HANDBOOK OF
`
`Pharmaceutical
`Manufacturing
`Formulations
`
`Semisolid Products
`VOLUME 4
`Sarfaraz K. Niazi
`
`CRC PRESS
`
`Boca Raton London New York Washington
`
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`

`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. Dnigs—Dosage forms—Handbooks, manuals, etc. I. Title
`
`RS200.N53 2004
`615T9—dc21
`
`2003051451
`
`This book contains information obtained from authentic and highly regarded sources. Reprinted material is quoted with permission, and sources are
`indicated. A wide variety of references are listed. Reasonable efforts have been made to publish reliable data and information, but the author and the
`publisher cannot assume responsibility for the validity of all materials or for the consequences of their use.
`
`Neither this book nor any part may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying,
`microfilming, and recording, or by any information storage or retrieval system, without prior permission in writing from the publisher.
`
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`
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`
`Trademark Notice: Product or corporate names may be trademarks or registered trademarks, and are used only for identification and explanation,
`without intent to infringe.
`
`Visit the CRC Press Web site at www.crcpress.com
`
`© 2004 by CRC Press LLC
`
`No claim to original U.S. Government works
`International Standard Book Number 0-8493-1749-5
`Library of Congress Card Number 2003051451
`Printed in the United States of America 1 234567890
`Printed on acid-free paper
`
`UNIVERSITY LIBRARY
`UNIVERSITY OF ALBERTA
`
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`

`Dedication
`
`Dedicated to the memory of
`John G. Wagner
`
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`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 phar­
`maceutical 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 Manufac­
`turing Formulations is the first major attempt to consoli­
`date the available knowledge about formulations in a com­
`prehensive, and by nature rather voluminous, presentation.
`The book is divided into six volumes, based strictly
`on the type of formulation science involved in the develop­
`ment of these dosage forms: sterile products, compressed
`solids, uncompressed solids, liquid products, semisolid
`products, and over-the-counter (OTC) products. The sep­
`aration 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 steril­
`ization of product, and of less importance is the bioavail­
`ability 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 fil­
`ing 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 pro­
`tocols 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, scien­
`tists 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
`
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`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, preserva­
`tion 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, 1 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. Obvi­
`ously, 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 identi­
`fication of ingredients to conserve space for those formu­
`lations that need more elaborate description.
`The regulatory agencies impose certain specific
`requirements on the formulation and efficacy determina­
`tion of drugs contained in these formulations. For exam­
`ple, the CGMP factors, scale-up and postapproval
`changes, and dermatological testing for irritation or pho­
`tosensitivity 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 refer­
`ence to semisolid drugs. The stability considerations, par­
`ticularly the evolving guidelines of the International Con­
`ference on Harmonization (ICH), are detailed in this volume,
`with particular reference to stability-testing requirements
`in postapproval stages. Unique to this category is the der­
`mal 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 Admin­
`istration (FDA) and the harmonized guidelines with the
`ICH listings. Although it is likely that some of the require­
`ments and recommendations made here might change, it
`is unlikely that the basic thrust in establishing these guide­
`lines 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. http://www.fda.gov, is very comprehensive and
`continuously evolving; pay special attention to the with­
`drawal and finalization of guidelines provided. Of particular
`importance is the listing of new and withdrawn guide­
`lines (http://www.fda.gov/cder/guidance/New-Revised-
`Withdrawn.PDF), 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 require­
`ments but. unfortunately, the one that is most easily misun­
`derstood 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 inad­
`vertently 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 piv­
`otal 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 think­
`ing of the regulator)' authorities on how the stability studies
`should be designed and conducted and how the data should
`be interpreted; the induction olTCH guidelines and an attempt
`to streamline the requirements of testing new drug products
`have resulted in much dispute when it comes to global mar­
`keting of products. Should the stability testing be done at all
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`environmental regional standards, or is it possible to extrap­
`olate 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 proce­
`dures 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 Consul­
`tation 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, trans­
`plant 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 reg­
`ulatory 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 car­
`cinogenicity? These are questions of importance to the
`regulatory authorities.
