handbook of pharmaceutical manufacturing formulations semisolid preparation

H A N D B O O K

O F

Pharmaceutical
Manufacturing
Formulations
Semisolid Products
VOLUME 4


Handbook of
Pharmaceutical Manufacturing Formulations
Volume Series
Sarfaraz K. Niazi
Volume 1
Handbook of Pharmaceutical Manufacturing Formulations:
Compressed Solid Products
Volume 2
Handbook of Pharmaceutical Manufacturing Formulations:
Uncompressed Solid Products
Volume 3
Handbook of Pharmaceutical Manufacturing Formulations:
Liquid Products
Volume 4
Handbook of Pharmaceutical Manufacturing Formulations:
Semisolid Products
Volume 5
Handbook of Pharmaceutical Manufacturing Formulations:
V

O L U MProducts
E 1
Over-the-Counter
Volume 6
Handbook of Pharmaceutical Manufacturing Formulations:
Sterile Products


H A N D B O O K

O F

Pharmaceutical
Manufacturing
Formulations
Semisolid Products
VOLUME 4

Sarfaraz K. Niazi

CRC PR E S S
Boca Raton London New York Washington, D.C.


Library of Congress Cataloging-in-Publication Data
Niazi, Sarfaraz, 1949–
Handbook of pharmaceutical manufacturing formulations / Sarfaraz K. Niazi.
p. cm.
Includes bibliographical references and index.
Contents: — v.4. Semisolid products.

ISBN 0-8493-1749-5 (alk. paper)
1. Drugs—Dosage forms—Handbooks, manuals, etc. I. Title
RS200.N53 2004
615'19—dc21
2003051451

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Dedication
Dedicated to the memory of
John G. Wagner

Preface to the Series
No industry in the world is more highly regulated than
the pharmaceutical industry because of potential threats
to patients’ lives from the use of pharmaceutical products.
The cost of taking a new chemical entity (amortized over
the cost of all molecules racing) to final regulatory
approval is a staggering $800 million, making the pharmaceutical industry one of the most research-intensive
industries in the world. In the year 2004, it is anticipated
that the industry will spend about $20 billion on research
and development. The generic market of drugs as new
entities come off patent is one of the fastest growing
segments of the pharmaceutical industry, with every major
multinational company having a significant presence in
this field.
Whereas many stages of new drug development are
inherently constrained with time, the formulation of drugs
into desirable dosage forms remains an area in which
expediency can be practiced with appropriate knowledge
by those who have mastered the skills of pharmaceutical
formulations. The Handbook of Pharmaceutical Manufacturing Formulations is the first major attempt to consolidate the available knowledge about formulations in 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, uncompressed solids, liquid products, semisolid
products, and over-the-counter (OTC) products. The separation of OTC products, though they may easily fall into
one of the other five categories, is made to comply with
the industry norms of separate research divisions for OTC
products. Sterile products require skills related to sterilization of product, and of less importance is the bioavailability issue, which is an inherent problem of compressed
dosage forms. These types of considerations have led to

the classification of products into these six categories.

Each volume includes a description of regulatory filing techniques for the formulations described. Also
included are the current regulatory guidelines on current
good manufacturing practice (CGMP) compliance specific
to the dosage form and advice is offered on how to scale
up the production batches.
It is expected that the formulation scientist would use
this information to benchmark internal development protocols and to cut the race to file short by adopting formulae
that have survived the test of time. Many of us who have
worked in the pharmaceutical industry suffer from a
closed paradigm when it comes to selecting formulations;
“not invented here” perhaps subconsciously reigns in the
minds of many seasoned formulations scientists when they
prefer to choose only a certain platform for development.
It is expected that with a quick review of possibilities
available to formulate made available in this book, scientists will benefit from the experience of others.
For the teachers of formulation sciences, this series
offers a wealth of information. Whether it is a selection
of a preservative system or the choice of a disintegrant,
the series offers a wide choice to study and rationalize.
Many have assisted me in the development of this
work, which has taken years to compile, and I am thankful
to scores of my graduate students and colleagues for their
help. A work of this size cannot be produced without
errors, though I hope these errors do not distract the reader
from the utility of the book. I would sincerely appreciate
readers pointing out these mistakes to me for corrections
in future editions.
Sarfaraz K. Niazi, Ph.D.

Deerfield, Illinois



Preface to the Volume
The semisolid drugs category is comprised of ointments,
creams, gels, suppositories, and special topical dosage
forms. The formulations of semisolid drugs share many
common attributes of consistency, presentation, preservation requirement, and the route of administration, mainly
topical. As a result, grouping them together for the purpose
of defining common formulation practices and problems
is justified. The topical dosage forms present unique
opportunities to design novel drug delivery systems such
as patches and other transdermal systems. Some of these
are described in the volume, but the reader is referred to
specific patents issued, wherein greater details are readily
obtainable. In selecting the formulations, I have tried to
provide representative techniques and technologies
involved in the preparation of semisolid products; for
example, I have included a significant number of what is
called “base” formulation, a formulation that can easily
carry a drug, depending on the proportion involved. Obviously, considerations such as incompatability of the drug
with the ingredients is of pivotal importance; these base
formulations of stable emulsions provide a good starting
point in the development of new products or even when
a different topical consistency is desired. I have also made
an effort to highlight those formulations that are currently
approved in the United States and provide them as they
appear in the Physicans Desk Reference, where possible.
Obviously, where the formulations are straightforward, I

have chosen to only give the composition or mere identification of ingredients to conserve space for those formulations that need more elaborate description.
The regulatory agencies impose certain specific
requirements on the formulation and efficacy determination of drugs contained in these formulations. For example, the CGMP factors, scale-up and postapproval
changes, and dermatological testing for irritation or photosensitivity are some of the specified elements.
In this volume, we present over 350 formulations and,
in keeping with the tradition in other volumes, a chapter
on formulation-related matters. In the regulatory section,
we offer a difficult area of compliance, changes to
approved new drug applications (NDAs) and abbreviated
new drug applications (ANDAs), particularly with reference to semisolid drugs. The stability considerations, particularly the evolving guidelines of the International Conference on Harmonization (ICH), are detailed in this volume,
with particular reference to stability-testing requirements
in postapproval stages. Unique to this category is the dermal testing of products, including photosensitivity testing
requirements that are still evolving. It is noteworthy that

