Handbook of pharmaceutical manufacturing formulations pdf free download

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Handbook of pharmaceutical manufacturing formulations pdf free download

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PDF Handbook Of Pharmaceutical Manufacturing Formulations Second Edition.

Whereas many stages of new drug development are inherently constrained with time, the formulation of drugs into desirable dosage forms remains an area where 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. Jahrom University of Medical Sciences. Pharmaceutical excipients are included in formulations for both adult and pediatric patients for a variety of reasons, for example to provide a carrier for the active pharmaceutical ingredient, to improve drug product processability, to facilitate drug solubility or absorption, or to ensure formulation stability and physiological compatibility.

Handbook of pharmaceutical manufacturing formulations sterile products pdf free download

PDF Handbook Of Pharmaceutical Manufacturing Formulations Second Edition.

HANDBOOK OF Pharmaceutical Manufacturing Formulations Semisolid Products VOLUME 4© 2004 by CRC Press LLCHandbook 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 PhVOarvmeOra-ctehueLt-iCcaoUluMntMearnuPfrEaocdtuucrit1nsg Formulations: Volume 6 Handbook of Pharmaceutical Manufacturing Formulations: Sterile Products© 2004 by CRC Press LLCHANDBOOK OF Pharmaceutical Manufacturing Formulations Semisolid Products VOLUME 4 Sarfaraz K. Niazi CRC PR ESS Boca Raton London New York Washington, D.C.© 2004 by CRC Press LLCLibrary of Congress Cataloging-in-Publication DataNiazi, 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 2003051451This book contains information obtained from authentic and highly regarded sources. Reprinted material is quoted with permission, and sources areindicated. A wide variety of references are listed. Reasonable efforts have been made to publish reliable data and information, but the author and thepublisher 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.The consent of CRC Press LLC does not extend to copying for general distribution, for promotion, for creating new works, or for resale. Specificpermission must be obtained in writing from CRC Press LLC for such copying.Direct all inquiries to CRC Press LLC, 2000 N.W. Corporate Blvd., Boca Raton, Florida 33431.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 © 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 2 3 4 5 6 7 8 9 0 Printed on acid-free paper© 2004 by CRC Press LLCDedication Dedicated to the memory of John G. Wagner© 2004 by CRC Press LLCPreface to the SeriesNo industry in the world is more highly regulated than Each volume includes a description of regulatory fil-the pharmaceutical industry because of potential threats ing techniques for the formulations described. Alsoto patients’ lives from the use of pharmaceutical products. included are the current regulatory guidelines on currentThe cost of taking a new chemical entity (amortized over good manufacturing practice (CGMP) compliance specificthe cost of all molecules racing) to final regulatory to the dosage form and advice is offered on how to scaleapproval is a staggering $800 million, making the phar- up the production batches.maceutical industry one of the most research-intensiveindustries in the world. In the year 2004, it is anticipated It is expected that the formulation scientist would usethat the industry will spend about $20 billion on research this information to benchmark internal development pro-and development. The generic market of drugs as new tocols and to cut the race to file short by adopting formulaeentities come off patent is one of the fastest growing that have survived the test of time. Many of us who havesegments of the pharmaceutical industry, with every major worked in the pharmaceutical industry suffer from amultinational company having a significant presence in closed paradigm when it comes to selecting formulations;this field. “not invented here” perhaps subconsciously reigns in the minds of many seasoned formulations scientists when they Whereas many stages of new drug development are prefer to choose only a certain platform for development.inherently constrained with time, the formulation of drugs It is expected that with a quick review of possibilitiesinto desirable dosage forms remains an area in which available to formulate made available in this book, scien-expediency can be practiced with appropriate knowledge tists will benefit from the experience of those who have mastered the skills of pharmaceuticalformulations. The Handbook of Pharmaceutical Manufac- For the teachers of formulation sciences, this seriesturing Formulations is the first major attempt to consoli- offers a wealth of information. Whether it is a selectiondate the available knowledge about formulations in a com- of a preservative system or the choice of a disintegrant,prehensive, and by nature rather voluminous, presentation. the series offers a wide choice to study and rationalize. The book is divided into six volumes, based strictly Many have assisted me in the development of thison the type of formulation science involved in the develop- work, which has taken years to compile, and I am thankfulment of these dosage forms: sterile products, compressed to scores of my graduate students and colleagues for theirsolids, uncompressed solids, liquid products, semisolid help. A work of this size cannot be produced withoutproducts, and over-the-counter (OTC) products. The sep- errors, though I hope these errors do not distract the readeraration of OTC products, though they may easily fall into from the utility of the book. I would sincerely appreciateone of the other five categories, is made to comply with readers pointing out these mistakes to me for correctionsthe industry norms of separate research divisions for OTC in future editions.products. Sterile products require skills related to steril-ization of product, and of less importance is the bioavail- Sarfaraz K. Niazi, Ph.D.ability issue, which is an inherent problem of compressed Deerfield, Illinoisdosage forms. These types of considerations have led tothe classification of products into these six categories.© 2004 by CRC Press LLCPreface to the VolumeThe semisolid drugs category is comprised of ointments, much of the regulatory discussion presented here is drawncreams, gels, suppositories, and special topical dosage from the requirements of the U.S. Food and Drug Admin-forms. The formulations of semisolid drugs share many istration (FDA) and the harmonized guidelines with thecommon attributes of consistency, presentation, preserva- ICH listings. Although it is likely that some of the require-tion requirement, and the route of administration, mainly ments and recommendations made here might change, ittopical. As a result, grouping them together for the purpose is unlikely that the basic thrust in establishing these guide-of defining common formulation practices and problems lines will change. As always, the applicants are highlyis justified. The topical dosage forms present unique encouraged to communicate with the FDA on the changesopportunities to design novel drug delivery systems such made to these guidelines and especially for any significantas patches and other transdermal systems. Some of these changes made to compliance requirements. The Web siteare described in the volume, but the reader is referred to of the FDA, is very comprehensive andspecific patents issued, wherein greater details are readily continuously evolving; pay special attention to the with-obtainable. In selecting the formulations, I have tried to drawal and finalization of guidelines provided. Of particularprovide representative techniques and technologies importance is the listing of new and withdrawn guide-involved in the preparation of semisolid products; for lines (I have included a significant number of what is Withdrawn.PDF), which should be reviewed “base” formulation, a formulation that can easilycarry a drug, depending on the proportion involved. Obvi- Chapter 1 provides details on how to handle changesously, considerations such as incompatability of the drug made to approved NDAs or ANDAs; this is a significantwith the ingredients is of pivotal importance; these base topic for continued compliance with the CGMP require-formulations of stable emulsions provide a good starting ments but, unfortunately, the one that is most easily misun-point in the development of new products or even when derstood or misconstrued. For example, at what level ofa different topical consistency is desired. I have also made change should the FDA be informed, either before makingan effort to highlight those formulations that are currently a change or after? What happens if a change is made inad-approved in the United States and provide them as they vertently and later discovered; how to report this change?appear in the Physicans Desk Reference, where possible. Years of experience teaches me that a manufacturer canObviously, where the formulations are straightforward, I never be too careful in avoiding a 483 issuance when ithave chosen to only give the composition or mere identi- comes to changes made to NDAs or ANDAs. The situationfication of ingredients to conserve space for those formu- gets extremely complex when there are multiple dosagelations that need more elaborate description. forms, for which the requirements may be different. The regulatory agencies impose certain specific Chapter 2 gets into details of changes made pursuantrequirements on the formulation and efficacy determina- to discussion in Chapter 1 when it comes to semisolidtion of drugs contained in these formulations. For exam- drugs. A more detailed description of level of changes isple, the CGMP factors, scale-up and postapproval described here, and advice is provided on when to conductchanges, and dermatological testing for irritation or pho- a regulatory review.tosensitivity are some of the specified elements. Chapter 3 continues the themes developed in the first In this volume, we present over 350 formulations and, two chapters and applies to changes made to equipment. Thisin keeping with the tradition in other volumes, a chapter is a topic of special interest to the FDA because in theon formulation-related matters. In the regulatory section, processing of semisolid products, the equipment plays a piv-we offer a difficult area of compliance, changes to otal role. The mixing of drugs within the base media is highlyapproved new drug applications (NDAs) and abbreviated affected by the process and mechanism of mixing used. Also,new drug applications (ANDAs), particularly with refer- because of the nature of product manufactured, often theence to semisolid drugs. The stability considerations, par- cleaning and validation of equipment become serious issues.ticularly the evolving guidelines of the International Con-ference on Harmonization (ICH), are detailed in this volume, Chapter 4 is a comprehensive review of the present think-with particular reference to stability-testing requirements ing of the regulatory authorities on how the stability studiesin postapproval stages. Unique to this category is the der- should be designed and conducted and how the data shouldmal testing of products, including photosensitivity testing be interpreted; the induction of ICH guidelines and an attemptrequirements that are still evolving. It is noteworthy that 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© 2004 by CRC Press LLCenvironmental regional standards, or is it possible to extrap- given by Erika Dery, Naomi Lynch, and others. Thougholate these data based on accelerated stability testing? These much care has gone into correcting errors, any errorsare some of the questions answered in this chapter, wherein remaining are altogether mine. I shall appreciate the read-the FDA and ICH guidelines are merged. ers bringing these to my attention for correction in future editions of this volume ([email protected]). Chapter 5 extends the discussion on stability testingprotocols to retest periods and elaborates on the proce- This volume is dedicated to John G. Wagner, the Johndures used for continued testing of products. G. Searle Professor Emeritus of Pharmaceutics in the College of Pharmacy and Professor Emeritus of Pharmacology in the Chapter 6 introduces a topic of great importance in Medical School, who passed away recently. Born in Weston,the development of semisolid, and particularly dermal, Ontario, Canada, in 1921, Wagner served in the Canada Airproducts: skin irritation and sensitization studies. Whereas Force during World War II and then worked as a researchthe standard test protocols have almost become universal scientist for the Upjohn Co. from 1953 to 1968, joining thein their nature, it is always advised that these should be University of Medicine in 1968. Wagner was the author ofagreed on, most appropriately in a pre-Investigational New two books and coauthor of more than 340 articles. Through-Drug Application (IND) filing. Established in 1988, the out his life he received numerous awards, including theOffice of Drug Evaluation IV (ODE IV) Pre-IND Consul- American Pharmaceutical Association (APhA) Ebert Prize,tation Program is designed to facilitate and foster informal 1961; Academy Fellow of the AphA Academy of Pharma-early communications between the divisions of ODE IV ceutical Sciences, 1969; the Centennial Achievement Award,and potential sponsors of new therapeutics for the treatment Ohio State University, 1970; the Host-Madsen Medal, Fed-of bacterial infections, HIV, opportunistic infections, trans- eration Internationale Pharmaceutique, 1972; Outstandingplant rejection, and other diseases. The program is intended Leadership and Research Award, Delta Chapter of Phito serve sponsors of all drug products that may be submitted Lambda Epsilon, 1983; AAPS Fellow, American Associationto any division within ODE IV, including but not limited to of Pharmaceutical Scientists, 1986; and Distinguisheddrugs for the treatment of life-threatening illnesses (21 CFR Professor, Michigan Association of Governing Boards, 1988.312.82(a)). Pre-IND advice may be requested for issues Following retirement, Wagner worked as a consultant torelated to drug development plans; data needed to support Upjohn, Schering Corp., Warner-Lambert/Parke-Davis, thethe rationale for testing a drug in humans; the design of Food and Drug Administration, and others.nonclinical pharmacology, toxicology, and drug activitystudies; data requirements for an IND application; and reg- John Wagner became famous with the publication ofulatory requirements for demonstrating safety and efficacy. his book, Biopharmaceutics and Relevant Pharmacokinet-Included among the ODE IV Pre-IND Program activities ics; he then followed with other books on the subject ofare coordination of all Pre-IND interactions with the FDA pharmacokinetics. This was the time, in the early 1970s,Topical Microbicide Working Group. when the discipline of mathematical pharmacokinetics was in its infancy, its creation spearheaded by such giants as Sid Chapter 7 deals with the topic of photosensitivity Riegelman, Milo Gibaldi, and Gerhard Levy. John took thecaused by drugs; photosafety is a serious issue in the lead in infusing complex mathematics to the resolution ofdevelopment of topical products. It is worth noting here pharmacokinetic modeling approach; his savvy of introduc-that certain classes of drugs such as quinolone antibiotics ing Laplace transforms to all kinetics problems bears wellare generally regarded unsafe without thorough testing for in my mind. I never found it difficult to get lost somewherephotosensitivity. Does photosensitivity correlate with car- in the long chain of mathematical transformations; Johncinogenicity? These are questions of importance to the could easily make any model mathematically awesome. Iregulatory authorities. met John several times when I had invited him to speak at the institutions where I was working to frequent meetings Chapter 8 includes a variety of topics related to for- at the Academy of Pharmaceutical Science. John was a slim,mulation of semisolid drugs, from CGMP considerations trim man who spoke with a comparably lean choice ofto packaging and validation issues; these topics are col- words. He was indeed a leader, a remarkable educator, andlated for their particular importance, but the discussions someone who left many indelible impressions on the stu-provided are not comprehensive, and the reader is referred dents in his era—me standard texts on formulation theories, particularlywhere establishing a preservative system is required. Sarfaraz K. Niazi, Ph.D. Pharmaceutical Scientist, Inc. I am grateful to CRC Press for taking this lead inpublishing what is possibly the largest such work in the 20 Reverside Drivefield of pharmaceutical manufacturing. It has been a dis- Deerfield, Illinois, 60015tinct privilege to have known Mr. Stephen Zollo, the SeniorEditor at CRC Press, for years. Stephen has done more thanany editor can to encourage me into completing this workon a timely basis. The editorial assistance provided by CRCPress staff was indeed exemplary, particularly the help© 2004 by CRC Press LLCAbout 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 (2004 by CRC Press LLCContents Part I Regulatory and Manufacturing Guidance Chapter 1 Changes to Approved New Drug Applications or Abbreviated New Drug Applications I. Introduction II. Reporting Categories III. General Requirements IV. Assessing the Effect of Manufacturing Changes A. Assessment of the Effects of the Change B. Equivalence C. Adverse Effect V. Components and Composition VI. Manufacturing Sites A. General Considerations B. Major Changes (Prior Approval Supplement) C. Moderate Changes (Supplement—Changes Being Effected). D. Minor Changes (Annual Report) VII. Manufacturing Process A. General Considerations B. Major Changes (Prior Approval Supplement) C. Moderate Changes (Supplement—Changes Being Effected). D. Minor Changes (Annual Report) VIII. Specifications A. General Considerations B. Major Changes (Prior Approval Supplement) C. Moderate Changes (Supplement—Changes Being Effected). D. Minor Changes (Annual Report) IX. Package A. General Considerations B. Major Changes (Prior Approval Supplement) C. Moderate Changes (Supplement—Changes Being Effected) D. Minor Changes (Annual Report) X. Labeling A. General Considerations B. Major Changes (Prior Approval Supplement) C. Moderate Changes (Supplement—Changes Being Effected). D. Minor Changes (Annual Report) XI. Miscellaneous Changes A. Major Changes (Prior Approval Supplement) B. Moderate Changes (Supplement—Changes Being Effected). C. Minor Changes (Annual Report) XII. Multiple Related Changes Glossary Chapter 2 Postapproval Changes to Semisolid Drugs I. Preservative II. Manufacturing Changes© 2004 by CRC Press LLCIII. Process IV. Manufacturing Site Chapter 3 Scale-Up and Postapproval Changes for Nonsterile Semisolid Dosage Forms: Manufacturing Equipment I. Introduction II. Particle Size Reduction and Separation A. Definitions B. Equipment Classifications III. Mixing A. Definitions. B. Equipment Classification IV. Transfer A. Definitions B. Equipment Classification V. Packaging A. Definitions B. Equipment Classification Chapter 4 Stability Testing of Drug Substances and Drug Products I. Introduction II. Stability Testing for New Drug Applications A. Drug Substance B. Drug Product C. New Dosage Forms [ICH Q1C] D. Other NDAs III. Stability Testing for Abbreviated NDAs A. Drug Substance Stability Data Submission B. Drug Substance Testing C. Drug Product D. ANDA Data Package Recommendations E. Exceptions to the ANDA Data Package Recommendations F. Data Package for Approval G. Stability Study Acceptance IV. Stability Testing for Investigational NDAs A. Phase 1 B. Phase 2 C. Phase 3 V. Approved Stability Protocol A. Stability Protocol B. Stability Commitment VI. Reporting Stability Data A. General B. Content of Stability Reports.. C. Formatting Stability Reports. VII. Specific Stability Topics A. Mean Kinetic Temperature B. Container and Closure C. Microbiological Control and Quality D. Stability Sampling Considerations E. Statistical Considerations and Evaluation© 2004 by CRC Press LLCF. Expiration Dating Period and Retest Period G. Bracketing H. Matrixing I. Site-Specific Stability Data for Drug and Biologic Applications J. Photostability K. Degradation Products L. Thermal Cycling M. Stability Testing in Foreign Laboratory Facilities N. Stability Testing of Biotechnology Drug Products VIII. Considerations for Specific Dosage Forms A. Tablets B. Capsules C. Emulsions D. Oral Solutions and Suspensions E. Oral Powders for Reconstitution F. Metered-Dose Inhalations and Nasal Aerosols G. Inhalation Solutions and Powders H. Nasal Sprays: Solutions and Suspensions I. Topical, Ophthalmic, and Otic Preparations J. Transdermals K. Suppositories L. SVPs M. LVPs N. Drug Additives.. O. Implantable Subdermal, Vaginal, and Intrauterine Devices that Deliver Drug Products IX. Stability Testing for Postapproval Changes A. General B. Change in Manufacturing Process of the Drug Substance C. Change in Manufacturing Site D. Change in Manufacturing Process or Equipment for the Drug Product E. Change in Batch Size of the Drug Product F. Reprocessing of a Drug Product G. Change in Container and Closure of the Drug Product H. Changes in the Stability Protocol References Glossary… Chapter 5 Guidelines for Evaluation of Stability Data in Retest Periods I. Introduction A. Background B. Scope of the Guideline II. Guidelines A. General Principles B. Data Presentation C. Extrapolation D. Data Evaluation for Retest Period or Shelf-Life Estimation for Drug Substances or Products Intended for “Room Temperature” Storage E. Data Evaluation for Retest Period or Shelf-Life Estimation for Drug Substances or Products Intended for Storage Below “Room Temperature F. General Statistical Approaches References Appendix A: Decision Tree for Data Evaluation for Retest Period or Shelf-Life Estimation for Drug Substances or Products (Excluding Frozen Products)© 2004 by CRC Press LLCChapter 6 Skin Irritation and Sensitization Testing of Generic Transdermal Drug Products I. Study Designs A. Recommendations for a Cumulative Skin Irritation Study B. Recommendations for a Skin Sensitization Study (Modified Draize Test) C. Combined Studies Appendix A Skin Irritation Scoring Systems Appendix B Adhesion Score Appendix C References Chapter 7 Photosafety Testing I. Introduction II. Background A. Photoirritation and Photococarcinogenicity B. Historical Approach to Photosafety Testing III. Testing Considerations A. General Considerations for Testing