`Chapter 8 includes a variety of topics related to for­
`mulation of semisolid drugs, from CGMP considerations
`to packaging and validation issues; these topics are col­
`lated 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 dis­
`tinct 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 read­
`ers bringing these to my attention for correction in future
`editions of this volume (niazi@pharmsci.com).
`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. Bom 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. Through­
`out his life he received numerous awards, including the
`American Pharmaceutical Association (APhA) Ebert Prize,
`1961; Academy Fellow of the AphA Academy of Pharma­
`ceutical Sciences, 1969; the Centennial Achievement Award,
`Ohio State University, 1970; the Host-Madsen Medal, Fed­
`eration 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., Wamer-Lambert/Parke-Davis, the
`Food and Drug Administration, and others.
`John Wagner became famous with the publication of
`his book. Biopharmaceutics and Relevant Pharmacokinet­
`ics-, 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 introduc­
`ing 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 1 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 stu­
`dents in his era—me included.
`
`Sarfaraz K. Niazi, Ph.D.
`Pharmaceutical Scientist, Inc.
`20 Riverside Drive
`Deerfield, Illinois, 60015
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`About the Author
`
`Dr. Sarfaraz K. Niazi has been teaching and conducting research in the pharma­
`ceutical industry for over 30 years. He has authored hundreds of scientific papers,
`textbooks, and presentations on the topics of pharmaceutical formulation, biophar­
`maceutics, and pharmacokinetics of drugs. He is also an inventor with scores of
`patents and is licensed to practice law before the U.S. Patent and Trademark Office.
`Having formulated hundreds of products from consumer products to complex bio-
`technology-derived products, he has accumulated a wealth of knowledge in the
`science of formulations and regulatory filings of Investigational New Drugs (INDs)
`and New Drug Applications (NDAs). Dr. Niazi advises the pharmaceutical industry
`internationally on issues related to formulations, pharmacokinetics and bioequivalence
`evaluation, and intellectual property issues (http://www.pharmsci.com).
`
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`Formulations of Semisolid Drugs
`
`Calamine Cream
`
`127
`
`Bill of Materials
`Scale (mg/g)
`Item
`1
`80.00
`10.00
`2
`50.00
`3
`4
`q.s.
`5
`100.00
`50.00
`6
`7
`20.00
`20.00
`8
`9
`q.s.
`
`Material Name
`Polawax GP200
`Polysorbate 60
`Caprylic/capric triglyceride
`Deionized water q.s. to
`Witch hazel distillate
`Glycerin
`Zinc oxide
`Calamine
`Preservative, color
`
`Quantity/kg (g)
`80.00
`10.00
`50.00
`1 kg
`100.00
`50.00
`20.00
`20.00
`q.s.
`
`MANUFACTURING DIRECTIONS
`
`1. Heat oil and water phases separately to
`65o-70°C.
`
`2. Add water phase to oil phase while stirring.
`3. Add zinc oxide and calamine under high shear.
`Stir to cool.
`
`Calamine Cream
`
`Bill of Materials
`Item
`Scale (mg/g)
`1
`20.00
`2
`100.00
`3
`1.80
`4
`0.20
`5
`100.00
`6
`25.00
`7
`50.00
`8
`50.00
`9
`653.00
`
`Material Name
`Microcrystalline cellulose (Avicel RC-591)
`Glycerin
`Methylparaben
`Propylparaben
`Glyceryl stearate and PEG-100 stearate
`Cetyl alcohol
`Zinc oxide
`Calamine
`Distilled water
`
`Quantity/kg (g)
`20.00
`100.00
`1.80
`0.20
`100.00
`25.00
`50.00
`50.00
`653.00
`
`MANUFACTURING DIRECTIONS
`
`1. Mix item 2 with item 9 and heat to 75°C.
`2. Add items 3 and 4; mix until dissolved using a
`shearing mixer.
`3. Maintain temperature at 75°C and gradually
`add item 1; continue mixing at 75°C for 15
`
`minutes or until item 1 is homogenously dis­
`persed. Mix well.
`4. When temperature drops to 60o-65°C, gradu­
`ally add items 7 and 8; mix well until powders
`are homogenously dispersed.