much of the regulatory discussion presented here is drawn
from the requirements of the U.S. Food and Drug Administration (FDA) and the harmonized guidelines with the
ICH listings. Although it is likely that some of the requirements and recommendations made here might change, it
is unlikely that the basic thrust in establishing these guidelines will change. As always, the applicants are highly
encouraged to communicate with the FDA on the changes
made to these guidelines and especially for any significant
changes made to compliance requirements. The Web site
of the FDA, , is very comprehensive and
continuously evolving; pay special attention to the withdrawal and finalization of guidelines provided. Of particular
importance is the listing of new and withdrawn guidelines ( which should be reviewed periodically.
Chapter 1 provides details on how to handle changes
made to approved NDAs or ANDAs; this is a significant
topic for continued compliance with the CGMP requirements but, unfortunately, the one that is most easily misunderstood or misconstrued. For example, at what level of
change should the FDA be informed, either before making
a change or after? What happens if a change is made inadvertently and later discovered; how to report this change?
Years of experience teaches me that a manufacturer can

never be too careful in avoiding a 483 issuance when it
comes to changes made to NDAs or ANDAs. The situation
gets extremely complex when there are multiple dosage
forms, for which the requirements may be different.
Chapter 2 gets into details of changes made pursuant
to discussion in Chapter 1 when it comes to semisolid
drugs. A more detailed description of level of changes is
described here, and advice is provided on when to conduct
a regulatory review.
Chapter 3 continues the themes developed in the first
two chapters and applies to changes made to equipment. This
is a topic of special interest to the FDA because in the
processing of semisolid products, the equipment plays a pivotal role. The mixing of drugs within the base media is highly
affected by the process and mechanism of mixing used. Also,
because of the nature of product manufactured, often the
cleaning and validation of equipment become serious issues.
Chapter 4 is a comprehensive review of the present thinking of the regulatory authorities on how the stability studies
should be designed and conducted and how the data should
be interpreted; the induction of ICH guidelines and an attempt
to streamline the requirements of testing new drug products
have resulted in much dispute when it comes to global marketing of products. Should the stability testing be done at all


environmental regional standards, or is it possible to extrapolate these data based on accelerated stability testing? These
are some of the questions answered in this chapter, wherein
the FDA and ICH guidelines are merged.
Chapter 5 extends the discussion on stability testing
protocols to retest periods and elaborates on the procedures used for continued testing of products.
Chapter 6 introduces a topic of great importance in
the development of semisolid, and particularly dermal,

products: skin irritation and sensitization studies. Whereas
the standard test protocols have almost become universal
in their nature, it is always advised that these should be
agreed on, most appropriately in a pre-Investigational New
Drug Application (IND) filing. Established in 1988, the
Office of Drug Evaluation IV (ODE IV) Pre-IND Consultation Program is designed to facilitate and foster informal
early communications between the divisions of ODE IV
and potential sponsors of new therapeutics for the treatment
of bacterial infections, HIV, opportunistic infections, transplant rejection, and other diseases. The program is intended
to serve sponsors of all drug products that may be submitted
to any division within ODE IV, including but not limited to
drugs for the treatment of life-threatening illnesses (21 CFR
312.82(a)). Pre-IND advice may be requested for issues
related to drug development plans; data needed to support
the rationale for testing a drug in humans; the design of
nonclinical pharmacology, toxicology, and drug activity
studies; data requirements for an IND application; and regulatory requirements for demonstrating safety and efficacy.
Included among the ODE IV Pre-IND Program activities
are coordination of all Pre-IND interactions with the FDA
Topical Microbicide Working Group.
Chapter 7 deals with the topic of photosensitivity
caused by drugs; photosafety is a serious issue in the
development of topical products. It is worth noting here
that certain classes of drugs such as quinolone antibiotics
are generally regarded unsafe without thorough testing for
photosensitivity. Does photosensitivity correlate with carcinogenicity? These are questions of importance to the
regulatory authorities.
Chapter 8 includes a variety of topics related to formulation of semisolid drugs, from CGMP considerations
to packaging and validation issues; these topics are collated for their particular importance, but the discussions
provided are not comprehensive, and the reader is referred

to standard texts on formulation theories, particularly
where establishing a preservative system is required.
I am grateful to CRC Press for taking this lead in
publishing what is possibly the largest such work in the
field of pharmaceutical manufacturing. It has been a distinct privilege to have known Mr. Stephen Zollo, the Senior
Editor at CRC Press, for years. Stephen has done more than
any editor can to encourage me into completing this work
on a timely basis. The editorial assistance provided by CRC
Press staff was indeed exemplary, particularly the help

given by Erika Dery, Naomi Lynch, and others. Though
much care has gone into correcting errors, any errors
remaining are altogether mine. I shall appreciate the readers bringing these to my attention for correction in future
editions of this volume ().
This volume is dedicated to John G. Wagner, the John
G. Searle Professor Emeritus of Pharmaceutics in the College
of Pharmacy and Professor Emeritus of Pharmacology in the
Medical School, who passed away recently. Born in Weston,
Ontario, Canada, in 1921, Wagner served in the Canada Air
Force during World War II and then worked as a research
scientist for the Upjohn Co. from 1953 to 1968, joining the
University of Medicine in 1968. Wagner was the author of
two books and coauthor of more than 340 articles. Throughout his life he received numerous awards, including the
American Pharmaceutical Association (APhA) Ebert Prize,
1961; Academy Fellow of the AphA Academy of Pharmaceutical Sciences, 1969; the Centennial Achievement Award,
Ohio State University, 1970; the Host-Madsen Medal, Federation Internationale Pharmaceutique, 1972; Outstanding
Leadership and Research Award, Delta Chapter of Phi
Lambda Epsilon, 1983; AAPS Fellow, American Association
of Pharmaceutical Scientists, 1986; and Distinguished
Professor, Michigan Association of Governing Boards, 1988.