a Drug Product or Drug Substance B. Testing for Photochemical Irritation IV. Testing for Enhancement of UV-Associated Skin Carcinogenesis (Direct Photochemical Carcinogenicity or Indirect Effects in Skin) A. Considerations and Decision Tree for Testing Photosensitizing Drugs for Long-Term Photosafety B. Decision Tree for Testing Nonphotoreactive Drugs for Long-Term Photosafety C. Mechanistically Based and Other Assays References Glossary Chapter 8 Guidance on Formulating Semisolid Drugs I. Potency Uniformity II. Equipment and Production Control A. Mixers B. Filling and Packaging C. Process Temperature Control III. Cleaning Validation A. Detailed Cleaning Procedures B. Sampling Plan for Contaminants C. Equipment Residue Limits IV. Microbiological A. Controls (Nonsterile Topicals) B. Preservative Activity V. Change Control VI. Transdermal Topical Products A. Formulations of Semisolid Drugs B. The Role of In Vitro Release Testing C. In Vivo Bioequivalence Studies References Glossary© 2004 by CRC Press LLCPart II Formulations of Semisolid Drugs Aceclofenac Gel-Cream Acetaminophen Suppositories Acetaminophen Suppositories Acetylsalicylic Acid Suppositories Alclometasone Dipropionate Cream and Ointment Acyclovir Cream Acyclovir Ointment Adapalene Cream Aloe Vera Gel Alum Cream Aminacrine Hydrochloride Cream Amoxacillin Lotion Ampicillin Lotion Anthralin Cream Antifungal Topical Cream Arginine and Oleoresin Capsicum Cream Arginine Cream Arginine-Aspartate Cream Atropine Opthalmic Ointment Azelaic Acid Cream and Gel Baby Lotion Bacitracin Zinc and Polymyxin B Sulfate Opthalmic Ointment Base Ointment Base Ointment Base Cream for Extemporaneous Preparations Base Ointment for Therapeutic Delivery Becaplermin Gel 0.01% Benzalkonium Chloride and Zinc Oxide Cream Benzalkonium Chloride Contraceptive Gel Benzocaine Cream Benzoyl Peroxide and Alpha-Bisabolol Gel Benzoyl Peroxide Cream Benzoyl Peroxide Gel Benzoyl Peroxide Lotion Betamethasone and Cinchocaine Suppositories Betamethasone and Neomycin Gel-Cream Betamethasone and Salicylic Acid Lotion Betamethasone Cream Betamethasone Dipropionate Cream, Lotion, and Ointment Betamethasone Dipropionate Ointment Betamethasone Gel Betamethasone Opthalmic Ointment Betamethasone Valerate and Cinchocaine Ointment Betamethasone Valerate Cream Betamethasone Valerate Foam Betamethasone Valerate Ointment Bisacodyl Suppositories Biscarboxychromonyloxy Propanol Ointment Breast Care Cream Budesonide Cream Budesonide Ointment© 2004 by CRC Press LLCBurn Cream Butenafine Hydrochloride Cream Butesin Picrate and Metaphen Ointment Butesin Picrate Ointment Butoconazole Nitrate Vaginal Cream Calamine and Diphenhydramine Hydrochloride Lotion Calamine Cream Calamine and Pramoxine Hydrochloride Lotion Calamine Cream Calamine Lotion Calcipotriene Cream Camphor, Eucalyptus Oil, and Menthol Ointment Carbamazepine Gel Carbamazepine Cream Carbamazepine Ointment Castor Oil Ointment Cefaclor and Benzoyl Peroxide Gel Cefaclor and Benzoyl Peroxide Lotion Cetrimonium Bromide Cream Chlorhexidine and Cetrimonium Bromide Cream Chlorhexidine Gel Chloramphenicol Opthalmic Ointment Chlorpromazine Suppositories Ciclopirox Cream, Lotion, and Gel Ciclopirox Nail Varnish Ciprofloxacin Hydrochloride Opthalmic Ointment Clindamycin Gel Clindamycin Lotion and Gel Clindamycin Phosphate Topical Gel Clindamycin Phosphate Vaginal Cream Clindamycin Phosphate Vaginal Suppository Clobetasol Propionate Cream Clobetasol Propionate Cream, Ointment, and Gel Clobetasol Propionate Ointment Clotrimazole and Betamethasone Cream and Lotion Clotrimazole Cream Clotrimazole Lotion Clotrimazone Vaginal Cream Inserts Clotrimazone Vaginal Cream Clotrimazole and Clindamycin Cream Clotrimazole and Clindamycin Suppositories Clotrimazole and Clindamycin Suppositories Coal Tar and Allantoin Cream Coal Tar and Allantoin Cream Coal Tar Cream Collagenase Ointment Conjugated Estrogens Vaginal Cream Cyanocobalamin Gel DBcAMP Ointment Desonide Cream, Ointment, and Lotion Desoximetasone Emollient Cream, Gel, and Ointment Dexamethasone Sodium Phosphate Ointment Dexpanthenol Cream Dexpanthenol Gel-Cream Diclofenac Diethylamine Gel© 2004 by CRC Press LLCDiclofenac Diethylammonium Gel Diclofenac Sodium Suppositories Diclofenac Sodium Suppositories Diclofenac Sodium Suppositories Dichlorobenzyl Alcohol Tooth Gel Dienestrol Vaginal Cream Diethylamine Salicylate Cream Diflorasone Diacetate Cream and Ointment Dimethicone and Zinc Oxide Ointment Dinoprostone Cervical Gel Dinoprostone Vaginal Insert and Suppositories Diphenhydramine Hydrochloride and Zinc Acetate Ointment Docosanol Lotion Econazole Nitrate and Benzoyl Peroxide Cream Econazole Nitrate and Benzoyl Peroxide Lotion Eflornithine Hydrochloride Cream Enzyme Extract Ointment Erythromycin Ointment Erythromycin Ointment Erythromycin and Neomycin Ointment Erythromycin Gel Estradiol and Norethindrone Acetate Transdermal System Estradiol Transdermal System Estradiol Vaginal Cream Ethylenediamine Tetracetate Ointment Fluocinonide Cream, Ointment, and Gel Fluocinonide Cream Fluorometholone Opthalmic Ointment Fluorouracil Cream Flurandrenolide Lotion Flurandrenolide Topical Film Fluticasone Propionate Ointment Fluticasone Ointment Fluticasone Propionate Cream Foscarnet Cream Gamma Benzene Hexachloride Lotion Gentamicin Sulfate Ointment Gentamicin Sulfate Cream Gentamicin Sulfate Ointment Glycerin Suppositories Glycolic Acid Cream Gramicidin, Neomycin, Nystatin, and Triamcinolone Ointment Halobetasol Propionate Cream and Ointment Heparin Gel-Cream Hexachlorophen Cream Hydrocortisone Acetate and Pramoxine Hydrochloride Cream and Lotion Hydrocortisone Ointment Hydrocortisone Acetate Suppositories Hydrocortisone and Nitrofurazone Cream Hydrocortisone Butyrate Cream and Ointment Hydrocortisone Cream Hydrocortisone Cream Hydrocortisone Cream and Ointment Hydrocortisone Gel Hydrocortisone Gel© 2004 by CRC Press LLCHydrocortisone Ointment Hydrogen Peroxide Ointment Hydrophilic Ointment USP Hydroquinone Cream and Gel Hydroquinone Gel Hydroquinone Cream Ibuprofen Cream Ibuprofen Gel-Cream Ibuprofen Gel-Cream Ibuprofen Gel Ibuprofen Gel Imiquimod Cream Indomethacin Gel Indomethacin Gel Indomethacin Suppositories Indomethacin Suppositories Kojic Dipalmitate Cream Ketoconazole Cream Lactic Acid Cream Lanolin Cream Lidocaine and Prilocaine Topical Adhesive System Cream Lidocaine Adhesive System Gel Lidocaine and Tribenoside Cream Lidocaine and Tribenoside Ointment Lidocaine and Tribenoside Suppositories Lidocaine Anorectal Cream Lidocaine Gels Lidocaine Ointment Lidocaine, Eugenol, and Menthol Dental Ointment Lindane Lotion Mafenide Acetate Cream Malathion Lotion Mandelic Acid Cream Menthol, Methyl Salicylate, and Menthol Cream and Ointment Mesalamine Suppository Methotrexate Cataplasms Methotrexate Gel Methotrexate Cream Methotrexate Lotion Methoxsalen Lotion Methyl Salicylate and Menthol Gel Methyl Salicylate and Menthol Ointment Methyl Salicylate Cream Methyl Salicylate Cream Methyl Salicylate Lotion Methyl Salicylate, Thyme, Pine, and Menthol Foot Cream Methyl Salicylate and Menthol Cream Methyl Salicylate and Menthol Lotion Methyl Salicylate Clear Gel Metoclopramide Suppositories Metoclopramide Suppositories Metoclopramide Suppositories Metronidazol Vaginal Gel Metronidazole Cream Metronidazole Lotion© 2004 by CRC Press LLCMetronidazole Gel Solution Miconazole Cream Miconazole Mouth Gel Miconazole Nitrate Vaginal Suppositories Miconazole Nitrate Vaginal Suppositories 400 mg Mometasone Furoate Lotion Mometasone Furoate Cream Monobenzone Cream Multivitamin Oral Gel Veterinary Multivitamin Oral Gel with Linoleic and Linolenic Acid Mupirocin Calcium Cream Mupirocin Ointment Naftifine Hydrochloride Cream Nanoxynol Suppository with Bacterial Culture Neomycin and Bacitracin Ointment Neomycin Gel Neomycin, Polymyxin B Sulfate, and Bacitracin Zinc Opthalmic Ointment Nicotine Polymer Gel Nitrofurazone Cream Nystatin Ointment Nystatin, Neomycin Sulfate, Gramicidin, and Triamcinolone Acetonide Cream Nystatin, Neomycin Sulfate, Gramicidin, and Triamcinolone Acetonide Ointment Octyl Methoxycinnamate, Octyl Salicylate, and Oxybenzone Gel Olibanum Gum Cream Oxiconazole Cream and Lotion Oxymorphone Hydrochloride Suppositories Oxytetracycline Ointment Panthenol and Chlorhexidine Lotion Panthenol Ointment Papain Ointment Penciclovir Cream Peppermint Cream Permethrin Cream and Lotion Petrolatum and Lanolin Ointment Phenylephrine Ointment, Cream, Suppositories, and Gel Piroxicam Ointment Piroxicam and Dexpanthenol Gel Polymyxin, Bacitracin, Hydrocortisone, and Zinc Ointment Povidone-Iodine and Lidocain Gel Povidone-Iodine Cream Povidone-Iodine Gel Povidone-Iodine Gel Povidone-Iodine Glucose Ointment Povidone-Iodine Vaginal Ovules Pramoxine Cream Pramoxine Hydrochloride and Zinc Acetate Lotion and Ointment Pramoxine Suppositories Pranoprofen Ointment Prednicarbate Emollient Cream Prochlorperazine Suppositories Progesterone Gel Promethazine Hydrochloride Suppositories Promethazine Suppository Resorcinol Acne Cream Salicylic Acid Cream© 2004 by CRC Press LLCSalicylic Acid Gel Scopolamine Transdermal Therapeutic System Selenium Sulfide Detergent Lotion Selenium Sulfide Lotion Silicone Cream Silver Sulfadiazine Cream Sodium Chloride Ointment Sodium Sulfacetamide Lotion Squalene Cream Starch Ointment Sucralafate Ointment Sucralafate and Hyaluronic Acid Ointment Sucralafate Opthalmic Ointment Sulfacetamide Ointment Sulfacetamide Sodium and Prednisolone Aetate Opthalmic Ointment Sulfanilamide Suppositories Sulfathiazole Cream Sulfur Ointment Tacrolimus Ointment Terconazole Vaginal Cream Terconazole Vaginal Suppositories Testosterone Gel Testosterone Transdermal System Testosterone Transdermal System Controlled Delivery Tetracaine Gel and Cream Tetracycline Hydrochloride Ointment TGF-α Ointment Therapeutic Skin Lotion Tolnafate and Undecylanate Cream Tretinoin and Alpha Bisabolol Gel Tretinoin and Dexpanthenol Gel Tretinoin Cream Tretinoin Gel Tretinoin Gel Microsphere Triacontanol Ointment Triclosan Foot Cream Tridax Procumbens Ointment Trolamine Salicylate Cream Ultrasonic Adhesive Gel Vitamin A Suppositories Vitamin A Ointment Vitamin C Vaginal Ointment Vitamin E Gel-Cream Zinc Oxide and Vitamin E Cream Zinc Oxide Lotion Zinc Oxide Ointment Zinc Oxide Ointment with Vitamin E and Aloe Zinc Pyrithione Detergent Lotion Zinc Undecylenate Cream Zirconium Oxide Lotion© 2004 by CRC Press LLC1 Changes to Approved New Drug Applications or Abbreviated New Drug Applications I. INTRODUCTION the change described in the supplement would impose an extraordinary hardship on the applicant. This type of sup-The holders of new drug applications (NDAs) and abbre- plement is called, and should be clearly labeled as, a Priorviated new drug applications (ANDAs) can make postap- Approval Supplement—Expedited Review R changes in accordance with added Section 506A Requests for expedited review based on extraordinaryof the FDA Modernization Act. There are specific report- hardship should be reserved for manufacturing changesing requirements for postapproval changes in components made necessary by catastrophic events (e.g., fire) or byand composition, manufacturing sites, manufacturing events that could not be reasonably foreseen and for whichprocess, specifications, package labeling, miscellaneous the applicant could not plan.changes, and multiple related changes. Reporting catego-ries for changes relating to specified biotechnology and A “moderate change” is a change that has a moderatespecified synthetic biological products regulated by the potential to have an adverse effect on the identity, strength,Center for Drug Evaluation and Research (CDER) are quality, purity, or potency of the product as these factorsfound in the guidance for industry entitled Changes to an may relate to the safety or effectiveness of the product.Approved Application for Specified Biotechnology and There are two types of moderate change. One type ofSpecified Synthetic Biological Products (July 1997). Infor- moderate change requires the submission of a supplementmation specific to products is developed by an applicant to the FDA at least 30 days before the distribution of theto assess the effect of the change on the identity, strength product made using the change (506A(d)(3)(B)(i)). This(e.g., assay, content uniformity), quality (e.g., physical, type of supplement is called, and should be clearly labeledchemical, and biological properties), purity (e.g., impuri- as, a Supplement—Changes Being Effected in 30 D and degradation products), or potency (e.g., biological The product made using a moderate change cannot beactivity, bioavailability, bioequivalence) of a product as distributed if the FDA informs the applicant within 30 daysthey may relate to the safety or effectiveness of the product. of receipt of the supplement that a Prior Approval Sup- plement is required (506A(d)(3)(B)(i)). For each change, CDER has published guidances, including the SUPAC the supplement must contain information determined by(scale-up and postapproval changes) guidances, that pro- the FDA to be appropriate and must include the informa-vide recommendations on reporting categories. tion developed by the applicant in assessing the effects of the change (506A(b)). If the FDA informs the applicant II. REPORTING CATEGORIES within 30 days of receipt of the supplement that informa- tion is missing, distribution must be delayed until theSection 506A of the Act provides for four reporting cat- supplement has been amended with the missing informa-egories that are distinguished in the following paragraphs. tion. The FDA may identify certain moderate changes for which distribution can occur when the FDA receives the A “major change” is a change that has a substantial supplement (506A(d)(3)(B)(ii)). This type of supplementpotential to have an adverse effect on the identity, strength, is called, and should be clearly labeled as, a Supple-quality, purity, or potency of a product as these factors ment—Changes Being Effected. If, after review, the FDAmay relate to the safety or effectiveness of the product disapproves a Changes Being Effected in 30 Days supple-(506A(c)(2)). A major change requires the submission of ment or a Changes Being Effected supplement, the FDAa supplement and approval by the Food and Drug Admin- may order the manufacturer to cease distribution of theistration (FDA) before distribution of the product made drugs that have been made using the disapproved changeusing the change (506A(c)(1)). This type of supplement (506A(d)(3)(B)(iii)) called, and should be clearly labeled as, a Prior ApprovalSupplement. An applicant may ask the FDA to expedite A “minor change” is a change that has minimal poten-its review of a Prior Approval Supplement for public tial to have an adverse effect on the identity, strength,health reasons (e.g., drug shortage) or if a delay in making quality, purity, or potency of the product as these factors 3© 2004 by CRC Press LLC4 Handbook of Pharmaceutical Manufacturing Formulations: Semisolid Productsmay relate to the safety or effectiveness of the product. the information developed by the applicant in assessing theThe applicant must describe minor changes in its next effects of the change (506A(b), (c)(1), (d)(2)(A), andannual report (506A(d)(1)(A) and (d)(2)). (d)(3)(A)). Recommendations on the type of information that should be included in a supplemental application or An applicant can submit one or more protocols (i.e., annual report are available in guidance documents. If nocomparability protocols) describing tests, validation stud- guidance is available on the type of information that shouldies, and acceptable limits to be achieved to demonstrate be submitted to support a change, the applicant is encour-the absence of an adverse effect from specified types of aged to contact the appropriate chemistry or microbiologychanges. A comparability protocol can be used to reduce review reporting category for specified changes. A proposedcomparability protocol should be submitted as a Prior 1. Conformance to SpecificationsApproval Supplement if not approved as part of the orig-inal application. An assessment of the effect of a change on the identity, strength, quality, purity, or potency of the drug product III. GENERAL REQUIREMENTS should include a determination that the drug substance intermediates, drug substance, in-process materials, orOther than for editorial changes in previously submitted drug product affected by the change conforms to theinformation (e.g., correction of spelling or typographical approved specifications. A “specification” is a qualityerrors, reformatting of batch records), an applicant must standard (i.e., tests, analytical procedures, and acceptancenotify the FDA about each change in each condition estab- criteria) provided in an approved application to confirmlished in an approved application beyond the variations the quality of drug substances, drug products, intermedi-already provided for in the application (506A(a)). ates, raw materials, reagents, and other components, including container closure systems and their components An applicant making a change to an approved appli- and in-process materials. For the purpose of defining spec-cation under Section 506A of the Act must also conform ifications, “acceptance criteria” are numerical limits,to other applicable laws and regulations, including current ranges, or other criteria for the tests described. Conform-good manufacturing practice (CGMP) requirements of the ance to a specification means that the material, when testedAct (21 U.S.C. 351(a)(2)(B)) and applicable regulations according to the analytical procedures listed in the spec-in Title 21 of the Code of Federal Regulations (e.g., 21 CFR ification, will meet the listed acceptance 210, 211, 314). For example, manufacturers mustcomply with relevant CGMP validation and record- 2. Additional Testingkeeping requirements and must ensure that relevantrecords are readily available for examination by autho- In addition to confirmation that the material affected byrized FDA personnel during an inspection. A Changes manufacturing changes continues to meet its specifica-Being Effected supplement for labeling changes must tion, the applicant should perform additional testing,include 12 copies of the final printed labeling (21 CFR when appropriate, to assess whether the identity, strength,314.50(e)(2)(ii)). quality, purity, or potency of the product as these factors may relate to the safety or effectiveness of the product Except for a supplemental application providing for a have been or will be affected. The assessment shouldchange in labeling, an applicant should include a statement include, as appropriate, evaluation of any changes in thein a supplemental application or amendment certifying chemical, physical, microbiological, biological, bioavail-that the required field copy (21 CFR 314.50) of the sup- ability, or stability profiles. This additional assessmentplement or amendment has been provided. could involve testing of the postchange drug product itself or, if appropriate, the component directly affected by the IV. ASSESSING THE EFFECT OF change. The type of additional testing that an applicant MANUFACTURING CHANGES should perform would depend on the type of manufac- turing change, the type of drug substance or drug product,A. ASSESSMENT OF THE EFFECTS OF THE CHANGE and the effect of the change on the quality of the product. For example:A drug made with a manufacturing change, whether a majormanufacturing change or otherwise, may be distributed only • Evaluation of changes in the impurity or deg-after the holder validates (i.e., assesses) the effects of the radation product profile could first involve pro-change on the identity, strength, quality, purity, and potency filing using appropriate chromatographicof the product as these factors may relate to the safety or techniques and then, depending on the observedeffectiveness of the product (506A(b)). For each change, changes in the impurity profile, toxicology teststhe supplement or annual report must contain informationdetermined by the FDA to be appropriate and must include© 2004 by CRC Press LLCChanges to Approved New Drug Applications or Abbreviated New Drug Applications 5 to qualify a new impurity or degradant or to with appropriate information to support the continued qualify an impurity that is above a previously safety and effectiveness of the product. During the review qualified level. of the Prior Approval Supplement, the FDA will assess the • Evaluation of the hardness or friability of a impact of any adverse effect on the product as it may relate tablet after changes in formulation or manufac- to the safety or effectiveness of the product. turing procedure. • Assessment of the effect of a change on bioequiv- V. COMPONENTS AND COMPOSITION alence when required under 21 CFR part 320 could include, for example, multipoint or multi- Changes in the qualitative or quantitative formulation, media dissolution profiling or an in vivo bioequiv- including inactive ingredients, as provided in the approved alence study. application, are considered major changes and should be • Evaluation of extractables from new packaging filed in a Prior Approval Supplement, unless exempted by components or moisture permeability of a new regulation or guidance (506A(c)(2)(A)). The deletion or container closure system. reduction of an ingredient intended to affect only the color of a product may be reported in an annual report. GuidanceB. EQUIVALENCE on changes in components and composition that may be filed in a Changes Being Effected Supplement or annualWhen testing is performed, the applicant should usually report is not included in this document because of theassess the extent to which the manufacturing change has complexity of these recommendations, but it may be cov-affected the identity, strength, quality, purity, or potency of ered in one or more guidance documents describing post-the drug product. Typically this is accomplished by com- approval changes (e.g., SUPAC documents) test results from prechange and postchange materialand determining whether the test results are equivalent. VI. MANUFACTURING SITESSimply stated: Is the product made after the change equiv-alent to the product made before the change? An exception A. GENERAL CONSIDERATIONSto this general approach is that when bioequivalence shouldbe redocumented for certain ANDA postapproval changes, CDER should be notified about a change to a differentthe comparator should be the reference-listed drug. Equiv- manufacturing site used by an applicant to manufacturealence comparisons frequently require a criterion for com- or process drug products, in-process materials, drug sub-parison with calculation of confidence intervals relative to