quality Unit(s)—An organizational unit independent of

pro-duction which fulfills both Quality Assurance andQuality Control responsibilities This can be in the form

of separate QA and QC units or a single individual orgroup, depending upon the size and structure of theorganization

Quarantine—The status of starting or packaging

materi-als, intermediates, or bulk or finished products lated physically or by other effective means while

iso-a decision is iso-awiso-aited on their releiso-ase, rejection, orreprocessing

Raw Material—A general term used to denote starting

ma-terials, reagents, and solvents intended for use in theproduction of intermediates or APIs

Reconciliation—A comparison between the theoretical

quantity and the actual quantity

Recovery—The introduction of all or part of previous

batches (or of redistilled solvents and similar ucts) of the required quality into another batch at

prod-a defined stprod-age of mprod-anufprod-acture It includes the moval of impurities from waste to obtain a pure sub-stance or the recovery of used materials for a separateuse

re-Reference Standard, Primary—A substance that has beenshown by an extensive set of analytical tests to be au-thentic material that should be of high purity

Reference Standard, Secondary—A substance of establishedquality and purity, as shown by comparison to a pri-mary reference standard, used as a reference standardfor routine laboratory analysis

Reprocessing—Subjecting all or part of a batch or lot of anin-process drug, bulk process intermediate (final bio-logical bulk intermediate) or bulk product of a singlebatch/ lot to a previous step in the validated manu-facturing process due to failure to meet predeterminedspecifications Reprocessing procedures are foreseen asoccasionally necessary for biological drugs and, in suchcases, are validated and preapproved as part of the mar-keting authorization

Retest Date—The date when a material should be ined to ensure that it is still suitable for use

reexam-Reworking—Subjecting an in-process or bulk process mediate (final biological bulk intermediate) or finalproduct of a single batch to an alternate manufacturingprocess due to a failure to meet predetermined specifi-cations Reworking is an unexpected occurrence and isnot pre-approved as part of the marketing authoriza-tion

inter-Self-Contained Area—Premises which provide completeand total separation of all aspects of an operation,including personnel and equipment movement, withwell-established procedures, controls, and monitoring.This includes physical barriers as well as separate air-handling systems, but does not necessarily imply twodistinct and separate buildings

Signature (Signed)—See definition for signed

Signed (Signature)—The record of the individual who formed a particular action or review This record can

per-be initials, full handwritten signature, personal seal, orauthenticated and secure electronic signature

Solvent—An inorganic or organic liquid used as a vehiclefor the preparation of solutions or suspensions in themanufacture of an intermediate or API

Specification—A list of detailed requirements with which theproducts or materials used or obtained during manu-facture have to conform They serve as a basis for qual-ity evaluation

Standard Operating Procedure (SOP)—An authorized ten procedure giving instructions for performing op-erations not necessarily specific to a given product ormaterial (e.g., equipment operation, maintenance andcleaning; validation; cleaning of premises and environ-mental control; sampling and inspection) Certain SOPsmay be used to supplement product-specific masterand batch production documentation

writ-Starting Material—Any substance of a defined quality used

in the production of a pharmaceutical product, but cluding packaging materials

ex-Validation—A documented program that provides a highdegree of assurance that a specific process, method,

or system will consistently produce a result meetingpredetermined acceptance criteria Action of proving,

in accordance with the principles of GMP, that any cedure, process, equipment, material, activity, or sys-tem actually leads to the expected results (see also Qual-ification)

pro-Validation Protocol—A written plan stating how tion will be conducted and defining acceptance cri-teria For example, the protocol for a manufacturing

valida-The FDA Drug Product Surveillance Program 19

process identifies processing equipment, critical cess parameters/operating ranges, product character-istics, sampling, test data to be collected, number ofvalidation runs, and acceptable test results

pro-Yield, Expected—The quantity of material or the

percent-age of theoretical yield anticipated at any appropriate

phase of production based on previous laboratory, pilotscale, or manufacturing data

Yield, Theoretical—The quantity that would be produced atany appropriate phase of production, based upon thequantity of material to be used, in the absence of anyloss or error in actual production