Following retirement, Wagner worked as a consultant to
Upjohn, Schering Corp., Warner-Lambert/Parke-Davis, the
Food and Drug Administration, and others.
John Wagner became famous with the publication of
his book, Biopharmaceutics and Relevant Pharmacokinetics; he then followed with other books on the subject of
pharmacokinetics. This was the time, in the early 1970s,
when the discipline of mathematical pharmacokinetics was
in its infancy, its creation spearheaded by such giants as Sid
Riegelman, Milo Gibaldi, and Gerhard Levy. John took the
lead in infusing complex mathematics to the resolution of
pharmacokinetic modeling approach; his savvy of introducing Laplace transforms to all kinetics problems bears well
in my mind. I never found it difficult to get lost somewhere
in the long chain of mathematical transformations; John
could easily make any model mathematically awesome. I
met John several times when I had invited him to speak at
the institutions where I was working to frequent meetings
at the Academy of Pharmaceutical Science. John was a slim,
trim man who spoke with a comparably lean choice of
words. He was indeed a leader, a remarkable educator, and
someone who left many indelible impressions on the students in his era—me included.
Sarfaraz K. Niazi, Ph.D.
Pharmaceutical Scientist, Inc.
20 Reverside Drive
Deerfield, Illinois, 60015


About the Author
Dr. Sarfaraz K. Niazi has been teaching and conducting research in the pharmaceutical industry for over 30 years. He has authored hundreds of scientific papers,
textbooks, and presentations on the topics of pharmaceutical formulation, biopharmaceutics, and pharmacokinetics of drugs. He is also an inventor with scores of
patents and is licensed to practice law before the U.S. Patent and Trademark Office.

Having formulated hundreds of products from consumer products to complex biotechnology-derived products, he has accumulated a wealth of knowledge in the
science of formulations and regulatory filings of Investigational New Drugs (INDs)
and New Drug Applications (NDAs). Dr. Niazi advises the pharmaceutical industry
internationally on issues related to formulations, pharmacokinetics and bioequivalence
evaluation, and intellectual property issues ().



Contents
Part I
Regulatory and Manufacturing Guidance ......................................................................................1
Chapter 1

Changes to Approved New Drug Applications or Abbreviated New Drug Applications ............................3

I.
II.
III.
IV.

Introduction................................................................................................................................................................3
Reporting Categories .................................................................................................................................................3
General Requirements ...............................................................................................................................................4
Assessing the Effect of Manufacturing Changes......................................................................................................4
A. Assessment of the Effects of the Change ..........................................................................................................4
B. Equivalence.........................................................................................................................................................5
C. Adverse Effect ....................................................................................................................................................5
V. Components and Composition ..................................................................................................................................5
VI. Manufacturing Sites...................................................................................................................................................5
A. General Considerations ......................................................................................................................................5

B. Major Changes (Prior Approval Supplement) ...................................................................................................6
C. Moderate Changes (Supplement—Changes Being Effected)............................................................................6
D. Minor Changes (Annual Report) .......................................................................................................................7
VII. Manufacturing Process ..............................................................................................................................................7
A. General Considerations ......................................................................................................................................7
B. Major Changes (Prior Approval Supplement) ...................................................................................................7
C. Moderate Changes (Supplement—Changes Being Effected)............................................................................8
D. Minor Changes (Annual Report) .......................................................................................................................9
VIII. Specifications .............................................................................................................................................................9
A. General Considerations ......................................................................................................................................9
B. Major Changes (Prior Approval Supplement) ...................................................................................................9
C. Moderate Changes (Supplement—Changes Being Effected)..........................................................................10
D. Minor Changes (Annual Report) .....................................................................................................................10
IX. Package ....................................................................................................................................................................11
A. General Considerations ....................................................................................................................................11
B. Major Changes (Prior Approval Supplement) .................................................................................................11
C. Moderate Changes (Supplement—Changes Being Effected)..........................................................................11
D. Minor Changes (Annual Report) .....................................................................................................................12
X. Labeling ...................................................................................................................................................................12
A. General Considerations ....................................................................................................................................12
B. Major Changes (Prior Approval Supplement) .................................................................................................13
C. Moderate Changes (Supplement—Changes Being Effected)..........................................................................13
D. Minor Changes (Annual Report) .....................................................................................................................13
XI. Miscellaneous Changes ...........................................................................................................................................13
A. Major Changes (Prior Approval Supplement) .................................................................................................13
B. Moderate Changes (Supplement—Changes Being Effected)..........................................................................13
C. Minor Changes (Annual Report) .....................................................................................................................14
XII. Multiple Related Changes .......................................................................................................................................14
Glossary.............................................................................................................................................................................15
Chapter 2

Postapproval Changes to Semisolid Drugs .................................................................................................17

I. Preservative ..............................................................................................................................................................18
II. Manufacturing Changes...........................................................................................................................................18


III. Process .....................................................................................................................................................................18
IV. Manufacturing Site ..................................................................................................................................................18
Chapter 3

Scale-Up and Postapproval Changes for Nonsterile Semisolid Dosage Forms:
Manufacturing Equipment ...........................................................................................................................21

I. Introduction..............................................................................................................................................................21
II. Particle Size Reduction and Separation ..................................................................................................................21
A. Definitions.........................................................................................................................................................21
B. Equipment Classifications ................................................................................................................................22
III. Mixing......................................................................................................................................................................22
A. Definitions.........................................................................................................................................................22
B. Equipment Classification..................................................................................................................................23
IV. Transfer ....................................................................................................................................................................23
A. Definitions.........................................................................................................................................................23
B. Equipment Classification..................................................................................................................................23
V. Packaging.................................................................................................................................................................24
A. Definitions.........................................................................................................................................................24
B. Equipment Classification..................................................................................................................................24
Chapter 4