stances, or drug substance intermediates; package druga predetermined equivalence interval. For this reason, as products; label drug products; or test components, drugwell as for other reasons, “equivalent” does not necessarily product containers, closures, packaging materials, in-mean “identical.” Equivalence may also relate to mainte- process materials, or drug products. Sites include thosenance of a quality characteristic (e.g., stability) rather than owned by the applicant or contract sites used by an appli-a single performance of a test. cant. Testing sites include those performing physical, chemical, biological, and microbiological testing to mon-C. ADVERSE EFFECT itor, accept, or reject materials, as well as those performing stability testing. Sites used to label drug products areSometimes manufacturing changes have an adverse effect considered to be those that perform labeling of the drugon the identity, strength, quality, purity, or potency of the product’s primary or secondary packaging product. In many cases, the applicant chooses not to Sites performing operations that place identifying infor-implement these suboptimal manufacturing changes, but mation on the dosage form itself (e.g., ink imprint on asometimes the applicant wishes to put them into practice. filled capsule) are considered to be facilities that manu-If an assessment concludes that a change has adversely facture or process the drug product. The supplement oraffected the identity, strength, quality, purity, or potency of annual report should identify whether the proposed man-the drug product, the change should be filed in a Prior ufacturing site is an alternative or replacement to thoseApproval Supplement, regardless of the recommended provided for in the approved application.reporting category for the change. For example, a type ofprocess change with a recommended filing category of a A move to a different manufacturing site, when it is aSupplement—Changes Being Effected in 30 Days could type of site routinely subject to FDA inspection, should because a new degradant to be formed that requires qualifi- filed as a Prior Approval Supplement if the site does notcation or identification. However, the applicant’s degrada- have a satisfactory CGMP inspection for the type of oper-tion qualification procedures may indicate that there are no ation being moved. For labeling, secondary packaging, andsafety concerns relating to the new degradant. The applicant testing site changes, the potential for adverse effect on theshould submit this change in a Prior Approval Supplement identity, strength, quality, purity, or potency of a product as these factors may relate to the safety or effectiveness of© 2004 by CRC Press LLC6 Handbook of Pharmaceutical Manufacturing Formulations: Semisolid Productsthe product is considered to be independent of the type of products include modified-release solid oraldrug product dosage form or specific type of operation dosage forms, transdermal systems, liposomalbeing performed. Therefore, the recommended reporting products, depot products, oral and nasal metered-category for any one of these manufacturing site changes dose inhalers, dry powder inhalers, and nasalwill be the same for all types of drug products and opera- spray pumpstions. For manufacturing sites used to manufacture or pro- 4. Transfer of manufacturing of an asepticallycess drug products, in-process materials, drug substances, processed sterile drug substance or asepticallyor drug substance intermediates or perform primary pack- processed sterile drug product to a newly con-aging operations, the potential for adverse effect and, con- structed or refurbished aseptic processing facil-sequently, the recommended reporting category depend on ity or area or to an existing aseptic processingvarious factors such as the type of product and operation facility or area that does not manufacture sim-being performed. For this reason, recommended reporting ilar (including container types and sizes)categories may differ depending on the type of drug prod- approved products; for example, transferringuct and operations. the manufacture of a lyophilized product to an existing aseptic process area where no approved Except for those situations described in Sections lyophilized products are manufactured or whereVI.B.4, VI.C.1.b, and VI.D.5, moving production opera- the approved lyophilized products being man-tions between buildings at the same manufacturing site or ufactured have dissimilar container types orwithin a building, or having construction activities occur sizes to the product being transferredat a manufacturing site, do not have to be reported to 5. Transfer of the manufacture of a finished prod-CDER. A move to a different manufacturing site that uct sterilized by terminal processes to a newlyinvolves other changes (e.g., process, equipment) should constructed facility at a different manufacturingbe evaluated as a multiple related change (see Section XII) site: Once this change has been approved,to determine the appropriate reporting category. subsequent site changes to the facility for sim- ilar product types and processes may be filedB. MAJOR CHANGES (PRIOR APPROVAL SUPPLEMENT) as a Supplement—Changes Being Effected in 30 DaysThe following are examples of changes that are consideredto have substantial potential to have an adverse effect on C. MODERATE CHANGES (SUPPLEMENT—CHANGESthe identity, strength, quality, purity, or potency of a prod- BEING EFFECTED)uct as these factors may relate to the safety or effectivenessof the product. The following are examples of changes that are considered to have a moderate potential to have an adverse effect on 1. A move to a different manufacturing site, the identity, strength, quality, purity, or potency of a prod- except one used to manufacture or process a uct as these factors may relate to the safety or effectiveness drug substance intermediate, when the new of the product. manufacturing site has never been inspected by the FDA for the type of operation that is being The following manufacturing site changes (excluding moved, or the move results in a restart at the changes relating to drug substance intermediate manufac- new manufacturing site of a type of operation turing sites) should be filed in a Prior Approval Supple- that has been discontinued for more than 2 years ment if the new site does not have a satisfactory CGMP inspection for the type of operation being moved (see 2. A move to a different manufacturing site, Sections VI.B.1 and 2). except one used to manufacture or process a drug; substance intermediate, when the new 1. Supplement—Changes Being Effected manufacturing site has not had a satisfactory in 30 Days CGMP inspection for the type of operation being moved a. A move to a different manufacturing site for the manufacture or processing of any drug product, 3. A move to a different manufacturing site for in-process material, or drug substance that is (1) the manufacture, processing, or primary not otherwise provided for in this guidance packaging of drug products when the primary packaging components control the dose deliv- b. For aseptically processed sterile drug substance ered to the patient or when the formulation or aseptically processed sterile drug product, a modifies the rate or extent of availability of the move to an aseptic processing facility or area at drug; or for (2) the manufacture or processing the same or different manufacturing site, except of in-process materials with modified-release as provided for in Section VI.B.4 characteristics; examples of these types of drug© 2004 by CRC Press LLCChanges to Approved New Drug Applications or Abbreviated New Drug Applications 7 c. A move to a different manufacturing site for the VII. MANUFACTURING PROCESS primary packaging of (1) any drug product that is not otherwise listed as a major change and of (2) A. GENERAL CONSIDERATIONS modified-release solid oral dosage–form products The potential for adverse effects on the identity, strength, d. A move to a different manufacturing site for quality, purity, or potency of a drug product as these fac- testing whether (1) the test procedures tors may relate to the safety or effectiveness of the product approved in the application or procedures that depends on the type of manufacturing process and the have been implemented via an annual report changes being instituted for the drug substance or drug are used, (2) all postapproval commitments product. In some cases there may be a substantial potential made by the applicant relating to the test pro- for adverse effect, regardless of direct testing of the drug cedures have been fulfilled (e.g., providing substance or drug product for conformance with the methods validation samples), and (3) the new approved specification. When there is a substantial poten- testing facility has the capability to perform tial for adverse effects, a change should be filed in a Prior the intended testing Approval Supplement.2. Supplement—Changes Being Effected B. MAJOR CHANGES (PRIOR APPROVAL SUPPLEMENT) a. A move to a different manufacturing site for The following are examples of changes that are considered the manufacture or processing of the final to have a substantial potential to have an adverse effect intermediate on the identity, strength, quality, purity, or potency of a product as these factors may relate to the safety or effec-D. MINOR CHANGES (ANNUAL REPORT) tiveness of the product.The following are examples of changes that are considered 1. Changes that may affect the controlled (or mod-to have a minimal potential to have an adverse effect on ified) release, metering, or other characteristicsthe identity, strength, quality, purity, or potency of a prod- (e.g., particle size) of the dose delivered to theuct as these factors may relate to the safety or effectiveness patient, including the addition or deletion of aof the product. code imprint by embossing, debossing, or engrav- ing on a modified-release solid oral dosage form The following manufacturing site changes (excludingchanges relating to drug substance intermediate manufac- 2. Changes that may affect product sterility assur-turing sites) should be filed in a Prior Approval Supple- ance including, where appropriate, processment if the new site does not have a satisfactory CGMP changes for sterile drug substances and sterileinspection for the type of operation being moved (see packaging components, includingSections VI.B.1 and 2). Changes in the sterilization method (e.g., gas, dry heat, irradiation); these include changes 1. A move to a different manufacturing site for from sterile filtered or aseptic processing to secondary packaging terminal sterilization, or vice versa Addition, deletion, or substitution of steriliza- 2. A move to a different manufacturing site for tion steps or procedures for handling sterile labeling materials in an aseptic processing operation Replacing sterilizers that operate by one set of 3. A move to a different manufacturing site for the principles with sterilizers that operate by manufacture or processing of drug substance another principle (e.g., substituting a grav- intermediates, other than the final intermediate ity-displacement steam process with a pro- cess using superheated water spray) 4. A change in the contract sterilization site for Addition to an aseptic processing line of new packaging components when the process is not equipment made of different materials (e.g., materially different from that provided for in stainless steel vs. glass, changes between the approved application, and the facility has a plastics) that will come in contact with ster- satisfactory CGMP inspection for the type of ilized bulk solution or sterile drug compo- operation being performed nents, or deletion of equipment from an aseptic processing line 5. A transfer of the manufacture of a finished Replacing a Class 100 aseptic fill area with a bar- product sterilized by terminal processes to a rier system or isolator for aseptic filling: Once newly constructed building or existing building this change has been approved, subsequent at the same manufacturing site 6. A move to a different manufacturing site for the ink imprinting of solid oral dosage–form products© 2004 by CRC Press LLC8 Handbook of Pharmaceutical Manufacturing Formulations: Semisolid Products process changes for similar product types in the ink as changed is not currently used on the same barrier system or isolator may be CDER-approved products filed as a Supplement—Changes Being 7. Establishing a new procedure for reprocessing Effected in 30 Days a batch of drug substance or drug product that Replacement or addition of lyophilization fails to meet the approved specification equipment of a different size that uses dif- ferent operating parameters or lengthens the C. MODERATE CHANGES (SUPPLEMENT—CHANGES overall process time BEING EFFECTED) Changes from bioburden-based terminal steril- ization to the use of an overkill process, and The following are examples of changes that are considered vice versa to have a moderate potential to have an adverse effect on Changes to aseptic processing methods, includ- the identity, strength, quality, purity, or potency of a prod- ing scale, that extend the total processing, uct as these factors may relate to the safety or effectiveness including bulk storage time, by more than of the product. 50% beyond the validated limits in the approved application 1. Supplement—Changes Being Effected Changes in sterilizer load configurations that in 30 Days are outside the range of previously validated loads a. For drug products, any change in the process, Changes in materials or pore-size rating of fil- process parameters, or equipment, except as ters used in aseptic processing otherwise provided for in this guidance3. The following changes for a natural product: Changes in the virus or adventitious agent b. For drug substances, any change in process or removal or inactivation methods; this is appli- process parameters, except as otherwise pro- cable to any material for which such proce- vided for in this guidance dures are necessary, including drug substance, drug product, reagents, and excipients c. For natural protein drug substances and drug For drug substance and drug product, changes products: in the source material (e.g., microorganism, Any change in the process, process parameters, plant) or cell line or equipment, except as otherwise provided For drug substance and drug product, establish- for in this guidance ment of a new master cell bank or seed An increase or decrease in production scale dur-4. Any fundamental change in the manufacturing ing finishing steps that involves new or dif- process or technology from that currently used ferent equipment by the applicant, for example: Replacement of equipment with that of similar, a. Drug product but not identical, design and operating prin- Dry to wet granulation, or vice versa ciple that does not affect the process method- Change from one type of drying process ology or process operating parameters to another (e.g., oven tray, fluid bed, d. For sterile products, drug substances, and com- microwave) ponents, as appropriate: b. Drug substance Changes in dry heat depyrogenation processes Filtration to centrifugation, or vice versa for glass container systems for products that Change in the route of synthesis of a drug are produced by terminal sterilization pro- substance cesses or aseptic processing5. The following changes for drug substance: Changes to filtration parameters for aseptic pro- Any process change made after the final inter- cessing (including flow rate, pressure, time, mediate processing step in drug substance or volume but not filter materials or pore size manufacture rating) that require additional validation Changes in the synthesis or manufacture of the studies for the new parameters drug substance that may affect its impurity Filtration process changes that provide for a profile or the physical, chemical, or biolog- change from single to dual product steriliz- ical properties ing filters in series, or for repeated filtration6. Addition of an ink code imprint or change to of a bulk or in the ink used for an existing imprint code Changes from one qualified sterilization cham- for a solid oral dosage–form drug product when ber to another for in-process or terminal ster- ilization that results in changes to validated operating parameters (time, temperature, F0 , and others)© 2004 by CRC Press LLCChanges to Approved New Drug Applications or Abbreviated New Drug Applications 9 Changes in scale of manufacturing for terminally VIII. SPECIFICATIONS sterilized products that increase the bulk so- lution storage time by more than 50% beyond A. GENERAL CONSIDERATIONS the validated limits in the approved application when bioburden limits are unchanged All changes in specifications from those in the approved application must be submitted in a Prior Approval Sup- e. For drug substances, redefinition of an interme- plement unless otherwise exempted by regulation or guid- diate, excluding the final intermediate, as a start- ance (506A(c)(2)(A)). ing material Specifications (i.e., tests, analytical procedures, and2. Supplement—Changes Being Effected acceptance criteria) are the quality standards provided in an approved application to confirm the quality of drug a. A change in methods or controls that provides substances, drug products, intermediates, raw materials, increased assurance that the drug substance or reagents, and other components, including container and drug product will have the characteristics of closure systems and in-process materials. For the purpose identity, strength, purity, or potency that it pur- of defining specifications, acceptance criteria are numer- ports to or is represented to possess ical limits, ranges, or other criteria for the tests described. Examples of a test, an analytical procedure, and accep- b. For sterile drug products, elimination of in-pro- tance criteria are an assay, a specific fully described high- cess filtration performed as part of the manu- pressure liquid chromatography procedure, and 98.0%– facture of a terminally sterilized product 102.0%. The recommendations in this section also apply to specifications associated with sterility assurance thatD. MINOR CHANGES (ANNUAL REPORT) are included in NDA and ANDA submissions. A regula- tory analytical procedure is the analytical procedure usedThe following are examples of changes that are considered to evaluate a defined characteristic of the drug substanceto have a minimal potential to have an adverse effect on or drug product. The analytical procedures in the U.S identity, strength, quality, purity, or potency of a prod- Pharmacopeia/National Formulary (USP/NF) are thoseuct as these factors may relate to the safety or effectiveness legally recognized under section 501(b) of the Act as theof the product. regulatory analytical procedures for compendial items. The applicant may include in its application alternative 1. For drug products and protein drug substances, analytical procedures to the approved regulatory proce- changes to equipment of the same design and dure for testing the drug substance and drug product. operating principle or changes in scale, except However, for purposes of determining compliance with as otherwise provided for in this guidance (e.g., the Act, the regulatory analytical procedure is used. In Section VII.C.1.c; see FDA guidance for indus- Sections B–D below, the use of the term “analytical try on the Submission of Documentation for procedure” without a qualifier such as “regulatory” or Sterilization Process Validation in Applications “alternative” refers to analytical procedures used to test for Human and Veterinary Drug Products materials other than the drug substance or drug product. [November 1994]) B. MAJOR CHANGES (PRIOR APPROVAL SUPPLEMENT) 2. A minor change in an existing code imprint for a dosage form; for example, changing from a The following are examples of changes in specifications numeric to alphanumeric code that are considered to have a substantial potential to have an adverse effect on the identity, strength, quality, purity, 3. Addition of an ink code imprint or a change in or potency of a product as these factors may relate to the the ink used in an existing code imprint for a solid safety or effectiveness of the product. oral dosage–form drug product when the ink is currently used on CDER-approved products 1. Relaxing an acceptance criterion, except as otherwise provided for in this guidance (e.g., 4. Addition or deletion of a code imprint by Section VIII.C.1.b) embossing, debossing, or engraving on a solid dosage–form drug product other than a modified- 2. Deleting any part of a specification, except as release dosage form otherwise provided for in this guidance (e.g., Section VIII.D.2) 5. A change in the order of addition of ingredients for solution dosage forms or solutions used in 3. Establishing a new regulatory analytical procedure unit operations (e.g., granulation solutions) 4. A change in a regulatory analytical procedure 6. Changes in scale of manufacturing for terminally that does not provide the same or increased sterilized products that increase the bulk solution assurance of the identity, strength, quality, storage time by no more than 50% beyond the validated limits in the approved application when bioburden limits are unchanged© 2004 by CRC Press LLC10 Handbook of Pharmaceutical Manufacturing Formulations: Semisolid Products purity, or potency of the material being tested intermediates (excluding final intermediate) that as the regulatory analytical procedure described does not provide the same or increased assurance in the approved application of the identity, strength, quality, purity, or potency 5. A change in an analytical procedure used for of the material being tested as the analytical pro- testing components, packaging components, the cedure described in the approved application, final intermediate, in-process materials after the except as provided for in Section VIII.B.6 final intermediate, or starting materials intro- d. Relaxing an in-process acceptance criterion asso- duced after the final intermediate that does not ciated with microbiological monitoring of the provide the same or increased assurance of the production environment, materials, and compo- identity, strength, quality, purity, or potency of nents that are included in NDA and ANDA sub- the material being tested as the analytical proce- missions; for example, increasing the microbio- dure described in the approved application, logical alert or action limits for critical processing except as otherwise noted; for example, a change environments in an aseptic fill facility or increas- from a high-pressure