`5. Pass through homogenizer if necessary; adjust
`theoretical weight with warm distilled water
`and continue mixing until the cream congeals.
`
`Calamine and Pramoxine Hydrochloride Lotion
`
`Active ingredients are calamine 8% and pramoxine hydro­
`chloride 1%. Inactive ingredients include caladryl lotion:
`alcohol USP, camphor, diazolidinyl urea, fragrance.
`
`hydroxypropyl methylcellulose, methylparaben, oil of lav­
`ender, oil of rosemary, polysorbate 80, propylene glycol,
`propylparaben, purified water, and xanthan gum.
`
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`228
`
`Handbook of Pharmaceutical Manufacturing Formulations: Semisolid Products
`
`Pramoxine Cream
`
`Bill of Materials
`Item
`Scale (mg/g)
`1
`150.00
`2
`50.00
`3
`0.72 mL
`4
`1.80
`5
`0.20
`6
`20.00
`7
`50.00
`8
`10.00
`
`Material Name
`Cetyl alcohol*
`Cetyl esters wax*
`Water purified
`Methylparaben
`Propylparaben
`Sodium lauryl sulfate
`Glycerin
`Pramoxine hydrochloride
`
`Quantity/kg (g)
`150.00
`50.00
`720 mb
`1.80
`0.20
`20.00
`50.00
`10.00
`
`*Beeswax 75.00 mg/g can be added and adjusted with items 1 and 2.
`
`MANUFACTURING DIRECTIONS
`
`1. Phase A: Add the cetyl alcohol (item 1) and the
`cetyl esters wax (item 2) to a suitable jacketed
`stainless steel tank fitted with efficient agitation.
`Heat to 60°-65°C and mix until materials are
`melted and phase is uniform.
`2. Preheat a suitable jacketed stainless steel batch
`tank to 60°-65°C. Strain phase A (step 1) into
`the batch tank, maintaining temperature at
`60°-65°C and gentle agitation.
`3. Phase B: Charge 530 mb of purified water (item
`3) into a suitable jacketed stainless steel tank
`fitted with a high-speed mixer. Adjust the water
`temperature to 80°-90°C and add methylpara­
`ben (item 4) and propylparaben (item 5). Stir
`until dissolved, ensuring that no solids are
`entrained in the bottom valve. Commence cool­
`ing to 60o-65°C.
`4. Add the sodium lauryl sulfate (item 6) with care
`and stir to dissolve.
`
`5. Add the glycerin (item 7) and mix until uni­
`form. Caution: Do not create excessive foam.
`6. Cool to 60o-65°C.
`7. Strain phase A and sweep mix. Rinse through
`with F2 mb of purified water.
`8. Phase C: To a suitable jacketed stainless steel
`tank fitted with high-speed agitation, charge
`166 mb of purified water and raise the temper­
`ature to 60°-65°C. Add the pramoxine hydro­
`chloride (item 8) and mix until dissolved. Strain
`the solution via a 100 to 150-pm aperture mesh
`into the mass from step above. Rinse through
`with 12 mb of purified water. Reduce agitation
`rate to prevent air entrainment and commence
`cooling to 32O-36°C. Please note that you
`should maintain cooling water at 10°C below
`batch temperature until 45°C, switching then to
`full cooling.
`9. Fill.
`
`Pramoxine Hydrochloride and Zinc Acetate Lotion and Ointment
`
`The lotion contains pramoxine hydrochloride 1% and zinc
`acetate 0.1% and inactive ingredients alcohol USP, cam­
`phor, citric acid, diazolidinyl urea, fragrance, glycerin,
`hydroxypropyl methylcellulose, methylparaben, oil of lav­
`ender, oil of rosemary, polysorbate 40, propylene glycol,
`propylparaben, purified water, and sodium citrate. The
`
`ointment contains active ingredients pramoxine HC1 1 %,
`zinc oxide 12.5%, and mineral oil as well as benzyl ben­
`zoate, calcium phosphate dibasic, cocoa butter, glyceryl
`monooleate, glyceryl monostearate, kaolin, peruvian bal­
`sam, and polyethylene wax.
`
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