Stability Testing of Drug Substances and Drug Products ..........................................................................25

I. Introduction..............................................................................................................................................................25
II. Stability Testing for New Drug Applications..........................................................................................................25
A. Drug Substance.................................................................................................................................................25
B. Drug Product ....................................................................................................................................................27
C. New Dosage Forms [ICH Q1C].......................................................................................................................34
D. Other NDAs......................................................................................................................................................34
III. Stability Testing for Abbreviated NDAs .................................................................................................................34
A. Drug Substance Stability Data Submission .....................................................................................................34
B. Drug Substance Testing....................................................................................................................................34
C. Drug Product ....................................................................................................................................................35
D. ANDA Data Package Recommendations.........................................................................................................35
E. Exceptions to the ANDA Data Package Recommendations ...........................................................................35
F. Data Package for Approval ..............................................................................................................................35
G. Stability Study Acceptance ..............................................................................................................................35
IV. Stability Testing for Investigational NDAs .............................................................................................................36
A. Phase 1..............................................................................................................................................................36
B. Phase 2..............................................................................................................................................................36
C. Phase 3 ............................................................................................................................................................36
V. Approved Stability Protocol ....................................................................................................................................37
A. Stability Protocol ..............................................................................................................................................37
B. Stability Commitment ......................................................................................................................................37
VI. Reporting Stability Data..........................................................................................................................................38
A. General..............................................................................................................................................................38
B. Content of Stability Reports.............................................................................................................................38
C. Formatting Stability Reports ............................................................................................................................39
VII. Specific Stability Topics ..........................................................................................................................................39
A. Mean Kinetic Temperature...............................................................................................................................39
B. Container and Closure......................................................................................................................................39
C. Microbiological Control and Quality...............................................................................................................40

D. Stability Sampling Considerations ...................................................................................................................41
E. Statistical Considerations and Evaluation........................................................................................................43


F. Expiration Dating Period and Retest Period....................................................................................................44
G. Bracketing.........................................................................................................................................................46
H. Matrixing ..........................................................................................................................................................47
I. Site-Specific Stability Data for Drug and Biologic Applications ...................................................................48
J. Photostability ....................................................................................................................................................49
K. Degradation Products .......................................................................................................................................53
L. Thermal Cycling...............................................................................................................................................54
M. Stability Testing in Foreign Laboratory Facilities ...........................................................................................54
N. Stability Testing of Biotechnology Drug Products..........................................................................................54
VIII. Considerations for Specific Dosage Forms.............................................................................................................59
A. Tablets...............................................................................................................................................................59
B. Capsules............................................................................................................................................................59
C. Emulsions .........................................................................................................................................................59
D. Oral Solutions and Suspensions.......................................................................................................................59
E. Oral Powders for Reconstitution......................................................................................................................59
F. Metered-Dose Inhalations and Nasal Aerosols................................................................................................59
G. Inhalation Solutions and Powders....................................................................................................................59
H. Nasal Sprays: Solutions and Suspensions........................................................................................................60
I. Topical, Ophthalmic, and Otic Preparations....................................................................................................60
J. Transdermals.....................................................................................................................................................60
K. Suppositories.....................................................................................................................................................60
L. SVPs .................................................................................................................................................................60
M. LVPs..................................................................................................................................................................61
N. Drug Additives..................................................................................................................................................61
O. Implantable Subdermal, Vaginal, and Intrauterine Devices that Deliver Drug Products ...............................61
IX. Stability Testing for Postapproval Changes ............................................................................................................61

A. General..............................................................................................................................................................61
B. Change in Manufacturing Process of the Drug Substance..............................................................................62
C. Change in Manufacturing Site .........................................................................................................................62
D. Change in Manufacturing Process or Equipment for the Drug Product.........................................................63
E. Change in Batch Size of the Drug Product .....................................................................................................63
F. Reprocessing of a Drug Product ......................................................................................................................63
G. Change in Container and Closure of the Drug Product ..................................................................................63
H. Changes in the Stability Protocol ....................................................................................................................63
References .........................................................................................................................................................................64
Glossary.............................................................................................................................................................................64
Chapter 5

Guidelines for Evaluation of Stability Data in Retest Periods...................................................................69

I. Introduction..............................................................................................................................................................69
A. Background.......................................................................................................................................................69
B. Scope of the Guideline.....................................................................................................................................69
II. Guidelines ................................................................................................................................................................69
A. General Principles ............................................................................................................................................69
B. Data Presentation..............................................................................................................................................70
C. Extrapolation.....................................................................................................................................................70
D. Data Evaluation for Retest Period or Shelf-Life Estimation for Drug Substances
or Products Intended for “Room Temperature” Storage .................................................................................70
E. Data Evaluation for Retest Period or Shelf-Life Estimation for Drug Substances
or Products Intended for Storage Below “Room Temperature”......................................................................71
F. General Statistical Approaches ........................................................................................................................72
References .........................................................................................................................................................................72
Appendix A: Decision Tree for Data Evaluation for Retest Period or Shelf-Life Estimation
for Drug Substances or Products (Excluding Frozen Products) .................................................................................73

Chapter 6

Skin Irritation and Sensitization Testing of Generic Transdermal Drug Products ....................................75

I. Study Designs ..........................................................................................................................................................75
A. Recommendations for a Cumulative Skin Irritation Study .............................................................................75
B. Recommendations for a Skin Sensitization Study (Modified Draize Test) ....................................................76
C. Combined Studies.............................................................................................................................................76
Appendix A .......................................................................................................................................................................76
Skin Irritation Scoring Systems .......................................................................................................................76
Appendix B .......................................................................................................................................................................77
Adhesion Score.................................................................................................................................................77
Appendix C .......................................................................................................................................................................77
References .........................................................................................................................................................................77
Chapter 7