liquid chromatography pro- ing the acceptance limit for bioburden in bulk cedure that distinguishes impurities to one that solution intended for filtration and aseptic filling does not, to another type of analytical procedure (e.g., titrimetric) that does not, or to one that 2. Supplement—Changes Being Effected distinguishes impurities but for which the limit of detection or limit of quantitation is higher a. An addition to a specification that provides 6. Relating to testing of raw materials for viruses increased assurance that the drug substance or or adventitious agents: (1) relaxing an accep- drug product will have the characteristics of tance criteria, (2) deleting a test, or (3) a change identity, strength, purity, or potency that it pur- in the analytical procedure that does not provide ports to or is represented to possess; for exam- the same or increased assurance of the identity, ple, adding a new test and associated analytical strength, quality, purity, or potency of the mate- procedure and acceptance criterion rial being tested as the analytical procedure described in the approved application b. A change in an analytical procedure used for testing components, packaging components, theC. MODERATE CHANGES (SUPPLEMENT—CHANGES final intermediate, in-process materials after the BEING EFFECTED) final intermediate, or starting materials intro- duced after the final intermediate that providesThe following are examples of changes in specifications the same or increased assurance of the identity,that are considered to have a moderate potential to have strength, quality, purity, or potency of the mate-an adverse effect on the identity, strength, quality, purity, rial being tested as the analytical procedureor potency of a product as these factors may relate to the described in the approved applicationsafety or effectiveness of the product. D. MINOR CHANGES (ANNUAL REPORT)1. Supplement—Changes Being Effected in 30 Days The following are examples of changes in specifications that are considered to have a minimal potential to have an a. Any change in a regulatory analytical procedure adverse effect on the identity, strength, quality, purity, or other than editorial or those identified as major potency of a product as these factors may relate to the changes safety or effectiveness of the product. b. Relaxing an acceptance criterion or deleting a 1. Any change in a specification made to comply test for raw materials used in drug substance with an official compendium manufacturing, in-process materials before the final intermediate, starting materials introduced 2. For drug substance and drug product, the addition, before the final drug substance intermediate, or deletion, or revision of an alternative analytical drug substance intermediates (excluding final procedure that provides the same or greater intermediate), except as provided for in Section level of assurance of the identity, strength, qual- VIII.B.6 ity, purity, or potency of the material being tested as the analytical procedure described in c. A change in an analytical procedure used for test- the approved application ing raw materials used in drug substance manu- facturing, in-process materials before the interme- 3. Tightening of acceptance criteria diate, starting materials introduced before the final 4. A change in an analytical procedure used for drug substance intermediate, or drug substance testing raw materials used in drug substance synthesis, starting materials introduced before© 2004 by CRC Press LLCChanges to Approved New Drug Applications or Abbreviated New Drug Applications 11 the final drug substance intermediate, in-process used on the permeable or semipermeable pack- materials before the final intermediate, or drug aging component to one that has never been substance intermediates (excluding final inter- used in a CDER-approved product of the same mediate) that provides the same or increased dosage form, same route of administration, and assurance of the identity, strength, quality, purity, same type of permeable or semipermeable or potency of the material being tested as the packaging component (e.g., low-density poly- analytical procedure described in the approved ethylene, polyvinyl chloride) application 3. A change in the primary packaging components for any product when the primary packaging IX. PACKAGE components control the dose delivered to the patient (e.g., the valve or actuator of a metered-A. GENERAL CONSIDERATIONS dose inhaler) 4. For sterile products, any other change that mayThe potential for adverse effect on the identity, strength, affect product sterility assurance such asquality, purity, or potency of a product as these factors A change from a glass ampule to a glass vialmay relate to the safety or effectiveness of the productwhen making a change to or in the container closure with an elastomeric closuresystem is generally dependent on the route of administra- A change to a flexible container system (bag)tion of the drug product, performance of the containerclosure system, and likelihood of interaction between the from another container systempackaging component and the dosage form. In some cases A change to a prefilled syringe dosage formthere may be a substantial potential for adverse effect,regardless of direct product testing for conformance with from another container systemthe approved specification. A change from a single-unit-dose container to A change to or in a packaging component will often a multiple-dose container systemresult in a new or revised specification for the packaging Changes that add or delete silicone treatmentscomponent. This situation does not have to be considereda multiple related change. Only the reporting category for to container closure systems (such as elas-the packaging change needs to be considered. tomeric closures or syringe barrels) Changes in the size or shape of a container forB. MAJOR CHANGES (PRIOR APPROVAL a sterile drug product SUPPLEMENT) 5. Deletion of a secondary packaging component intended to provide additional protection to theThe following are examples of changes that are considered drug product (e.g., carton to protect from light,to have a substantial potential to have an adverse effect overwrap to limit transmission of moisture oron the identity, strength, quality, purity, or potency of a gases)product as these factors may relate to the safety or effec- 6. A change to a new container closure system iftiveness of the product. the new container closure system does not pro- vide the same or better protective properties 1. For liquid (e.g., solution, suspension, elixir) and than the approved container closure system semisolid (e.g., creams, ointments) dosage forms, a change to or in polymeric materials (e.g., plastic, C. MODERATE CHANGES (SUPPLEMENT—CHANGES rubber) of primary packaging components, when BEING EFFECTED) the composition of the component as changed has never been used in a CDER-approved product The following are examples of changes that are considered of the same dosage form and same route of to have a moderate potential to have an adverse effect on administration; for example, a polymeric material the identity, strength, quality, purity, or potency of a prod- that has been used in a CDER-approved topical uct as these factors may relate to the safety or effectiveness ointment would not be considered CDER- of the product. approved for use with an ophthalmic ointment 1. Supplement—Changes Being Effected 2. For liquid (e.g., solution, suspension, elixir) and in 30 Days semisolid (e.g., creams, ointments) dosage forms in permeable or semipermeable container a. A change to or in a container closure system, closure systems, a change to an ink or adhesive except as otherwise provided for in this guid- ance b. Changes in the size or shape of a container for a sterile drug substance© 2004 by CRC Press LLC12 Handbook of Pharmaceutical Manufacturing Formulations: Semisolid Products2. Supplement—Changes Being Effected approved in the NDA or ANDA for other strengths of the product a. A change in the size or shape of a container for 4. The following changes in the container closure a nonsterile drug product, except for solid dos- system of nonsterile liquid products, as long age forms (see Section IX.D.2 regarding solid as the new package provides the same or better dosage forms) protective properties and any new primary packaging component materials have been b. A change in or addition or deletion of a desiccant used in and been in contact with CDER- approved liquid products with the same routeD. MINOR CHANGES (ANNUAL REPORT) of administration (i.e., the material in contact with a liquid topical should already have beenThe following are examples of changes that are considered used with other CDER-approved liquid topicalto have a minimal potential to have an adverse effect on products):the identity, strength, quality, purity, or potency of a prod- Adding or changing a child-resistant closure,uct as these factors may relate to the safety or effectiveness changing from a metal to plastic screw cap,of the product. or changing from a plastic to metal screw cap Increasing the wall thickness of the container 1. A change in the container closure system for a A change in or addition of a cap liner nonsterile drug product, based on a showing of A change in or addition of a seal (e.g., heat equivalency to the approved system under a induction seal) protocol approved in the application or pub- 5. A change in the container closure system of lished in an official compendium unit-dose packaging (e.g., blister packs) for nonsterile solid dosage form–products, as long 2. A change in the size or shape of a container as the new package provides the same or better containing the same number of dose units, for protective properties and any new primary a nonsterile solid dosage form packaging component materials have been used in and been in contact with CDER-approved 3. The following changes in the container closure products of the same type (e.g., solid oral dos- system of solid oral dosage–form products as age form, rectal suppository) long as the new package provides the same or 6. The following changes in the container closure better protective properties (e.g., light, mois- system of nonsterile semisolid products, as long ture) and any new primary packaging compo- as the new package provides the same or better nent materials have been used in and been in protective properties and any new primary contact with CDER-approved solid oral dos- packaging component materials have been used age–form products: in and been in contact with CDER-approved Adding or changing a child-resistant closure, semisolid products: changing from a metal to plastic screw cap, or Changes in the closure or cap changing from a plastic to metal screw cap Increasing the wall thickness of the container Changing from one plastic container to another A change in or addition of a cap liner of the same type of plastic (e.g., high-density A change in or addition of a seal polyethylene container to another high-den- A change in the crimp sealant sity polyethylene container) 7. A change in the flip seal cap color, as long as the Changes in packaging materials used to control cap color is consistent with any established color- odor (e.g., charcoal packets) coding system for that class of drug products Changes in bottle filler (e.g., change in weight of cotton or amount used) without changes X. LABELING in the type of filler (e.g., cotton to rayon) Increasing the wall thickness of the container A. GENERAL CONSIDERATIONS A change in or addition of a cap liner A change in or addition of a seal (e.g., heat A drug product labeling change includes changes in the induction seal) package insert, package labeling, or container label. An A change in an antioxidant, colorant, stabilizer, applicant should promptly revise all promotional labeling or mold-releasing agent for production of the and drug advertising to make it consistent with any labeling container or closure to one that is used at change implemented in accordance with the regulations. similar levels in the packaging of CDER- approved solid oral dosage–form products A change to a new container closure system when the container closure system is already© 2004 by CRC Press LLCChanges to Approved New Drug Applications or Abbreviated New Drug Applications 13All labeling changes for ANDA products must be consis- D. MINOR CHANGES (ANNUAL REPORT)tent with section 505(j) of the Act. Labeling with editorial or similar minor changes or withB. MAJOR CHANGES (PRIOR APPROVAL SUPPLEMENT) a change in the information concerning the description of the drug product or information about how the drug isAny proposed change in the labeling, except those that supplied that does not involve a change in the dosageare designated as moderate or minor changes by regulation strength or dosage form should be described in an annualor guidance, should be submitted as a Prior Approval report. The following list includes some examples that areSupplement. The following list contains some examples currently considered by CDER to fall into this reportingof changes that are currently considered by CDER to fall this reporting category. 1. Changes in the layout of the package or con- 1. Changes based on postmarketing study results, tainer label that are consistent with FDA regu- including, but not limited to, labeling changes lations (e.g., 21 CFR part 201) without a change associated with new indications and usage in the content of the labeling 2. Change in, or addition of, pharmacoeconomic 2. Editorial changes, such as adding a distributor’s claims based on clinical studies name 3. Changes to the clinical pharmacology or the 3. Foreign language versions of the labeling, if no clinical study section reflecting new or modified change is made to the content of the approved data labeling and a certified translation is included 4. Changes based on data from preclinical studies 4. Labeling changes made to comply with an offi- 5. Revision (expansion or contraction) of popula- cial compendium tion based on data XI. MISCELLANEOUS CHANGES 6. Claims of superiority to another product 7. Change in the labeled storage conditions, unless A. MAJOR CHANGES (PRIOR APPROVAL SUPPLEMENT) exempted by regulation or guidance The following are examples of changes that are considered to have a substantial potential to have an adverse effectC. MODERATE CHANGES (SUPPLEMENT—CHANGES on the identity, strength, quality, purity, or potency of a BEING EFFECTED) product as these factors may relate to the safety or effec- tiveness of the product.A Changes Being Effected Supplement should be submit-ted for any labeling change that adds or strengthens a 1. Changes requiring completion of studies incontraindication, warning, precaution, or adverse reaction; accordance with 21 CFR part 320 to demonstrateadds or strengthens a statement about drug abuse, depen- equivalence of the drug to the drug as manu-dence, psychological effect, or overdosage; adds or factured without the change or to a reference-strengthens an instruction about dosage and administra- listed drug (506A(c)(2)(B))tion that is intended to increase the safe use of the product;deletes false, misleading, or unsupported indications for 2. Addition of a stability protocol or comparabilityuse or claims for effectiveness; or is specifically requested protocolby the FDA. The submission should include 12 copies offinal printed labeling. The following list includes some 3. Changes to an approved stability protocol orexamples of changes that are currently considered by comparability protocol unless otherwise providedCDER to fall into this reporting category. for in this guidance (e.g., VIII.C, VIII.D, XI.C.2) 1. Addition of an adverse event because of infor- 4. An extension of an expiration dating period mation reported to the applicant or agency based on data obtained under a new or revised stability testing protocol that has not been 2. Addition of a precaution arising out of a post- approved in the application or on full shelf-life marketing study data on pilot-scale batches using an approved protocol 3. Clarification of the administration statement to ensure proper administration of the product B. MODERATE CHANGES (SUPPLEMENT—CHANGES BEING EFFECTED) 4. Labeling changes, normally classified as major changes, that the FDA specifically requests be The following are examples of changes that are considered implemented using a Changes Being Effected to have a moderate potential to have an adverse effect on Supplement the identity, strength, quality, purity, or potency of a product© 2004 by CRC Press LLC14 Handbook of Pharmaceutical Manufacturing Formulations: Semisolid Productsas these factors may relate to the safety or effectiveness individual changes differ, CDER recommends that theof the product. filing be in accordance with the most restrictive of those reporting categories recommended for the individual1. Supplement—Changes Being Effected changes. When the multiple related changes all have the in 30 Days same recommended reporting category, CDER recom- mends that the filing be in accordance with the reporting a. Reduction of an expiration dating period to pro- category for the individual changes. For the purposes of vide increased assurance of the identity, strength, determining the reporting category for moves between quality, purity, or potency of the drug product; buildings, the terms “different manufacturing site” and extension of an expiration date that has previously “same manufacturing site” are defined as follows. Same been reduced under this provision should be manufacturing site: The new and old buildings are filed in a Supplement—Changes Being Effected included under the same drug establishment registration in 30 Days even if it is based on data obtained number, and the same FDA district office is responsible under a protocol approved in the application for inspecting the operations in both the new and old buildings. Different manufacturing site: The new and old2. Supplement—Changes Being Effected buildings have different drug establishment registration numbers, or different FDA district offices are responsible a. No changes have been identified. for inspecting operations in the new and old building.C. MINOR CHANGES (ANNUAL REPORT) The change to a different manufacturing site should be filed in a Prior Approval Supplement when the newThe following are examples of changes that are considered manufacturing site has never been inspected by the FDAto have a minimal potential to have an adverse effect on for the type of operation being moved, the move resultsthe identity, strength, quality, purity, or potency of a prod- in a restart at the new manufacturing site of a type ofuct as these factors may relate to the safety or effectiveness operation that has been discontinued for more than 2of the product. years, or the new manufacturing site does not have a satisfactory CGMP inspection for the type of operation 1. An extension of an expiration dating period being moved. based on full shelf-life data on full production batches obtained under a protocol approved in Examples of postapproval manufacturing site changes the application and filing consequences include: 2. Addition of time points to the stability protocol • An applicant wants to move the manufacture of or deletion of time points beyond the approved an immediate-release tablet to a different man- expiration dating period ufacturing site that currently manufactures, and has satisfactory CGMP status for, capsules and 3. A change from previously approved stability powders for oral solution. This manufacturing storage conditions to storage conditions recom- site change should be filed in a Prior Approval mended in International Conference on Har- Supplement because the new manufacturing monisation (ICH) guidances site does not have a satisfactory CGMP inspec- tion for immediate-release tablets. 4. Non-USP reference standards: Replacement of an in-house reference standard • An applicant wants to contract out his or her or reference panel (or panel member) packaging operations for immediate-release tab- according to procedures in an approved lets and capsules and modified-release capsules. application The potential contract packager has a satisfactory Tightening of acceptance criteria for existing CGMP status for immediate-release and modi- reference standards to provide greater assur- fied-release capsules but has never packaged ance of product purity and potency immediate-release tablets. The packaging site change for the immediate-release tablet products XII. MULTIPLE RELATED CHANGES should be filed in a Prior Approval Supplement. The packaging site change for the capsule prod-Multiple related changes involve various combinations of ucts should be filed as recommended in sectionindividual changes. For example, a site change may also VI of this guidance for packaging sites with ainvolve equipment and manufacturing process changes, satisfactory CGMP a components and composition change may necessitatea change in a specification. For multiple related changes • An applicant wishes to consolidate his or herfor which the recommended reporting categories for the product testing to a single analytical laboratory at a manufacturing site. This manufacturing site© 2004 by CRC Press LLCChanges to Approved New Drug Applications or Abbreviated New Drug Applications 15 produces various solid oral dosage–form prod- GLOSSARY ucts, has an operational analytical laboratory currently at the site, and has satisfactory CGMP Acceptance Criteria—Numerical limits, ranges, or other inspections for the manufacturing occurring at criteria for the tests described the facility. Some of the products that will be Active Ingredient/Drug Substance—Any component that tested at the analytical laboratory when the con- is intended to furnish pharmacological activity or other solidation occurs are not solid oral dosage form direct effect in the diagnosis, cure, mitigation, treatment, or products. Unlike most other production opera- prevention of a disease, or to affect the structure or any tions, testing laboratories are not inspected on function of the human body, but does not include interme- a dosage form/type of drug substance-specific diates used in the synthesis of such ingredient, including basis. The satisfactory CGMP inspection of the those components that may undergo chemical change in the analytical laboratory, which was performed as manufacture of the drug product and are present in the drug part of the CGMP inspection for manufacture product in a modified form intended to furnish the specified of the solid oral dosage form products, is con- activity or effect (21 CFR 210.3(b)(7) and 314.3) sidered to apply to all dosage forms, including Component—Any ingredient intended for use in the man- those not actually produced at the site. ufacture of a drug product, including those that may not appear in such drug product (21 CFR 210.3(b)(3))Different reporting categories are proposed for changes to Container Closure System—The sum of packaging com-or the addition of certain components based on whether the ponents that together contain and protect the dosage form;component/material has been used in and has been in con- this includes primary packaging components and second-tact with CDER-approved products. Different reporting cat- ary packaging components, if the latter are intended toegories are recommended once CDER has reviewed certain provide additional protection to the drug productcomponents/materials in association with a product Drug Product—A finished dosage form, for example,approval because similar subsequent changes then have a tablet, capsule, or solution, that contains an active ingre-reduced potential to have an adverse effect on the identity, dient, generally, but not necessarily, in association withstrength, quality, purity, or potency of a product as they may inactive ingredients (21 CFR 210.3(b)(4))relate to the safety or effectiveness of the product. For Final Intermediate—The last compound synthesizedexample, certain changes in the container closure systems before the reaction that produces the drug substance. Theof solid oral dosage form products may be included in the final step forming the drug substance must involve cova-annual report, as long as the new package provides the lent bond formation or breakage; ionic bond formationsame or better protective properties and any new primary (i.e., making the salt of a compound) does not qualify. Aspackaging component materials have been used in and been a consequence, when the drug substance is a salt, thein contact with CDER-approved solid oral dosage–form precursors to the organic acid or base, rather than the acidproducts (see Section IX.D.3). If the primary packaging or base itself, should be considered the final intermediatecomponent material has not been used in or has not been Inactive Ingredients—Any intended component of thein contact with CDER-approved solid oral dosage–form drug product other than an active ingredientproducts, then submission of the change in an annual In-Process Material—Any material fabricated, compoun-report is not recommended. CDER-approved products are ded, blended, or derived by chemical reaction that is pro-considered those subject to an approved NDA or ANDA. duced for, and used in, the preparation of the drug productWhen information is not available, an applicant should use (21 CFR 210.3(b)(9)). For drug substance, in-processreliable sources of information to determine that the com- materials are considered those materials that are undergo-ponent or material has been used in and has been in contact ing change (e.g., molecular, physical)with a CDER-approved product of the same dosage form Intermediate—A material produced during steps of theand route of administration, as appropriate. The applicant synthesis of a drug substance that must undergo furthershould identify in the supplement or annual report the basis molecular change before it becomes a drug substancefor the conclusion that the component or material is used Package—The container closure system and labeling, asso-in a CDER-approved product. ciated components (e.g., dosing cups, droppers, spoons), and external packaging (e.g., cartons, shrink wrap) If an applicant cannot confirm that a component or Packaging Component—Any single part of a containermaterial has been used in and has been in contact with a closure systemCDER-approved product of the same dosage form and route Primary Packaging Component—A packaging compo-of administration, the applicant has the option of filing the nent that is or may be in direct contact with the dosagechange for a single NDA or ANDA, using the higher rec- formommended reporting category and, after approval, filing Reference-Listed Drug—The listed drug identified bysimilar subsequent changes for other NDAs and ANDAs, the FDA as the drug product on which an applicant reliesusing the lower recommended reporting category.© 2004 by CRC Press LLC16 Handbook of Pharmaceutical Manufacturing Formulations: Semisolid Productsin seeking approval of its abbreviated application (21 in the reference entitled A Handbook for Requesting Infor-CFR 314.3) mation and Records from FDA. An electronic version of thisSatisfactory CGMP Inspection—A satisfactory CGMP reference is available on the Internet at is an FDA inspection during which no objection- opacom/backgrounders/ conditions or practices were found during (No Action Secondary Packaging Component—A packaging com-Indicated), or an inspection during which objectionable con- ponent that is not and will not be in direct contact withditions were found, but corrective action is left to the firm the dosage formto take voluntarily, and the objectionable conditions will not Specifications—The quality standards (i.e., tests, analyt-be the subject of further administrative or regulatory actions ical procedures, and acceptance criteria) provided in an(Voluntary Action Indicated). Information about the CGMP approved application to confirm the quality of drug sub-status of a firm may be obtained by requesting a copy of the stances, drug products, intermediates, raw materials,Quality Assurance Profile (QAP) from the FDA’s Freedom reagents, and other components including container clo-of Information (FOI) Office. The QAP reports information sure systems and in-process materialson the CGMP compliance status of firms that manufacture,package, assemble, repack, relabel, or test human drugs, Validate the Effects of the Change—To assess thedevices, biologics, and veterinary drugs. All FOI requests effect of a manufacturing change on the identity, strength,must be in writing and should follow the instructions found quality, purity, or potency of a drug as these factors relate to the safety or effectiveness of the drug© 2004 by CRC Press LLC2 Postapproval Changes to Semisolid DrugsTo ensure continuing product quality and performance dating period, according to the approved proto-characteristics of the semisolid topical formulations, reg- col, on either the first or first three (see belowulatory approvals are required for changes to for details) production batches and to report the results in subsequent annual reports. 1. Components or composition 2. Manufacturing (process and equipment) Definition of level 1 changes are those that are unlikely 3. Scale up/scale down of manufacture to have any detectable effect on formulation quality and 4. Site of manufacture of a semisolid formulation performance. Examples: during the postapproval period A. Deletion or partial deletion of an ingredient intended to affect the color, fragrance, or flavorIt is important to define of the drug product. 1. The levels of change B. Any change in an excipient up to 5% of 2. Recommended chemistry, manufacturing, and approved amount of that excipient. The total additive effect of all excipient changes should controls tests to support each level of change not be more than 5%. Changes in the compo- 3. Recommended in vitro release tests or in vivo sition should be based on the approved target composition and not on previous level 1 bioequivalence tests to support each level of changes in the composition. A change in diluent change (q.s. excipient) caused by component and com- 4. Documentation to support the change position changes in excipient may be made and is excluded from the 5% change limit.The effect that scale-up and postapproval changes mayhave on the stability of the drug product should be eval- C. Change in a supplier of a structure forminguated. For general guidance on conducting stability stud- excipient that is primarily a single chemicalies, see the FDA Guideline for Submitting Documentation entity (purity 95%) or change in a supplier orfor the Stability of Human Drugs and Biologics. For scale- technical grade of any other and postapproval changes submissions, the followingpoints should also be considered: Definition of level 2 changes are those that could have a significant effect on formulation quality and performance. A. In most cases, except those involving scale up, Examples: stability data from pilot scale batches will be acceptable to support the proposed change. A. Changes of >5% and <10% of approved amount of an individual excipient; the total B. Where stability data show a trend toward additive effect of all excipient changes should potency loss or degradant increase under not be more than 10% accelerated conditions, it is recommended that historical accelerated stability data from a rep- B. Changes in the composition should be based resentative prechange batch be submitted for on the approved target composition and not on comparison. It is also recommended that under previous level 1 or level 2 changes in the com- these circumstances, all available long-term position data on test batches from ongoing studies be provided in the supplement. Submission of C. Changes in diluent (q.s. excipient) caused by historical accelerated and available long-term component and composition changes in excip- data would facilitate review and approval of ients are acceptable and are excluded from the the supplement. 10% change limit C. A commitment should be included to conduct D. Change in supplier of a structure forming long-term stability studies through the expiration excipient not covered under level 1© 2004 by CRC Press LLC18 Handbook of Pharmaceutical Manufacturing Formulations: Semisolid Products E. Change in the technical grade of structure- changes should be properly validated and may be inspected forming excipient by appropriate agency personnel. Level 1 changes in batch size are those up to and including a factor of 10 times the F. Change in particle size distribution of the drug size of the pivotal clinical trial or biobatch, where the substance if the drug is in suspension equipment used to produce the test batch or batches is of the same design and operating principles, the batch orDefinition of level 3 changes are those that are likely to batches are manufactured in full compliance with currenthave a significant effect on formulation quality and per- good manufacturing practice (CGMPs), and the same stan-formance. Examples: dard operating procedures (SOPs) and controls, as well as the same formulation and manufacturing procedures, are A. Any qualitative and quantitative changes in an used on the test batch or batches and on the full-scale excipient beyond the ranges noted in level 2 production batch or batches. Level 2 changes in batch size change. are those from beyond a factor of 10 times the size of the pivotal clinical trial or biobatch, where the equipment used B. Change in crystalline form of the drug sub- to produce the test batch or batches is of the same design stance, if the drug is in suspension and operating principles, the batch or batches is manufac- tured in full compliance with CGMPs, and the same SOPs I. PRESERVATIVE and controls, as well as the same formulation and manu- facturing procedures, are used on the test batch or batchesFor semisolid products, any change in the preservative and on the full-scale production batch or batches. No levelmay affect the quality of the product. If any quantitative 3 changes are anticipated in this qualitative changes are made in the formulation, addi-tional testing should be performed. No in vitro release IV. MANUFACTURING SITEdocumentation or in vivo bioequivalence documentationis needed for preservative changes. Manufacturing site changes consist of changes in location in the site of manufacture, packaging and filling opera- II. MANUFACTURING CHANGES tions, or testing for both company-owned and contract manufacturing facilities, and they do not include any otherManufacturing changes may affect both equipment used level 2 or 3 changes; for example, changes in scale, man-in the manufacturing process and the process itself. A level ufacturing (including process or equipment), and compo-1 change is a change from nonautomated or nonmechan- nents or composition. New manufacturing locationsical equipment to automated or mechanical equipment to should have had a satisfactory CGMP inspection withintransfer ingredients or a change to alternative equipment the past 2 years. A stand-alone analytical testing labora-of the same design and operating principles. A level 2 tory site change may be submitted as a Changes Beingchange is a change in equipment to a different design or Effected Supplement if the new facility has a current anddifferent operating principles or a change in type of mixing satisfactory CGMP compliance profile with the FDA forequipment, such as high shear to low shear and vice versa. the type of testing operation in question. The supplementNo level 3 changes are anticipated in this category. should contain a commitment to use the same test methods employed in the approved application, written certification III. PROCESS from the testing laboratory stating that they are in con- formance with CGMPs, and a full description of the test-Level 1 changes include changes such as rate of mixing, ing to be performed by the testing lab. If the facility hasmixing times, operating speeds, and holding times within not received a satisfactory CGMP inspection for the typeapproved application ranges, in addition to the order of of testing involved, a prior approval supplement is recom-addition of components (excluding actives) to either the mended. No stability data are needed for a change in aoil or water phase. Level 2 changes include changes such stand-alone analytical facility. Level 1 changes consist ofas rate of mixing, mixing times, rate of cooling, operating site changes within a single facility where the same equip-speeds, and holding times outside approved application ment, SOPs, environmental conditions (e.g., temperatureranges for all dosage forms in addition to any changes in and humidity) and controls, and personnel common tothe process of combining the phases. No level 3 changes both manufacturing sites are used, and where no changesare anticipated in this category. are made to the manufacturing batch records, except for administrative information and the location of the facility.Batch Size (Scale Up or Down) “Common” is defined as employees already working on the campus who have suitable experience with the manufacturingThe minimum batch size for the NDA pivotal clinical trialbatch or the ANDA/AADA biobatch is at least 100 kg or10% of a production batch, whichever is larger. All scale© 2004 by CRC Press LLCPostapproval Changes to Semisolid Drugs 19process. Level 2 changes consist of site changes within a same original contiguous site or where the facilities arecontiguous campus, or between facilities in adjacent city not in adjacent city blocks. To qualify as a level 3 change,blocks, where similar equipment, SOPs, environmental similar equipment, SOPs, environmental conditions, andconditions (e.g., temperature and humidity) and controls, controls should be used in the manufacturing process atand personnel common to both manufacturing sites are the new site. Changes should not be made to the manu-used, and where no changes are made to the manufacturing facturing batch records except when consistent with otherbatch records, except for administrative information and level 1 changes. Administrative information, location, andthe location of the facility. Level 3 changes consist of a language translation may be revised as needed. Anysite change in manufacturing site to a different campus. change to a new contract manufacturer also constitutes aA different campus is defined as one that is not on the level 3 change.© 2004 by CRC Press LLC3 Scale-Up and Postapproval Changes for Nonsterile Semisolid Dosage Forms: Manufacturing Equipment I. INTRODUCTION II. PARTICLE SIZE REDUCTION AND SEPARATIONAny equipment changes should be validated in accordancewith current good manufacturing practices (CGMPs). The A. DEFINITIONSresulting data will be subject to examination by field inves-tigators during routine GMP inspections. The information 1. Unit Operationshere is presented in broad categories of unit operation(particle size reduction or separation, mixing, emulsifica- a. Particle Size Reductiontion, deaeration, transfer, and packaging). Particle size reduction is the mechanical process of break- ing particles into smaller pieces via one or more size- Under scale-up and postapproval changes (semi- reduction mechanisms. The mechanical process used issolid) (SUPAC-SS), equipment within the same class and generally referred to as milling.subclass are considered to have the same design andoperating principle. For example, a change from a plan- i. Particleetary mixer from manufacturer A to another planetary A particle is either a discrete crystal or a grouping ofmixer from manufacturer B would not represent a change crystals, generally known as an design or operating principle and would be consideredthe same. ii. Particle Size Reduction Mechanisms A change from equipment in one class to equipment • Impact—Particle size reduction caused by apply-in a different class would usually be considered a change ing an instantaneous force perpendicular to thein design and operating principle. For example, a change particle or agglomerate surface; the force canfrom a planetary mixer to a dispersator mixer demon- result from particle-to-particle or particle-to-millstrates a change in operating principle from low-shear surface collisionconvection mixing to high-shear convection mixing. Thesetypes of equipment would be considered different under • Attrition—Particle size reduction by applyingSUPAC-SS. force parallel to the particle surface Applicants should carefully consider and evaluate on • Compression—Particle size reduction by applyinga case-by-case basis changes in equipment that are in a force slowly (as compared with impact) to thethe same class but different subclasses. In many situa- particle surface toward the center of the particletions, these changes in equipment would be consideredsimilar. For example, in Section III, Mixing, under the • Cutting—Particle size reduction by applying aconvection mixers, low shear, a change from an impeller shearing force to a materialmixer (subclass) to a planetary mixer (subclass) repre-sents a change within a class and between subclasses. b. Particle SeparationProvided the manufacturing process with the new equip- Particle separation is particle size classification accordingment is validated, this change would likely not need a to particle size alone.Changes Being Effected (CBE) Supplement. At the timeof such a change the applicant should have available the 2. Operating Principlesscientific data and rationale used to make this determi-nation. It is up to the applicant to determine the filing a. Fluid Energy Millingcategory. Fluid energy milling is particle size reduction by high- speed particle-to-particle impact or attrition (also known as micronizing).© 2004 by CRC Press LLC22 Handbook of Pharmaceutical Manufacturing Formulations: Semisolid Productsb. Impact Milling 4. Compression MillsParticle size reduction by high-speed mechanical impactor impact with other particles (also known as milling, Although compression mills, also known as roller mills,pulverizing, or comminuting) is known as impact milling. can differ in whether one or both surfaces move, no com- pression mill subclasses have been identified.c. CuttingCutting is particle size reduction by mechanical shearing. 5. Screening Millsd. Compression Milling Screening mill subclasses primarily differ in the rotatingParticle size reduction by compression stress and shear element.between two surfaces is known as compression milling. • Oscillating bare. Screening • Rotating impellerParticle size reduction by mechanically induced attrition • Rotating screenthrough a screen (commonly referred to as milling ordeagglomeration) is called screening. 6. Tumbling Millsf. Tumble Milling Tumbling mill subclasses primarily differ in the grindingTumble milling is particle size reduction by attrition, using media used and whether the mill is vibrated.grinding media. • Ball mediag. Separating • Rod mediaParticle segregation based on size alone, without any sig- • Vibratingnificant particle size reduction (commonly referred to asscreening or bolting), is also known as separating. 7. SeparatorsB. EQUIPMENT CLASSIFICATIONS Separator subclasses primarily differ in the mechanical means used to induce particle movement.1. Fluid Energy Mills • CentrifugalFluid energy mill subclasses have no moving parts and • Vibratory or shakerprimarily differ in the configuration or shape of theirchambers, nozzles, and classifiers. Please note that if a single piece of equipment is capable of performing multiple discrete unit operations, it has been • Fixed target evaluated solely for its ability to affect particle size or • Fluidized bed separation. • Loop or oval • Moving target III. MIXING • Opposed jet • Opposed jet with dynamic classifier A. DEFINITIONS • Tangential jet 1. Unit Operation2. Impact Mills Mixing is the reorientation of particles relative to oneImpact mill subclasses primarily differ in the configura- another to achieve uniformity or randomness. This processtion of the grinding heads, chamber grinding liners (if can include wetting of solids by a liquid phase, dispersionany), and classifiers. of discrete particles, or deagglomeration into a continuous phase. Heating and cooling via indirect conduction may • Cage be used in this operation to facilitate phase mixing or • Hammer air swept stabilization. • Hammer conventional • Pin or disc 2. Operating Principles3. Cutting Mills a. Convection Mixing, Low Shear Convection mixing, low shear, is a mixing process with aAlthough cutting mills can differ in whether the knives repeated pattern of cycling material from top to bottom inare movable or fixed, and in classifier configuration, no which dispersion occurs under low power per unit masscutting mill subclasses have been identified. through rotating low shear forces.© 2004 by CRC Press LLCScale-Up and Postapproval Changes for Nonsterile Semisolid Dosage Forms: Manufacturing Equipment 23b. Convection Mixing, High Shear imparted to the mixture (axial-flow propeller or radial-Convection mixing, high shear, is a mixing process with flow turbines), no subclasses have been defined.a repeated pattern of cycling material from top to bottomin which dispersion occurs under high power per unit mass IV. TRANSFERthrough rotating high shear forces. A. DEFINITIONSc. Roller Mixing (Milling) 1. Unit OperationAlso known as milling, roller mixing is a mixing processby high mechanical shearing action where compression Transfer is the controlled movement or transfer of mate-stress is achieved by passing material between a series of rials from one location to another.rotating rolls. This is commonly referred to as compres-sion or roller milling. 