Photosafety Testing......................................................................................................................................79

I. Introduction..............................................................................................................................................................79
II. Background ..............................................................................................................................................................79
A. Photoirritation and Photococarcinogenicity .....................................................................................................79
B. Historical Approach to Photosafety Testing ....................................................................................................80
III. Testing Considerations.............................................................................................................................................80
A. General Considerations for Testing a Drug Product or Drug Substance .......................................................80
B. Testing for Photochemical Irritation ................................................................................................................81
IV. Testing for Enhancement of UV-Associated Skin Carcinogenesis
(Direct Photochemical Carcinogenicity or Indirect Effects in Skin) .....................................................................82
A. Considerations and Decision Tree for Testing Photosensitizing Drugs
for Long-Term Photosafety ..............................................................................................................................82

B. Decision Tree for Testing Nonphotoreactive Drugs for Long-Term Photosafety...........................................83
C. Mechanistically Based and Other Assays ........................................................................................................84
References .........................................................................................................................................................................84
Glossary.............................................................................................................................................................................86
Chapter 8

Guidance on Formulating Semisolid Drugs................................................................................................87

I. Potency Uniformity .................................................................................................................................................87
II. Equipment and Production Control.........................................................................................................................87
A. Mixers ...............................................................................................................................................................87
B. Filling and Packaging.......................................................................................................................................87
C. Process Temperature Control ...........................................................................................................................88
III. Cleaning Validation..................................................................................................................................................88
A. Detailed Cleaning Procedures ..........................................................................................................................88
B. Sampling Plan for Contaminants .....................................................................................................................88
C. Equipment Residue Limits ...............................................................................................................................88
IV. Microbiological........................................................................................................................................................89
A. Controls (Nonsterile Topicals) .........................................................................................................................89
B. Preservative Activity.........................................................................................................................................90
V. Change Control........................................................................................................................................................90
VI. Transdermal Topical Products .................................................................................................................................90
A. Formulations of Semisolid Drugs ....................................................................................................................90
B. The Role of In Vitro Release Testing...............................................................................................................91
C. In Vivo Bioequivalence Studies........................................................................................................................91
References .........................................................................................................................................................................92
Glossary.............................................................................................................................................................................92


Part II

Formulations of Semisolid Drugs...................................................................................................95
Aceclofenac Gel-Cream ....................................................................................................................................................97
Acetaminophen Suppositories...........................................................................................................................................97
Acetaminophen Suppositories...........................................................................................................................................98
Acetylsalicylic Acid Suppositories ...................................................................................................................................98
Alclometasone Dipropionate Cream and Ointment .........................................................................................................99
Acyclovir Cream ...............................................................................................................................................................99
Acyclovir Ointment.........................................................................................................................................................100
Adapalene Cream ............................................................................................................................................................100
Aloe Vera Gel ..................................................................................................................................................................100
Alum Cream ....................................................................................................................................................................101
Aminacrine Hydrochloride Cream..................................................................................................................................101
Amoxacillin Lotion .........................................................................................................................................................102
Ampicillin Lotion............................................................................................................................................................102
Anthralin Cream..............................................................................................................................................................102
Antifungal Topical Cream...............................................................................................................................................103
Arginine and Oleoresin Capsicum Cream ......................................................................................................................103
Arginine Cream ...............................................................................................................................................................103
Arginine-Aspartate Cream ..............................................................................................................................................104
Atropine Opthalmic Ointment ........................................................................................................................................104
Azelaic Acid Cream and Gel ..........................................................................................................................................105
Baby Lotion.....................................................................................................................................................................105
Bacitracin Zinc and Polymyxin B Sulfate Opthalmic Ointment ...................................................................................105
Base Ointment .................................................................................................................................................................106
Base Ointment .................................................................................................................................................................107
Base Cream for Extemporaneous Preparations ..............................................................................................................107
Base Ointment for Therapeutic Delivery........................................................................................................................108
Becaplermin Gel 0.01% ..................................................................................................................................................108
Benzalkonium Chloride and Zinc Oxide Cream ............................................................................................................109
Benzalkonium Chloride Contraceptive Gel ....................................................................................................................110

Benzocaine Cream...........................................................................................................................................................110
Benzoyl Peroxide and Alpha-Bisabolol Gel...................................................................................................................111
Benzoyl Peroxide Cream ................................................................................................................................................111
Benzoyl Peroxide Gel .....................................................................................................................................................112
Benzoyl Peroxide Lotion ................................................................................................................................................113
Betamethasone and Cinchocaine Suppositories .............................................................................................................113
Betamethasone and Neomycin Gel-Cream.....................................................................................................................114
Betamethasone and Salicylic Acid Lotion......................................................................................................................114
Betamethasone Cream.....................................................................................................................................................115
Betamethasone Dipropionate Cream, Lotion, and Ointment .........................................................................................115
Betamethasone Dipropionate Ointment ..........................................................................................................................116
Betamethasone Gel..........................................................................................................................................................116
Betamethasone Opthalmic Ointment ..............................................................................................................................117
Betamethasone Valerate and Cinchocaine Ointment......................................................................................................117
Betamethasone Valerate Cream.......................................................................................................................................118
Betamethasone Valerate Foam ........................................................................................................................................118
Betamethasone Valerate Ointment ..................................................................................................................................119
Bisacodyl Suppositories ..................................................................................................................................................120
Biscarboxychromonyloxy Propanol Ointment................................................................................................................121
Breast Care Cream ..........................................................................................................................................................121
Budesonide Cream ..........................................................................................................................................................122
Budesonide Ointment......................................................................................................................................................122


Burn Cream .....................................................................................................................................................................123
Butenafine Hydrochloride Cream ...................................................................................................................................124
Butesin Picrate and Metaphen Ointment........................................................................................................................124
Butesin Picrate Ointment ................................................................................................................................................125
Butoconazole Nitrate Vaginal Cream..............................................................................................................................126
Calamine and Diphenhydramine Hydrochloride Lotion ................................................................................................126