2. Operating Principlesd. Static Mixing a. PassiveIn static mixing, material passes through a tube with sta- Passive transfer is the movement of materials across ationary baffles. The mixer is generally used in conjunction nonmechanically induced pressure gradient, usuallywith an in-line pump. through a conduit or pipe.B. EQUIPMENT CLASSIFICATION b. Active The movement of materials across a mechanically induced1. Convection Mixers, Low Shear pressure gradient, usually through conduit or pipe, is known as active transfer.This group of mixers normally operates under low shearconditions and is broken down by impeller design and B. EQUIPMENT CLASSIFICATIONmovement. Design can also include a jacketed vessel tofacilitate heat transfer. 1. Low Shear • Anchor or sweepgate Equipment used for active or passive material transfer, • Impeller with a low degree of induced shear, is classified as “low- • Planetary shear” equipment:2. Convection Mixers, High Shear • Diaphragm • GravityThese mixers normally operate only under high-shear • Peristalticconditions. Subclasses are differentiated by how the high • Pistonshear is introduced into the material, such as by a dis- • Pneumaticpersator with serrated blades or homogenizer with rotor • Rotating lobestator. • Screw or helical screw • Dispersator • Rotor stator3. Roller Mixers (Mills) 2. High ShearNo roller mixer subclasses have been identified. Active or mechanical material transfer with a high degree of induced shear is performed by what is known as “high-4. Static Mixers shear” equipment:No static mixer subclasses have been identified. • Centrifugal or turbine Please note that if a single piece of equipment is • Piston • Rotating gearcapable of performing multiple discrete unit operations,it has been evaluated solely for its ability to mix materials. A single piece of equipment can be placed in either a low- or high-shear class, depending on its operating parameters.5. Low-Shear Emulsifiers If a single piece of equipment is capable of performing multiple discrete unit operations, the unit has been eval-Although low-shear emulsification equipment (mechani- uated solely for its ability to transfer stirrers or impellers) can differ in the type of fluid flow© 2004 by CRC Press LLC24 Handbook of Pharmaceutical Manufacturing Formulations: Semisolid Products V. PACKAGING based on an auger, gear, orifice, peristaltic, or piston pump. A head-space blanketing system can also be used.A. DEFINITIONS d. Sealing1. Unit Operation Primary packages can be sealed using a variety of meth- ods, including conducted heat and electromagnetic (induc-a. Holding tion or microwave) or mechanical manipulation (crimpingThe process of storing product after completion of man- or torquing).ufacturing process and before filling final primary packsis known as holding. B. EQUIPMENT CLASSIFICATIONb. Transfer 1. HoldersTransfer is the process of relocating bulk finished productfrom holding to filling equipment using pipe, hose, pumps, Although holding vessels can differ in their geometry andor other associated components. ability to control temperature or agitation, their primary differences are based on how materials are fed. Feedingc. Filling devices include the following:Filling is the delivery of target weight or volume of bulkfinished product to primary pack containers. • Auger • Gravityd. Sealing • Pneumatic (nitrogen, air, etc.)A device or process for closing or sealing primary packcontainers, known collectively as sealing, follows the fill- 2. Fillersing process. The primary differences in filling equipment are based on2. Operating Principles how materials are metered. Different varieties of filling equipment include the following:a. HoldingThe storage of liquid, semisolids, or product materials in • Augera vessel that may or may not have temperature control or • Gear pumpagitation is called holding. • Orifice • Peristaltic pumpb. Transfer • PistonThe controlled movement or transfer of materials fromone location to another is known as transfer. 3. Sealersc. Filling The differences in primary container sealing are based onFilling operating principles involve several associated how energy is transferred or applied. Energy transfer cansubprinciples. The primary package can be precleaned be accomplished via the following:to remove particulates or other materials by the use ofionized air, vacuum, or inversion. A holding vessel equipped • Heatwith an auger, gravity, or pressure material feeding system • Inductionshould be used. The vessel may or may not be able to control • Microwavetemperature or agitation. Actual filling of the dosage form • Mechanical or crimpinginto primary containers can involve a metering system • Torque© 2004 by CRC Press LLC4 Stability Testing of Drug Substances and Drug Products I. INTRODUCTION II. STABILITY TESTING FOR NEW DRUG APPLICATIONSThere are specific regulatory recommendations regardingthe design, conduct, and use of stability studies that should A. DRUG SUBSTANCEbe performed to support Information on the stability of a drug substance under • Investigational new drug applications (INDs) defined storage conditions is an integral part of the sys- (21 CFR 312.23(a)(7)) tematic approach to stability evaluation. Stress testing helps to determine the intrinsic stability characteristics of • New drug applications (NDAs) for both new a molecule by establishing degradation pathways to iden- molecular entities and non–new molecular enti- tify the likely degradation products and to validate the ties, new dosage forms (21 CFR 314.50(d)(1)) stability, indicating the power of the analytical procedures used. • Abbreviated new drug applications (ANDAs) (21 CFR 314.92–314.99) Stress testing is conducted to provide data on forced decomposition products and decomposition mechanisms • Supplements and annual reports (21 CFR for the drug substance. The severe conditions that may be 314.70, and 601.12) encountered during distribution can be covered by stress testing of definitive batches of the drug substance. These • Biologics license application (BLAs) and prod- studies should establish the inherent stability characteris- uct license applications (PLAs) (21 CFR 601.2) tics of the molecule, such as the degradation pathways, and lead to identification of degradation products and Given below is a comprehensive description of the hence support the suitability of the proposed analyticalprinciple established in International Conference on Har- procedures. The detailed nature of the studies will dependmonisation (ICH) Q1A—that information on stability on the individual drug substance and type of drug product.generated in any one of the three areas of the EuropeanUnion, Japan, and the U.S. would be mutually acceptable This testing is likely to be carried out on a single batchin both of the other two areas. Also included here is a of a drug substance. Testing should include the effects ofdiscussion of biological products and products submitted temperatures in 10°C increments above the acceleratedto the Center for Biologics Evaluation and Research temperature test condition (e.g., 50°, 60°C) and humidity,(CBER). (Note that effective July 2003, the U.S. Food and where appropriate (e.g., 75% or greater). In addition, oxi-Drug Administration has transferred several therapeutic dation and photolysis on the drug substance plus its sus-proteins to the Center for Drug Evaluation and Research ceptibility to hydrolysis across a wide range of pH values[CDER] from CBER.) when in solution or suspension should be evaluated. Results from these studies will form an integral part of Given below are recommendations for the design of the information provided to regulatory authorities. Lightstability studies for drug substances and drug products that testing should be an integral part of stress testing. Theshould result in a statistically acceptable level of confi- standard test conditions for photostability are discussed indence for the established retest or expiration dating period the ICH Q1B each type of application. The applicant is responsiblefor confirming the originally established retest and expi- It is recognized that some degradation pathways canration dating periods by continual assessment of stability be complex and that under forced conditions, decomposi-properties (21 CFR 211.166). Continuing confirmation of tion products may be observed that are unlikely to bethese dating periods should be an important consideration formed under accelerated or long-term testing. This infor-in the applicant’s stability program. The choice of test mation may be useful in developing and validating suitableconditions defined in this guidance is based on an analysis analytical methods, but it may not always be necessary toof the effects of climatic conditions in the European examine specifically for all degradation products if it hasUnion, Japan, and the U.S. The mean kinetic temperature been demonstrated that, in practice, these decompositionin any region of the world can be derived from climatic products are not (Grimm, W., Drugs Made in Germany, 28:196–202,1985, and 29:39–47, 1986). [ICH Q1A] 25© 2004 by CRC Press LLC26 Handbook of Pharmaceutical Manufacturing Formulations: Semisolid Products Primary stability studies are intended to show that a particular, temperature-sensitive drug substances should bedrug substance will remain within specifications during stored under an alternative lower-temperature condition,the retest period if stored under recommended storage which will then become the designated long-term testingconditions. [ICH Q1A] storage temperature. The 6-month accelerated testing should then be carried out at a temperature at least 15°C above this1. Selection of Batches designated long-term storage temperature (together with the appropriate relative humidity conditions for that tempera-Stability information from accelerated and long-term test- ture). The designated long-term testing conditions will being should be provided on at least three batches. Long- reflected in the labeling and retest date. [ICH Q1A]term testing should cover a minimum of 12 months’ dura-tion on at least three batches at the time of submission. Where significant change occurs during 6 months ofThe batches manufactured to a minimum of pilot-plant storage under conditions of accelerated testing at 40° ±scale should be formed by the same synthetic route and 2°C/75% RH ± 5%, additional testing at an intermediateuse a method of manufacture and procedure that simulates condition (such as 30° ± 2°C/60% RH ± 5%) should bethe final process to be used on a manufacturing scale. The conducted for a drug substance to be used in the manufac-overall quality of the batches of drug substance placed on ture of a dosage form tested for long-term at 25° ± 2°C/60%stability should be representative of both the quality of RH ± 5%, and this information should be included in thethe material used in preclinical and clinical studies and drug application. The initial drug application should includethe quality of material to be made on a manufacturing at the intermediate storage condition a minimum of 6scale. Supporting information may be provided using sta- months of data from a 12-month study. [ICH Q1A]bility data on batches of drug substance made on a labo-ratory scale. [ICH Q1A] Significant change at 40°C/75% RH or 30°C/60% RH is defined as failure to meet the specifications. [ICH Q1A] The first three production batches of drug substance If any parameter fails significant change criteria during themanufactured postapproval, if not submitted in the origi- accelerated stability study, testing of all parameters duringnal drug application, should be placed on long-term sta- the intermediate stability study should be studies postapproval, using the same stability pro-tocol as in the approved drug application. [ICH Q1A] If stability samples have been put into the intermediate condition but have not been tested, these samples may be2. Test Procedures and Test Criteria tested as soon as the accelerated study shows significant change in the drug substance. Alternatively, studies in theThe testing should cover those features that are susceptible intermediate condition would be started from the initialto change during storage and that are likely to influence time point.quality, safety, or efficacy. Stability information shouldcover, as necessary, the physical, chemical, biological, and Where a significant change occurs during 12 monthsmicrobiological test characteristics. Validated stability- of storage at 30°C/60% RH, it may not be appropriate toindicating test methods should be applied. The extent of label the drug substance for controlled room temperaturereplication will depend on the results of validation studies. (CRT) storage with the proposed retest period even if the[ICH Q1A] stability data from the full long-term studies at 25°C/60% RH appear satisfactory. In such cases, alternate approaches,3. Specifications such as qualifying higher acceptance criteria for a degradant, shorter retest period, refrigerator temperature storage, orLimits of acceptability should be derived from the quality more protective container and closure, should be consid-profile of the material as used in the preclinical and clinical ered during drug development.batches. Specifications will need to include individual andtotal upper limits for impurities and degradation products, The long-term testing should be continued for a suf-the justification for which should be influenced by the ficient period of time beyond 12 months to cover all appro-levels observed in material used in preclinical studies and priate retest periods, and the further accumulated data canclinical trials. [ICH Q1A] be submitted to the FDA during the assessment period of the drug application. [ICH Q1A]4. Storage Conditions The data (from accelerated testing or from testing at anThe length of the studies and the storage conditions should intermediate storage condition) may be used to evaluate thebe sufficient to cover storage, shipment, and subsequent use. effect of short-term excursions outside the label storageApplication of the same storage conditions applied to the conditions such as might occur during shipping. [ICH Q1A]drug product will facilitate comparative review and assess-ment. Other storage conditions are allowable if justified. In 5. Testing Frequency Frequency of testing should be sufficient to establish the stability characteristics of the drug substance. Testing under the defined long-term conditions will normally be© 2004 by CRC Press LLCStability Testing of Drug Substances and Drug Products 27every 3 months over the first year, every 6 months over observed data, and hence the use of extrapolation must bethe second year, and then annually. [ICH Q1A] justified in each application in terms of what is known about such factors as the mechanism of degradation, the6. Packaging and Containers goodness of fit of any mathematical model, the batch size, and the existence of supportive data. Any evaluation shouldThe containers to be used in the long-term, real-time sta- cover not only the assay but also the levels of degradationbility evaluation should be the same as or simulate the actual products and other appropriate attributes. [ICH Q1A]packaging used for storage and distribution. [ICH Q1A] 8. Statements and Labeling7. Evaluation A storage temperature range may be used in accordanceThe design of the stability study is to establish a retest with relevant national and regional requirements. The rangeperiod applicable to all future batches of the bulk drug should be based on the stability evaluation of the drugsubstance manufactured under similar circumstances, substance. Where applicable, specific requirements shouldbased on testing a minimum of three batches of the drug be stated, particularly for drug substances that cannot tol-substance and evaluating the stability information (cover- erate freezing. The use of terms such as “ambient condi-ing as necessary the physical, chemical, and microbiolog- tions” or “room temperature” is unacceptable. [ICH Q1A]ical test characteristics). The degree of variability of indi-vidual batches affects the confidence that a future A retest period should be derived from the stabilityproduction batch will remain within specifications until information. [ICH Q1A]the retest date. [ICH Q1A] B. DRUG PRODUCT An acceptable approach for quantitative characteris-tics that are expected to decrease with time is to determine 1. Generalthe time at which the 95% one-sided confidence limit forthe mean degradation curve intersects the acceptable lower The design of the stability protocol for the drug productspecification limit. If analysis shows that the batch-to- should be based on the knowledge obtained on the behav-batch variability is small, it is advantageous to combine ior, properties, and stability of the drug substance and thethe data into one overall estimate, which can be done by experience gained from clinical formulation studies. Thefirst applying appropriate statistical tests (for example, changes are likely to occur on storage, and the rationaleP values for level of significance of rejection of more than for the selection of drug product parameters to be moni-.25) to the slopes of the regression lines and zero time tored should be stated. [ICH Q1A]intercepts for the individual batches. If it is inappropriateto combine data from several batches, the overall retest 2. Selection of Batchesperiod may depend on the minimum time a batch may beexpected to remain within acceptable and justified limits. Stability information from accelerated and long-term test-[ICH Q1A] ing is to be provided on three batches of the same formu- lation of the dosage form in the container and closure The nature of any degradation relationship will deter- proposed for marketing. Two of the three batches shouldmine the need for transformation of the data for linear be at least pilot scale. The third batch may be smaller (e.g.,regression analysis. Usually the relationship can be rep- 25,000 to 50,000 tablets or capsules for solid oral dosageresented by a linear, quadratic, or cubic function on an forms). The long-term testing should cover at leastarithmetic or logarithmic scale. Statistical methods should 12 months’ duration at the time of submission. The man-be employed to test the goodness of fit of the data on all ufacturing process to be used should meaningfully simu-batches and combined batches (where appropriate) to the late that to be applied to large-scale production batchesassumed degradation line or curve. [ICH Q1A] for marketing. The process should provide product of the same quality intended for marketing and should meet the The data may show so little degradation and so little same quality specification to be applied for release ofvariability that it is apparent from looking at the data that material. Where possible, batches of the finished productthe requested retest period will be granted. Under the should be manufactured using identifiably differentcircumstances, it is normally unnecessary to go through batches of the drug substance. [ICH Q1A]the formal statistical analysis; providing a full justificationfor the omission is usually sufficient. [ICH Q1A] Data on laboratory-scale batches are not acceptable as primary stability information. Data on associated formu- Limited extrapolation may be undertaken of the real- lations or packaging may be submitted as supportive infor-time data beyond the observed range to extend the retest mation. The first three production batches manufacturedperiod at approval time, particularly where the accelerated postapproval, if not submitted in the original application,data support this. However, this assumes that the same should be placed on accelerated and long-term stabilitydegradation relationship will continue to apply beyond the© 2004 by CRC Press LLC28 Handbook of Pharmaceutical Manufacturing Formulations: Semisolid Productsstudies using the same stability protocols as in the become the designated long-term storage temperature.approved drug application. [ICH Q1A] Special consideration may need to be given to products that change physically or even chemically at lower storage3. Test Procedures and Test Criteria temperatures (e.g., suspensions or emulsions that may sed- iment, or cream, oils, and semisolid preparations, whichThe test parameters should cover those features that are may show an increased viscosity). Where a lower temper-susceptible to change during storage and that are likely to ature condition is used, the 6-month accelerated testinginfluence quality, safety, or efficacy. Analytical test pro- should be carried out at a temperature at least 15°C abovecedures should be fully validated, and the assays should be its designated long-term storage temperature (togetherstability-indicating. The need for replication will depend with appropriate relative humidity conditions for that tem-on the results of validation studies. [ICH Q1A] perature). For example, for a product to be stored long- term under refrigerated conditions, accelerated testing The range of testing should cover not only chemical should be conducted at 25° ± 2°C/60% RH ± 5%. Theand biological stability, but also loss of preservative effi- designated long-term testing conditions will be reflectedcacy, physical properties and characteristics, organoleptic in the labeling and expiration date. [ICH Q1A]properties, and, where required, microbiological attributes.Preservative efficacy testing and assays on stored samples Storage under conditions of high relative humidityshould be carried out to determine the content and efficacy applies particularly to solid dosage forms. For drug prod-of antimicrobial preservatives. [ICH Q1A] ucts such as solutions and suspensions contained in packs designed to provide a permanent barrier to water loss, spe-4. Specifications cific storage under conditions of high relative humidity is not necessary, but the same range of temperatures shouldWhere applicable, limits of acceptance should relate to be applied. Low relative humidity (e.g., 10%–20% RH) canthe release limits to be derived from consideration of all adversely affect products packed in semipermeable con-the available stability information. The shelf-life specifi- tainers (e.g., solutions in plastic bags, nose drops in smallcations could allow acceptable and justifiable deviations plastic containers), and consideration should be given tofrom the release specifications based on the stability eval- appropriate testing under such conditions. [ICH Q1A]uation and the changes observed on storage. They need toinclude specific upper limits for degradation products, the Where significant change occurs because of acceler-justification for which should be influenced by the levels ated testing, additional testing at an intermediate conditionobserved in material used in preclinical studies and clinical (e.g., 30° ± 2°C/60% RH ± 5%) should be conducted. Sig-trials. The justification for the limits proposed for certain nificant change at the accelerated conditions is defined asother tests, such as particle size or dissolution rate, willrequire reference to the results observed for the batch or • A 5% potency loss from the initial assay valuebatches used in bioavailability or clinical studies. Any of a batchdifferences between the release and the shelf-life specifi-cations for antimicrobial preservatives content should be • Any specified degradant exceeding its specifi-supported by preservative efficacy testing. [ICH Q1A] cation limit5. Storage Test Conditions • The product exceeding its pH limits • Dissolution exceeding the specification limitsThe length of the studies and the storage conditions shouldbe sufficient to cover storage, shipment, and subsequent for 12 capsules or tablets (USP [U.S. Pharma-use (e.g., reconstitution or dilution as recommended in the copeia] Stage 2)labeling). The recommended accelerated and long-term • Failure to meet specifications for appearancestorage conditions and minimum times are and physical properties (e.g., color, phase sep- aration, ability to be resuspended, delivery per Long-term testing 25°C ± 2°C/60% actuation, caking, hardness) [ICH Q1A] RH ± 5% 12 Months; Should significant change occur at 40°C/75% RH, the Accelerated Testing 40°C ± 2°C/75% initial application should include a minimum of 6 months’ RH ± 5% 6 Months. data from an ongoing 1-year study at 30°C/60% RH; the same significant change criteria shall then apply. [ICH Q1A]Assurance that long-term testing will continue to coverthe expected shelf life should be provided. [ICH Q1A] If any parameter fails significant change criteria during the accelerated stability study, testing of all parameters dur- Other storage conditions are allowable if justified. Heat- ing the intermediate stability study should be performed.sensitive drug products should be stored under an alterna-tive lower temperature condition, which will eventually If stability samples have been put into the intermediate condition but have not been tested, testing these samples may begin as soon as the accelerated study shows significant change in the drug product. Alternatively, the study at the© 2004 by CRC Press LLCStability Testing of Drug Substances and Drug Products 29intermediate condition would be started from the initial • Accelerated condition: 40° ± 2°C/15% RH ±time point. 