Calamine Cream..............................................................................................................................................................127
Calamine and Pramoxine Hydrochloride Lotion............................................................................................................127
Calamine Cream..............................................................................................................................................................128
Calamine Lotion..............................................................................................................................................................129
Calcipotriene Cream........................................................................................................................................................129
Camphor, Eucalyptus Oil, and Menthol Ointment.........................................................................................................129
Carbamazepine Gel .........................................................................................................................................................130
Carbamazepine Cream ....................................................................................................................................................130
Carbamazepine Ointment................................................................................................................................................130
Castor Oil Ointment ........................................................................................................................................................131
Cefaclor and Benzoyl Peroxide Gel ..............................................................................................................................131
Cefaclor and Benzoyl Peroxide Lotion ..........................................................................................................................132
Cetrimonium Bromide Cream.........................................................................................................................................132
Chlorhexidine and Cetrimonium Bromide Cream..........................................................................................................133
Chlorhexidine Gel ...........................................................................................................................................................133
Chloramphenicol Opthalmic Ointment...........................................................................................................................133
Chlorpromazine Suppositories ........................................................................................................................................133
Ciclopirox Cream, Lotion, and Gel ................................................................................................................................134
Ciclopirox Nail Varnish...................................................................................................................................................134
Ciprofloxacin Hydrochloride Opthalmic Ointment ........................................................................................................134
Clindamycin Gel .............................................................................................................................................................135
Clindamycin Lotion and Gel ..........................................................................................................................................135
Clindamycin Phosphate Topical Gel...............................................................................................................................135
Clindamycin Phosphate Vaginal Cream..........................................................................................................................136
Clindamycin Phosphate Vaginal Suppository.................................................................................................................136
Clobetasol Propionate Cream..........................................................................................................................................136
Clobetasol Propionate Cream, Ointment, and Gel .........................................................................................................137
Clobetasol Propionate Ointment .....................................................................................................................................137
Clotrimazole and Betamethasone Cream and Lotion.....................................................................................................137
Clotrimazole Cream ........................................................................................................................................................138

Clotrimazole Lotion ........................................................................................................................................................139
Clotrimazone Vaginal Cream Inserts ..............................................................................................................................139
Clotrimazone Vaginal Cream ..........................................................................................................................................140
Clotrimazole and Clindamycin Cream ...........................................................................................................................141
Clotrimazole and Clindamycin Suppositories ................................................................................................................141
Clotrimazole and Clindamycin Suppositories ................................................................................................................142
Coal Tar and Allantoin Cream ........................................................................................................................................142
Coal Tar and Allantoin Cream ........................................................................................................................................143
Coal Tar Cream ...............................................................................................................................................................143
Collagenase Ointment .....................................................................................................................................................143
Conjugated Estrogens Vaginal Cream ............................................................................................................................143
Cyanocobalamin Gel .......................................................................................................................................................144
DBcAMP Ointment.........................................................................................................................................................144
Desonide Cream, Ointment, and Lotion.........................................................................................................................144
Desoximetasone Emollient Cream, Gel, and Ointment .................................................................................................145
Dexamethasone Sodium Phosphate Ointment................................................................................................................145
Dexpanthenol Cream.......................................................................................................................................................145
Dexpanthenol Gel-Cream................................................................................................................................................146
Diclofenac Diethylamine Gel..........................................................................................................................................146


Diclofenac Diethylammonium Gel .................................................................................................................................147
Diclofenac Sodium Suppositories...................................................................................................................................147
Diclofenac Sodium Suppositories...................................................................................................................................148
Diclofenac Sodium Suppositories...................................................................................................................................149
Dichlorobenzyl Alcohol Tooth Gel.................................................................................................................................149
Dienestrol Vaginal Cream ...............................................................................................................................................149
Diethylamine Salicylate Cream ......................................................................................................................................150
Diflorasone Diacetate Cream and Ointment...................................................................................................................150
Dimethicone and Zinc Oxide Ointment .........................................................................................................................151

Dinoprostone Cervical Gel..............................................................................................................................................151
Dinoprostone Vaginal Insert and Suppositories..............................................................................................................151
Diphenhydramine Hydrochloride and Zinc Acetate Ointment ......................................................................................151
Docosanol Lotion ............................................................................................................................................................151
Econazole Nitrate and Benzoyl Peroxide Cream ...........................................................................................................152
Econazole Nitrate and Benzoyl Peroxide Lotion ...........................................................................................................152
Eflornithine Hydrochloride Cream..................................................................................................................................152
Enzyme Extract Ointment...............................................................................................................................................153
Erythromycin Ointment...................................................................................................................................................153
Erythromycin Ointment...................................................................................................................................................154
Erythromycin and Neomycin Ointment..........................................................................................................................154
Erythromycin Gel............................................................................................................................................................155
Estradiol and Norethindrone Acetate Transdermal System............................................................................................155
Estradiol Transdermal System ........................................................................................................................................155
Estradiol Vaginal Cream .................................................................................................................................................156
Ethylenediamine Tetracetate Ointment ...........................................................................................................................157
Fluocinonide Cream, Ointment, and Gel........................................................................................................................157
Fluocinonide Cream ........................................................................................................................................................158
Fluorometholone Opthalmic Ointment ...........................................................................................................................158
Fluorouracil Cream .........................................................................................................................................................158
Flurandrenolide Lotion....................................................................................................................................................158
Flurandrenolide Topical Film..........................................................................................................................................159
Fluticasone Propionate Ointment....................................................................................................................................159
Fluticasone Ointment ......................................................................................................................................................160
Fluticasone Propionate Cream ........................................................................................................................................160
Foscarnet Cream..............................................................................................................................................................161
Gamma Benzene Hexachloride Lotion...........................................................................................................................161
Gentamicin Sulfate Ointment..........................................................................................................................................162
Gentamicin Sulfate Cream ..............................................................................................................................................163
Gentamicin Sulfate Ointment..........................................................................................................................................163