5% (hereafter referred to as 40°C/15% 326 RH)[ICH Q1A] Where a significant change occurs during 12 monthsof storage at 30°C/60% RH, it may not be appropriate to • Intermediate condition: 30° ± 2°C/40% RH ±label the drug product for CRT storage with the proposed 5% (hereafter referred to as 30°C/40% RH)expiration dating period even if the stability data from thefull long-term studies at 25°C/60%RH appear satisfactory. • Long-term condition: 25C ± 2C/40% RH ± 5%In such cases, alternate approaches, such as qualifyinghigher acceptance criteria for a degradant, shorter expira- For liquids in glass bottles, vials, or sealed glasstion dating period, refrigerator temperature storage, more ampoules, which provide an impermeable barrier to waterprotective container and closure, and modification to the loss,formulation or manufacturing process, should be consid-ered during drug development. If CRT storage is ulti- • Accelerated condition: 40°C/ambient humiditymately justified, it may be necessary to add to the product is an acceptable alternative to 40°C/75% RHlabeling a cautionary statement against prolonged expo-sure at or above 30°C. • Intermediate condition: 30°C/ambient humidity is an acceptable alternative to 30°C/60% RH The long-term testing will be continued for a sufficientperiod of time beyond 12 months to cover shelf life at • Long-term condition: 25°C/ambient humidityappropriate test periods. The further accumulated data is an acceptable alternative to 25°C/60% RHshould be submitted to the FDA during the assessmentperiod of the drug application. [ICH Q1A] b. Stability Storage Conditions for Drug Products Intended to be Stored The first three production batches manufactured post- at Refrigerator Temperatureapproval, if not submitted in the original application,should be placed on accelerated and long-term stability • Accelerated conditions: 25°C/60% RH, withstudies using the same stability protocol as in the approved ambient humidity an acceptable alternative fordrug application. [ICH Q1A] A minimum of four test aqueous products that would not be affected bystations (e.g., at 0, 2, 4, and 6 months) are recommended humidity conditionsfor the 6-month accelerated stability study. • Long-term conditions: 5° ± 3°C, with monitor-6. Stability Storage Conditions not Defined ing, but not control of, humidity in ICH Q1A c. Stability Storage Conditions for Drug ProductsThe stability sample storage conditions for most dosage Intended to be Stored at Freezer Temperatureforms (e.g., solid oral dosage forms, solids for reconsti-tution, dry and lyophilized powders in glass vials) are • Accelerated conditions: 5° ± 3°C/ambientdefined in Section V.E of the ICH Q1A Guidance and in humiditySection II.B.5 of this guidance. However, the stabilitystorage conditions are not indicated in ICH Q1A for cer- • Long-term conditions: −15° ± 5°Ctain other drug products including those packaged in semi-permeable containers (except for accelerated studies), d. Stability Storage Conditions for Someproducts intended to be stored under refrigerator or freezer Inhalation Productstemperatures, or certain studies on metered dose inhala-tions (MDIs) and dry powder inhalers (DPIs). Further Additional storage conditions may apply to inhalationinformation about these products and containers is pro- powders and suspension inhalation aerosols when signif-vided in this section. icant change in aerodynamic particle size distribution or in dose content uniformity occurs at accelerated condi-a. Stability Storage Conditions for Drug Products tions (40°C/75% RH). (At present, the agency is develop- in Semipermeable and Permeable Containers ing a draft guidance to address chemistry, manufacturing, and controls documentation for MDIs and DPIs.)For large-volume parenterals (LVPs), small-volumeparenterals (SVPs), ophthalmics, otics, and nasal sprays 7. Testing Frequencypackaged in semipermeable containers, such as plastic bags,semirigid plastic containers, ampoules, vials and bottles Frequency of testing should be sufficient to establish thewith or without droppers or applicators, which may be stability characteristics of the drug product. Testing willsusceptible to water loss, the recommended stability stor- normally be every 3 months over the first year, everyage conditions are 6 months over the second year, and then annually. Matrix- ing or bracketing can be used if justified. [ICH Q1A] A minimum of four test stations (e.g., at 0, 2, 4, and 6 months)© 2004 by CRC Press LLC30 Handbook of Pharmaceutical Manufacturing Formulations: Semisolid Productsare recommended for the 6-month accelerated stability However, if the applicant wishes to verify product stabilitystudy. under the ICH conditions over a shorter time span, three production batches within 1 year, instead of three consec-8. Application of ICH Stability Study Storage utive annual batches, may be studied. Conditions to Approved Applications ii. Products without an Approved Stability ProtocolAlthough the ICH Guidance for Stability Testing of New Applicants who have previously performed stability stud-Drug Substances and Products applies only to new molec- ies on a drug product without an approved protocol areular entities and associated drug products, applicants may required to submit an appropriate protocol under a Priorwish to voluntarily switch to the ICH-recommended stor- Approval Supplement under 21 CFR 314.70(b) or (g) orage conditions as defined in ICH Q1A or other FDA- 601.12(b) (see Section V regarding an Approved Stabilityrecommended conditions as described in Section II.B.6, Protocol). On approval of the protocol, applicants mayas appropriate, for previously approved drug or biologic initiate stability studies on all annual batches under theproducts. Applicants are not required to make such a switch ICH long-term conditions. Data from the first three con-for either annual stability batches or batches intended to secutive annual batches after the switch can be used tosupport supplemental changes. Although the following verify the current—or establish a new—expiration datingdiscussions refer only to the ICH conditions, the same period. However, if the applicant wishes to verify productrecommendations can be applied when a switch to other stability under the ICH conditions over a shorter time span,FDA-recommended conditions is contemplated. three production batches within 1 year, instead of three consecutive annual batches, may be studied Two plans are presented to assist applicants who desireto switch their approved drug products to the ICH-recom- iii. Stability Data for Supplemental Changesmended storage conditions. Under each plan, recommen- Stability data submitted in support of supplemental changesdations will be made on how to initiate a switch to the ICH for an existing drug product may be generated with sam-storage testing conditions, select batches, collect data, report ples stored at the ICH-recommended accelerated testingresults, and proceed if products fail the approved specifi- conditions, long-term testing conditions, and, if applica-cations under the ICH conditions. ble, intermediate conditions, as described in V.E of the ICH Q1A guidance (Section II.B or Section III.B).a. Plan A: Using the ICH Storage Testing Conditions for an Approved Stability iv. Other Considerations For a moisture-sensitive product, the applicant may wish toThis plan may be most suitable for drug products that have explore the possibility of improving the container and clo-been confirmed to be stable when exposed to the controlled sure before embarking on the switch to the ICH of humidity on a long-term basis. Only one set ofconditions (i.e., the ICH conditions) and one set of testing Although 30°C/60% RH is an acceptable alternativefor each of the three verification batches, as defined below, to 25°C/60% RH for long-term studies, these conditionsare necessary under this plan. should not be used as the basis for a labeling statement such as “store at 30°C” or “store at 15°–30°C” to gaini. Drug Products with an Approved Stability Protocol marketing advantage.Applicants who have previously performed drug productstability studies under an approved protocol at 25°, 30°, With respect to ongoing stability studies, applicantsor 25°–30°C without humidity controls may switch over may carry them to completion under the previously approvedto the ICH long-term conditions, as defined in V.E. of the conditions or may, for practical or economic reasons,ICH Q1A guidance and incorporated in Section II.B of this choose to make an immediate switch to ICH conditionsguidance, for all of their annual stability studies. A revised and report the change in the next annual report.stability protocol may be submitted in the annual report,reflecting changes in temperature and humidity to conform v. Data Submission to the FDAto those recommended by the ICH. Any other changes tothe stability protocol should be submitted as a Prior Approval Satisfactory Data If the stability data generated on the firstSupplement. Once adopted through an annual report, the three annual batches after the switch to the ICH-recom-ICH conditions should be used to generate stability data mended long-term testing conditions using an approvedfor subsequent supplemental changes. Alternatively, the protocol, as defined above, support the previouslyapplicant may report the ICH switch in a supplement, which approved expiration dating period under the non-ICH con-requires stability data, if the supplement occurs before the ditions, the data can be submitted in the next annual report,next scheduled annual report. Data from the first three and the current expiration dating period can be retained.consecutive annual batches after the switch can be usedto verify the previously approved expiration dating period. Unsatisfactory Data If the stability data under the ICH conditions fall outside the specifications established for the previously approved expiration dating period, the© 2004 by CRC Press LLCStability Testing of Drug Substances and Drug Products 31applicant should perform an investigation to determine the ICH long-term conditions as the alternative, as wellthe probable cause of the failure in accordance with as the ICH-recommended accelerated testing conditions.current good manufacturing practices (CGMPs) regula- On approval of the protocol, applicants may initiate sta-tions under 21 CFR 211.192. In addition, the applicant bility studies on three consecutive annual batches at bothshould submit an NDA Field-Alert Report in accordance 25°C/ambient humidity and 25°C/60% RH or 25°C/40%with 21 CFR 314.81(b)(1)(ii) or an error and accident RH. Data from these annual batches under the ICH con-report for a biological product under 21 CFR 600.14. A ditions can be used to verify the current—or establish arecall of the corresponding product in the marketplace new—expiration dating also be necessary. If it is determined that the ICHstorage conditions, particularly the added humidity, are iii. Other Considerationsthe cause for the stability failure, the applicant may Same as in Plan A.shorten the expiration dating period in a Changes BeingEffected Supplement while retaining the ICH storage iv. Protocol Revisionscondition. Subsequently, if justified, the applicant may Products with an Approved Stability Protocol Applicantsrequest an approval for a revision of the product speci- who have an approved stability protocol may submit thefications and for reinstating the previously approved alternate stability protocol in the annual report, reflectingexpiration dating period under the non-ICH conditions the temperature and humidity as recommended by the ICH.through a Prior Approval Supplement. Other measures Other changes to the stability protocol generally should(e.g., more protective container and closure, or product be submitted in a Prior Approval Supplement, unless thereformulation) may be considered through a Prior changes are to comply with the current compendium.Approval Supplement. Once adopted as an alternate protocol through an annual Alternatively, the applicant may, after careful consid- report, the ICH conditions can be used, in parallel witheration of all aspects, request for a return to the previous the previously approved conditions, to generate stabilitystorage conditions in a Changes Being Effected Supple- data for subsequent supplemental changes. Alternatively,ment if justification, including all related data and inves- the applicant may report the alternative ICH conditions intigational results, is provided. a supplement, which requires stability data, if the supple- ment occurs before the next scheduled annual report.b. Plan B: Using the ICH Conditions under an Alternate Protocol If the complete stability data generated on the first three annual batches under the ICH long-term conditionsAn alternative to Plan A is to conduct two side-by-side using an approved alternate protocol (as defined above)studies by simultaneously placing samples from the same support the previously approved expiration dating periodbatch of drug product under the ICH conditions as well under the non-ICH conditions, the alternate stability pro-as the previously approved storage condition. The protocol tocol can be adopted as the primary stability protocolcontaining the ICH storage conditions is considered an through an annual report.alternative to the approved protocol. This plan may proveto be particularly useful if the drug product is believed to Products without an Approved Stability Protocol For appli-be sensitive to moisture. cations that do not contain an approved stability protocol as defined above, a new or revised stability protocol mayi. Products with an Approved Stability Protocol be submitted in a Prior Approval Supplement markedApplicants may initiate stability studies under the ICH- “expedited review requested.” This protocol should encom-recommended long-term testing conditions, in addition to pass 25°C/ambient humidity as the primary long-termthe previously approved conditions at 25°, 30°, or storage conditions, and the ICH long-term conditions as25°–30°C without humidity controls, for three consecutive the alternate, as well as accelerated stability storage con-annual batches. Data from these annual batches under the ditions as defined by the ICH Guidance and above, inICH conditions should be used to verify the current expi- addition to other recommendations described in this guid-ration dating period. However, if the applicant wishes to ance. On approval of the protocol, stability studies mayverify the ICH conditions over a shorter time span, three be initiated on annual batches and on batches intended toproduction batches within 1 year or less may be selected, support supplemental changes.instead of three consecutive annual batches. v. Stability Data for Supplemental Changesii. Products without an Approved Stability Protocol Applicants may provide stability data in support of post-Applicants who have previously performed stability stud- approval supplemental changes with samples stored at theies on a drug product without an approved protocol should ICH-recommended accelerated testing conditions and long-submit an appropriate protocol as a Prior Approval Supple- term testing conditions, both previously approved andment. This protocol should contain 25°C/ambient humidity ICH, as well as, if applicable, intermediate conditions. Seeas the primary long-term storage testing conditions, and Change in Stability Protocol (Section IX.J) for the recom- mended filing mechanism.© 2004 by CRC Press LLC32 Handbook of Pharmaceutical Manufacturing Formulations: Semisolid Productsvi. Data Submission The design of the stability study is to establish a shelf life and to label storage instructions applicable to all futureSatisfactory Data If the complete stability data generated batches of the dosage form manufactured and packedon the first three annual batches under the ICH long-term under similar circumstances based on testing a minimumconditions using an approved alternate protocol support of three batches of the drug product. The degree of vari-the previously approved expiration dating period under ability of individual batches affects the confidence that athe non-ICH conditions, the data can be submitted in the future production batch will remain within specificationsannual report and the current expiration dating period can until the expiration retained. An acceptable approach for quantitative characteris-Unsatisfactory Data If the stability data under the ICH tics that are expected to decrease with time is to determineconditions fall outside the acceptance criteria while data the time at which the 95% one-sided confidence limit forfrom the parallel study under the previously approved the mean degradation curve intersects the acceptable lowerconditions or 25°C/ambient humidity, whichever applies, specification limit. If analysis shows that the batch-to-batchare satisfactory during the previously approved expiration variability is small, it may be advantageous to combinedating period, and the added humidity is determined to be the data into one overall estimate by first applying appro-the cause for the stability failure, the product will still be priate statistical tests (e.g., P values for level of significanceconsidered to be in compliance with the regulatory spec- of rejection of more than.25) to the slopes of the regressionifications approved in the application. If the applicant lines and zero time intercepts for the individual batches.decides to adopt the ICH conditions, a Changes Being If combining data from several batches is inappropriate,Effected Supplement with a shortened expiration dating the overall retest period may depend on the minimum timeperiod or a Prior Approval Supplement with revised prod- a batch may be expected to remain within acceptable anduct specifications may be submitted where justified. Other justified limits.measures (e.g., more protective container and closure orproduct reformulation) may be considered through a Prior The nature of the degradation relationship will deter-Approval Supplement. mine the need for transformation of the data for linear regression analysis. Usually the relationship can be rep- Alternatively, after careful consideration of all aspects, resented by a linear, quadratic, or cubic function of anthe applicant may decide not to pursue the switch to the arithmetic or logarithmic scale. Statistical methods shouldICH conditions for the product. The applicant may elim- be employed to test the goodness of fit of the data on allinate the alternate stability protocol in the next annual report batches and, combined batches (where appropriate) to theif a full explanation, including all related data and inves- assumed degradation line or curve.tigational results, is provided. Where the data show so little degradation and so little In the case where the product fails to meet the speci- variability that it is apparent from looking at the them thatfications under the non-ICH conditions, irrespective of the requested shelf life will be granted, it is normallywhether it also fails under the ICH conditions, a thorough unnecessary to go through the formal statistical analysis,investigation in accordance with CGMP should be per- but a justification for the omission should be and appropriate corrective actions should be taken,including a Field-Alert Report and recall of the affected Limited extrapolation may be taken of the real-timeproduct from the marketplace if warranted. data beyond the observed range to extend expiration dating at approval time, particularly where the accelerated data9. Packaging Materials [ICH Q1A] support this. However, this assumes that the same degrada- tion relationship will continue to apply beyond the observedThe testing should be carried out in the final packaging data, and, hence, the use of extrapolation must be justifiedproposed for marketing. Additional testing of the unpro- in each application in terms of what is known about suchtected drug product can form a useful part of the stress factors as the mechanism of degradation, goodness of fittesting and package evaluation, as can studies carried out of any mathematical model, batch size, and existence ofin other related packaging materials in supporting the supportive data.definitive pack or packs. Any evaluation should cover not only the assay but also10. Evaluation [ICH Q1A] the levels of degradation products and appropriate attributes. Where appropriate, attention should be paid toA systematic approach should be adopted in the presen- reviewing the adequacy of the mass balance, different sta-tation of the evaluation of the stability information, which bility, and degradation cover, as necessary, physical, chemical, biological,and microbiological quality characteristics, including par- The stability of the drug product after reconstituting orticular properties of the dosage form (e.g., dissolution rate diluting according to labeling should be addressed to pro-for oral solid dose forms). vide appropriate and supportive information. See Section VIII.N for additional information on drug products that are reconstituted or diluted.