Glycerin Suppositories ....................................................................................................................................................164
Glycolic Acid Cream.......................................................................................................................................................165
Gramicidin, Neomycin, Nystatin, and Triamcinolone Ointment ...................................................................................165
Halobetasol Propionate Cream and Ointment ................................................................................................................166
Heparin Gel-Cream .........................................................................................................................................................166
Hexachlorophen Cream...................................................................................................................................................167
Hydrocortisone Acetate and Pramoxine Hydrochloride Cream and Lotion ..................................................................168
Hydrocortisone Ointment................................................................................................................................................168
Hydrocortisone Acetate Suppositories ............................................................................................................................168
Hydrocortisone and Nitrofurazone Cream......................................................................................................................169
Hydrocortisone Butyrate Cream and Ointment ..............................................................................................................169
Hydrocortisone Cream ....................................................................................................................................................170
Hydrocortisone Cream ....................................................................................................................................................171
Hydrocortisone Cream and Ointment .............................................................................................................................172
Hydrocortisone Gel .........................................................................................................................................................172
Hydrocortisone Gel .........................................................................................................................................................173


Hydrocortisone Ointment................................................................................................................................................174
Hydrogen Peroxide Ointment .........................................................................................................................................174
Hydrophilic Ointment USP.............................................................................................................................................175
Hydroquinone Cream and Gel ........................................................................................................................................175
Hydroquinone Gel ..........................................................................................................................................................176
Hydroquinone Cream ......................................................................................................................................................177
Ibuprofen Cream..............................................................................................................................................................178
Ibuprofen Gel-Cream ......................................................................................................................................................178
Ibuprofen Gel-Cream ......................................................................................................................................................179
Ibuprofen Gel ..................................................................................................................................................................180
Ibuprofen Gel ..................................................................................................................................................................181
Imiquimod Cream ...........................................................................................................................................................181

Indomethacin Gel ............................................................................................................................................................181
Indomethacin Gel ............................................................................................................................................................182
Indomethacin Suppositories ............................................................................................................................................182
Indomethacin Suppositories ............................................................................................................................................183
Kojic Dipalmitate Cream ................................................................................................................................................184
Ketoconazole Cream .......................................................................................................................................................184
Lactic Acid Cream ..........................................................................................................................................................185
Lanolin Cream.................................................................................................................................................................186
Lidocaine and Prilocaine Topical Adhesive System Cream...........................................................................................186
Lidocaine Adhesive System Gel .....................................................................................................................................187
Lidocaine and Tribenoside Cream ..................................................................................................................................187
Lidocaine and Tribenoside Ointment..............................................................................................................................188
Lidocaine and Tribenoside Suppositories .......................................................................................................................188
Lidocaine Anorectal Cream ............................................................................................................................................188
Lidocaine Gels.................................................................................................................................................................189
Lidocaine Ointment.........................................................................................................................................................190
Lidocaine, Eugenol, and Menthol Dental Ointment ......................................................................................................191
Lindane Lotion ................................................................................................................................................................191
Mafenide Acetate Cream.................................................................................................................................................191
Malathion Lotion.............................................................................................................................................................191
Mandelic Acid Cream .....................................................................................................................................................192
Menthol, Methyl Salicylate, and Menthol Cream and Ointment...................................................................................192
Mesalamine Suppository .................................................................................................................................................192
Methotrexate Cataplasms ................................................................................................................................................193
Methotrexate Gel.............................................................................................................................................................193
Methotrexate Cream ........................................................................................................................................................194
Methotrexate Lotion ........................................................................................................................................................194
Methoxsalen Lotion.........................................................................................................................................................195
Methyl Salicylate and Menthol Gel................................................................................................................................195
Methyl Salicylate and Menthol Ointment ......................................................................................................................195

Methyl Salicylate Cream.................................................................................................................................................196
Methyl Salicylate Cream.................................................................................................................................................197
Methyl Salicylate Lotion.................................................................................................................................................197
Methyl Salicylate, Thyme, Pine, and Menthol Foot Cream ..........................................................................................198
Methyl Salicylate and Menthol Cream...........................................................................................................................199
Methyl Salicylate and Menthol Lotion...........................................................................................................................199
Methyl Salicylate Clear Gel............................................................................................................................................200
Metoclopramide Suppositories........................................................................................................................................200
Metoclopramide Suppositories........................................................................................................................................201
Metoclopramide Suppositories........................................................................................................................................202
Metronidazol Vaginal Gel ...............................................................................................................................................203
Metronidazole Cream......................................................................................................................................................203
Metronidazole Lotion......................................................................................................................................................203


Metronidazole Gel Solution ...........................................................................................................................................203
Miconazole Cream ..........................................................................................................................................................204
Miconazole Mouth Gel ...................................................................................................................................................204
Miconazole Nitrate Vaginal Suppositories......................................................................................................................205
Miconazole Nitrate Vaginal Suppositories 400 mg ........................................................................................................206
Mometasone Furoate Lotion ...........................................................................................................................................206
Mometasone Furoate Cream ...........................................................................................................................................207
Monobenzone Cream ......................................................................................................................................................207
Multivitamin Oral Gel Veterinary ...................................................................................................................................208
Multivitamin Oral Gel with Linoleic and Linolenic Acid .............................................................................................209
Mupirocin Calcium Cream..............................................................................................................................................209
Mupirocin Ointment........................................................................................................................................................210
Naftifine Hydrochloride Cream ......................................................................................................................................211
Nanoxynol Suppository with Bacterial Culture .............................................................................................................212
Neomycin and Bacitracin Ointment ...............................................................................................................................213

Neomycin Gel .................................................................................................................................................................213
Neomycin, Polymyxin B Sulfate, and Bacitracin Zinc Opthalmic Ointment ...............................................................214
Nicotine Polymer Gel......................................................................................................................................................214
Nitrofurazone Cream.......................................................................................................................................................214
Nystatin Ointment ...........................................................................................................................................................215
Nystatin, Neomycin Sulfate, Gramicidin, and Triamcinolone Acetonide Cream..........................................................216
Nystatin, Neomycin Sulfate, Gramicidin, and Triamcinolone Acetonide Ointment .....................................................217
Octyl Methoxycinnamate, Octyl Salicylate, and Oxybenzone Gel ...............................................................................217
Olibanum Gum Cream ....................................................................................................................................................218
Oxiconazole Cream and Lotion ......................................................................................................................................218
Oxymorphone Hydrochloride Suppositories ..................................................................................................................218
Oxytetracycline Ointment ...............................................................................................................................................219
Panthenol and Chlorhexidine Lotion ..............................................................................................................................219
Panthenol Ointment.........................................................................................................................................................220
Papain Ointment ..............................................................................................................................................................220
Penciclovir Cream ...........................................................................................................................................................220
Peppermint Cream...........................................................................................................................................................221
Permethrin Cream and Lotion ........................................................................................................................................221
Petrolatum and Lanolin Ointment ..................................................................................................................................221
Phenylephrine Ointment, Cream, Suppositories, and Gel..............................................................................................221
Piroxicam Ointment ........................................................................................................................................................222
Piroxicam and Dexpanthenol Gel ...................................................................................................................................222
Polymyxin, Bacitracin, Hydrocortisone, and Zinc Ointment.........................................................................................223
Povidone-Iodine and Lidocain Gel .................................................................................................................................223
Povidone-Iodine Cream...................................................................................................................................................224
Povidone-Iodine Gel .......................................................................................................................................................225
Povidone-Iodine Gel .......................................................................................................................................................226
Povidone-Iodine Glucose Ointment................................................................................................................................226
Povidone-Iodine Vaginal Ovules.....................................................................................................................................227
Pramoxine Cream............................................................................................................................................................228

Pramoxine Hydrochloride and Zinc Acetate Lotion and Ointment ...............................................................................228
Pramoxine Suppositories.................................................................................................................................................229
Pranoprofen Ointment .....................................................................................................................................................230
Prednicarbate Emollient Cream ......................................................................................................................................230
Prochlorperazine Suppositories.......................................................................................................................................230
Progesterone Gel .............................................................................................................................................................231
Promethazine Hydrochloride Suppositories....................................................................................................................231
Promethazine Suppository...............................................................................................................................................231
Resorcinol Acne Cream ..................................................................................................................................................231
Salicylic Acid Cream ......................................................................................................................................................232


Salicylic Acid Gel ...........................................................................................................................................................233
Scopolamine Transdermal Therapeutic System..............................................................................................................233
Selenium Sulfide Detergent Lotion.................................................................................................................................234
Selenium Sulfide Lotion .................................................................................................................................................234
Silicone Cream ................................................................................................................................................................235
Silver Sulfadiazine Cream ..............................................................................................................................................235
Sodium Chloride Ointment .............................................................................................................................................236
Sodium Sulfacetamide Lotion.........................................................................................................................................236
Squalene Cream...............................................................................................................................................................237
Starch Ointment...............................................................................................................................................................237
Sucralafate Ointment.......................................................................................................................................................237
Sucralafate and Hyaluronic Acid Ointment....................................................................................................................238
Sucralafate Opthalmic Ointment.....................................................................................................................................238
Sulfacetamide Ointment ..................................................................................................................................................238
Sulfacetamide Sodium and Prednisolone Aetate Opthalmic Ointment .........................................................................238
Sulfanilamide Suppositories............................................................................................................................................239
Sulfathiazole Cream ........................................................................................................................................................239
Sulfur Ointment...............................................................................................................................................................239

Tacrolimus Ointment.......................................................................................................................................................239
Terconazole Vaginal Cream ............................................................................................................................................240
Terconazole Vaginal Suppositories .................................................................................................................................240
Testosterone Gel ..............................................................................................................................................................240
Testosterone Transdermal System...................................................................................................................................240
Testosterone Transdermal System Controlled Delivery .................................................................................................241
Tetracaine Gel and Cream...............................................................................................................................................241
Tetracycline Hydrochloride Ointment.............................................................................................................................241
TGF-α Ointment .............................................................................................................................................................242
Therapeutic Skin Lotion..................................................................................................................................................242
Tolnafate and Undecylanate Cream ................................................................................................................................243
Tretinoin and Alpha Bisabolol Gel .................................................................................................................................243
Tretinoin and Dexpanthenol Gel.....................................................................................................................................244
Tretinoin Cream ..............................................................................................................................................................244
Tretinoin Gel ...................................................................................................................................................................245
Tretinoin Gel Microsphere..............................................................................................................................................245
Triacontanol Ointment ....................................................................................................................................................245
Triclosan Foot Cream......................................................................................................................................................246
Tridax Procumbens Ointment .........................................................................................................................................246
Trolamine Salicylate Cream............................................................................................................................................247
Ultrasonic Adhesive Gel .................................................................................................................................................247
Vitamin A Suppositories .................................................................................................................................................248
Vitamin A Ointment ........................................................................................................................................................248
Vitamin C Vaginal Ointment...........................................................................................................................................249
Vitamin E Gel-Cream......................................................................................................................................................249
Zinc Oxide and Vitamin E Cream ..................................................................................................................................250
Zinc Oxide Lotion...........................................................................................................................................................251
Zinc Oxide Ointment ......................................................................................................................................................251
Zinc Oxide Ointment with Vitamin E and Aloe.............................................................................................................252
Zinc Pyrithione Detergent Lotion ...................................................................................................................................252

Zinc Undecylenate Cream...............................................................................................................................................252
Zirconium Oxide Lotion .................................................................................................................................................253
Index ...............................................................................................................................................................................255


Part I
Regulatory and Manufacturing Guidance