© 2004 by CRC Press LLCStability Testing of Drug Substances and Drug Products 3311. Statements and Labeling or less) may be labeled as above, provided there are ade- quate stability data (at least 3 months at 40° ± 2°C/15%A storage temperature range may be used in accordance RH ± 5% or 40°C/NMT 20% RH) to support such FDA regulations. The range should be based on thestability evaluation of the drug product. Where applicable, ii. All Other Dosage Formsspecific requirements should be stated, particularly for For all other dosage forms (e.g., solid oral dosage forms,drug products that cannot tolerate freezing. dry powders, aqueous liquid, semisolid, and suspension dosage forms) that have been demonstrated to be stable The use of terms such as “ambient conditions” or “room at the ICH-recommended conditions (25° ± 2°C/60% RH ±temperature” is unacceptable. There should be a direct 5%, or 30°C/60% RH ± 5%) or at non-ICH conditions,linkage between the label statement and the demonstrated such as 30°, 25°–30°, or 25°C without humidity controlsstability characteristics of the drug product. A single set and intended to be stored at room temperature, the rec-of uniform storage statements for NDAs, ANDAs, PLAs, ommended labeling statement isand BLAs is recommended to avoid different labelingstorage statements for products stored under controlled Store at 25°C (77°EF); excursions permitted to 15°–30°Croom-temperature conditions. The storage statements and (59°–86°F) [see USP Controlled Room Temperature].storage conditions listed in this section are intended to bestandardized and harmonized with the CRT definition in iii. Where Space on the Immediate Container is Limitedthe USP and the recommendations in the ICH guidance. Where an abbreviated labeling statement is necessary because space on the immediate container is limited, eithera. Room Temperature Storage Statements of the following statements is acceptable provided the full labeling statement, as shown above, appears on the outeri. Liquid Dosage Forms in Semipermeable Containers carton and in the package insert:The recommended storage statement for LVPs, SVPs,ophthalmics, otics, and nasal sprays packaged in semiper- Store at 25°C (77°F); excursions 15°–30°C (59°–86°F);meable containers, such as plastic bags, semirigid plasticcontainers, ampoules, vials, and bottles with or without Store at 25°C (77°F) (see insert).droppers or applicators, that may be susceptible to waterloss but that have been demonstrated to be stable at 25° b. Refrigerator Storage Statement± 2°C/40% or 60% RH ± 5% (or 30° ± 2°C/40% or 60% For a drug product demonstrated to be stable at 5° ± 3°,RH ± 5%); at 25°C/NMT 40% or 30°C/NMT 40% RH; 2°–5°, or 2°–8°C with or without humidity control andor at 30°, 25°–30°, or 25°C without humidity controls, is: that is intended to be stored at refrigerator temperature, the recommended storage statement for labeling may be Store at 25°C (77°F); excursions permitted to 15°–30°C one of the following: (59°–86°F) [see USP Controlled Room Temperature]. Store in a refrigerator, 2°–8°C (36°–46°F);For sterile water for injection and LVP solutions of inor-ganic salts packaged in semipermeable containers (e.g., Store refrigerated, 2°–8°C (36°–46°F).plastic bags), the following statement may be used on theimmediate container labels: Where an abbreviated labeling statement is necessary because space on the immediate container is limited, the Store at 25°C (77°F); excursions permitted to 15°–30°C following statement is acceptable, provided one of the full (59°–86°F) [see USP Controlled Room Temperature] (see labeling statements, as shown above, appears on the outer insert for further information), container and in the package insert:and the following statement may be used in the “How Refrigerate (see insert).Supplied” section of the package insert: c. Room Temperature or Refrigerator Store at 25°C (77°F); excursions permitted to 15°–30°C Storage Statement (59°–86°F) [see USP Controlled Room Temperature]. For a drug product demonstrated to be stable both at 25° ±Brief exposure to temperatures up to 40°C/104°F may be 2°C/60% RH ± 5% and at refrigerator temperature, bothtolerated provided the mean kinetic temperature does not of the room temperature and refrigerator labeling state-exceed 25°C (77°F). However, such exposure should be ments, as described above, are acceptable, depending onminimized. the storage conditions intended for the product. A state- ment such as “store at 2°–25°C” is not recommended. LVP solutions packaged in a semipermeable container(e.g., a plastic bag) and containing simple organic salts (e.g.,acetate, citrate, gluconate, and lactate, and dextrose 10%© 2004 by CRC Press LLC34 Handbook of Pharmaceutical Manufacturing Formulations: Semisolid Productsd. Additional Cautionary Statements However, a reduced stability database at submission timeIf warranted, additional cautionary statements to protect a (e.g., 6 months’ accelerated and 6 months’ data from ongo-drug product from excessive heat, light, humidity, freezing, ing studies at the long-term condition) may be acceptableand other damaging conditions should be included on the in certain justified cases, such as when there is a significantcontainer label and the package insert. If the space on the body of information on the stability of the drug productcontainer label is too limited to display all the recommended and the dosage form.statements in detail, a reference to the package insert forfurther information (e.g., “see insert”) is recommended. III. STABILITY TESTING FOR ABBREVIATED NDASe. Other ConsiderationsThe applicant may wish to include the definition of USP Much of the general information provided in this guidanceCRT in its entirety in the package insert to provide easy is applicable to ANDAs. However, depending on the avail-reference. ability of significant information on, and the complexity of, these drug products and dosage forms, the amount off. Implementation of the Uniform Storage information necessary to support these applications may Statements in Labeling for New Product vary from that proposed for NDAs. This section is Applications intended to provide specific recommendations on abbre- viated applications.The recommended storage statements in labeling shouldbe adopted for new or pending NDA, ANDA, BLA, or PLA A. DRUG SUBSTANCE STABILITY DATA SUBMISSIONproducts. For applications approved before the publicationof the guidance, the recommended storage statements For drug products submitted under an ANDA, includingshould be adopted through the annual report mechanism antibiotics, supporting information may be provided directlyat the next printing opportunity if desired, but within 3 years to the drug product ANDA or by reference to an appro-of the date of the final guidance. With respect to room priately referenced drug master file. Publications may betemperature storage statements for already approved prod- provided or referenced as supportive information. Foructs, new stability studies under the ICH conditions are ANDA bulk drug substances, stability data should be gen-not required to adopt the recommended room temperature erated on a minimum of one pilot-scale batch. All batcheslabeling statements, provided the products have been dem- should be made using equipment of the same design andonstrated to be stable through expiry under one of the operating principle as the manufacturing-scale productionfollowing controlled temperatures: 30°, 25°–30°, and 25°C, equipment, with the exception of capacity. For ANDA bulkand at ambient humidity. drug substances produced by fermentation, stability data should be provided on three production batches, at leastC. NEW DOSAGE FORMS [ICH Q1C] two of which should be generated from different starter cultures.A new dosage form is defined as a drug product that is adifferent pharmaceutical product type but that contains the B. DRUG SUBSTANCE TESTINGsame active substance as included in an existing drugproduct approved by the FDA. A program for stability assessment may include storage at accelerated, long-term, and, if applicable, intermediate New dosage forms include products of different admin- stability study storage conditions (refer to IV.G of the ICHistration route (e.g., oral, when the original new drug product Q1A Guidance and Section II.A). Stability samples shouldwas a parenteral), new specific functionality and delivery be stored in the bulk storage container equivalent (e.g.,system (e.g., modified release tablet, when the original new same composition and type of container, closure, and liner,drug product was an immediate release tablet), and different but smaller in size) forms of the same administration route (e.g., cap-sule to tablet, solution to suspension). If not previously generated or available by reference, stress-testing studies should be conducted to establish Stability protocols for new dosage forms should fol- the inherent stability characteristics of the drug sub-low the guidance in the ICH Q1A in principle. However, stance and support the suitability of the proposed ana-a reduced stability database at submission time (e.g., lytical procedures. The detailed nature of the studies6 months’ accelerated and 6 months’ long-term data from will depend on the individual drug substance, type ofongoing studies) may be acceptable in certain justified cases. drug product, and available supporting information. Any necessary testing may be carried out as described inD. OTHER NDAS Section II.A.Stability protocols for new combination products or newformulations (which require clinical data for approval)should follow the guidance in the ICH Q1A in principle.© 2004 by CRC Press LLC.

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EBook [PDF] Handbook Of Pharmaceutical Manufacturing Formulations.

EBook includes PDF, ePub and Kindle version. V O L U M E F O U R Second Edition Handbook of Pharmaceutical Manufacturing Formulations Semisolid Products S a r f a r a z K. N i a z i Pharmaceutical Scientist, Inc. Deerfield, Illinois, USA Handbook of Pharmaceutical Manufacturing Formulations Second Edition Volume Series Sarfaraz K. Niazi Volume 1 Handbook of Pharmaceutical Manufacturing Formulations: Compressed Solid Products Volume 2 Handbook of Pharmaceutical Manufacturing Formulations: Uncompressed Solid Products Volume 3 Handbook of Pharmaceutical Manufacturing Formulations: Liquid Products Volume 4 Handbook of Pharmaceutical Manufacturing Formulations: Semisolid Products Volume 5 Handbook of Pharmaceutical Manufacturing Formulations: Over-the-Counter Products Volume 6 Handbook of Pharmaceutical Manufacturing Formulations: Sterile Products Informa Healthcare USA, Inc. 52 Vanderbilt Avenue New York, NY 10017  C 2009 by Informa Healthcare USA, Inc. Informa Healthcare is an Informa business No claim to original U.S. Government works Printed in the United States of America on acid-free paper 10 9 8 7 6 5 4 3 2 1 International Standard Book Number-10: 1-4200-8116-0 (Volume 1; Hardcover) International Standard Book Number-13: 978-1-4200-8116-9 (Volume 1: Hardcover) International Standard Book Number-10: 1-4200-8118-7 (Volume 2; Hardcover) International Standard Book Number-13: 978-1-4200-8118-3 (Volume 2; Hardcover) International Standard Book Number-10: 1-4200-8123-3 (Volume 3; Hardcover) International Standard Book Number-13: 978-1-4200-8123-7 (Volume 3; Hardcover) International Standard Book Number-10: 1-4200-8126-8 (Volume 4; Hardcover) International Standard Book Number-13: 978-1-4200-8126-8 (Volume 4; Hardcover) International Standard Book Number-10: 1-4200-8128-4 (Volume 5; Hardcover) International Standard Book Number-13: 978-1-4200-8128-2 (Volume 5; Hardcover) International Standard Book Number-10: 1-4200-8130-6 (Volume 6; Hardcover) International Standard Book Number-13: 978-1-4200-8130-5 (Volume 6; Hardcover) This book contains information obtained from authentic and highly regarded sources. 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For organizations that have been granted a photocopy license by the CCC, a separate system of payment has been arranged. Trademark Notice: Product or corporate names may be trademarks or registered trademarks, and are used only for identification and explanation without intent to infringe. Library of Congress Cataloging-in-Publication Data Niazi, Sarfaraz, 1949– Handbook of pharmaceutical manufacturing formulations / Sarfaraz K. Niazi. – 2nd ed. p. ; cm. Includes bibliographical references and index. ISBN-13: 978-1-4200-8106-0 (set) (hardcover alk. paper) ISBN-10: 1-4200-8106-3 (set) (hardcover alk. paper) ISBN-13: 978-1-4200-8116-9 (v. 1) (hardcover alk. paper) ISBN-10: 1-4200-8116-0 (v. 1) (hardcover alk. paper) [etc.] 1. Drugs–Dosage forms–Handbooks, manuals, etc. I. Title. [DNLM: 1. Drug Compounding–Handbooks. 2. Dosage Forms–Handbooks. 3. Formularies as Topic–Handbooks. 4. Technology, Pharmaceutical–Handbooks. QV 735 N577h 2009] RS200.N53 2009 615.19–dc22 2009009979 For Corporate Sales and Reprint Permission call 212-520-2700 or write to: Sales Department, 52 Vanderbilt Avenue, 16th floor, New York, NY 10017. Visit the Informa Web site at and the Informa Healthcare Web site at to the memory of John G. Wagner Preface to the Series—Second Edition The science and the art of pharmaceutical formulation keeps evolving as new materials, methods, and machines become readily available to produce more reliable, stable, and releasecontrolled formulations. At the same time, globalization of sourcing of raw and finished pharmaceuticals brings challenges to regulatory authorities and results in more frequent revisions to the current good manufacturing practices, regulatory approval dossier requirements, and the growing need for cost optimization. Since the publication of the first edition of this book, a lot has changed in all of these areas of importance to pharmaceutical manufacturers. The second edition builds on the dynamic nature of the science and art of formulations and provides an evermore useful handbook that should be highly welcomed by the industry, the regulatory authorities, as well as the teaching institutions. The first edition of this book was a great success as it brought under one umbrella the myriad of choices available to formulators. The readers were very responsive and communicated with me frequently pointing out to the weaknesses as well as the strengths of the book. The second edition totally revised attempts to achieve these by making major changes to the text, some of which include: 6. 7. 8. 1. Complete, revised errors corrected and subject matter reorganized for easy reference. Whereas this series has six volumes differentiated on the basis of the type of dosage form and a separate inclusion of the U.S. OTC products, ideally the entire collection is needed to benefit from the myriad of topics relating to formulations, regulatory compliance, and dossier preparation. 2. Total number of pages is increased from 1684 to 2726. 3. Total number of formulations is expanded by about 30% with many newly approved formulations. 4. Novel formulations are now provided for a variety of drugs; these data are collected from the massive intellectual property data and suggest toward the future trend of formulations. While some of these formulations may not have been approved in the United States or Europe, these do provide additional choices, particularly for the NDA preparation. As always, it is the responsibility of the manufacturer to assure that the intellectual property rights are not violated. 5. A significant change in this edition is the inclusion of commercial products; while most of this information is culled out from the open source such as the FOIA (I have made attempts to reconstruct the critical portions of it based on what I call the generally acceptable standards. The drug companies are advised to assure that any intellectual property rights are not violated and this applies to all information contained in this book. The freedom of information act (FOIA) is an extremely useful conduit for reliable information and manufacturers are strongly 9. 10. 11. v urged to make use of this information. Whereas this information is provided free of charge, the process of obtaining the information may be cumbersome, in which case, commercial sources of these databases can prove useful, particularly for the non-U.S. companies. Also included are the new Good Manufacturing Guidelines (2007) with amendments (2008) for the United States and similar updates for European Union and WHO; it is strongly urged that the companies discontinue using all old documents as there are significant changes in the revised form, and many of them are likely to reduce the cost of GMP compliance. Details on design of clean rooms is a new entry that will be of great use to sterile product manufacturers; whereas the design and flow of personnel and material flow is of critical nature, regulatory agencies view these differently and the manufacturer is advised always to comply with most stringent requirements. Addition of a self-auditing template in each volume of the series. While the cGMP compliance is a complex issue and the requirements diversified across the globe, the basic compliance remains universal. I have chosen the European Union guidelines (as these are more in tune with the ICH) to prepare a self-audit module that I recommend that every manufacturer adopt as a routine to assure GMP compliance. In most instances reading the template by those responsible for compliance with keep them sensitive to the needs of GMP. OTC products cross-referenced in other volumes where appropriate. This was necessary since the regulatory authorities worldwide define this class of drug differently. It is important to iterate that regardless of the prescription or the OTC status of a product, the requirements for compliance with the cGMP apply equally. OTC monograph status is a new section added to the OTC volume and this should allow manufacturers to chose appropriate formulations that may not require a filing with the regulatory agencies; it is important to iterate that an approved OTC monograph includes details of formulation including the types and quantities of active drug and excipients, labeling, and presentation. To qualify the exemption, the manufacturer must comply with the monograph in its entirety. However, subtle modifications that are merely cosmetic in nature and where there is an evidence that the modification will not affect the safety and efficacy of the products can be made but require prior approval of the regulatory agencies and generally these approvals are granted. Expanded discussion on critical factors in the manufacturing of formulations provided; from basic shortcuts to smart modifications now extend to all dosage forms. Pharmaceutical compounding is one of the oldest professions and whereas the art of formulations has been vi Preface to the Series—Second Edition relegated to more objective parameters, the art nevertheless remains. An experienced formulator, like an artist, would know what goes with what and why; he avoids the pitfalls and stays with conservative choices. These sections of the book present advice that is time tested, although it may appear random at times; this is intended for experienced formulators. 12. Expanded details on critical steps in the manufacturing processes provided but to keep the size of the book manageable, and these are included for prototype formulations. The reader is advised to browse through similar formulations to gain more insight. Where multiple formulations are provided for the same drug, it intended to show the variety of possibilities in formulating a drug and whereas it pertains to a single drug, the basic formulation practices can be extended to many drugs of same class or even of diversified classes. Readers have often requested that more details be provided in the Manufacturing Direction sections. Whereas sufficient details are provided, this is restricted to prototype formulations to keep the size of the book manageable and to reduce redundancy. 13. Addition of a listing of approved excipients and the level allowed by regulatory authorities. This new section allows formulators a clear choice on which excipients to choose; the excipients are reported in each volume pertaining to the formulation type covered. The listing is drawn from the FDA-approved entities. For the developers of an ANDA, it is critical that the level of excipients be kept within the range generally approved to avoid large expense in justifying any unapproved level. The only category for which the listing is not provided separately is the OTC volume since it contains many dosage forms and the reader is referred to dosage form–specific title of the series. The choice of excipients forms keeps increasing with many new choices that can provide many special release characteristics to the dosage forms. Choosing correct excipients is thus a tedious exercise and requires sophisticated multivariate statistical analysis. Whereas the formulator may choose any number of novel or classical components, it is important to know the levels of excipients that are generally allowed in various formulations to reduce the cost of redundant exercises; I have therefore included, as an appendix to each volume, a list of all excipients that are currently approved by the U.S. FDA along their appropriate levels. I suggest that a formulator consult this table before deciding on which level of excipient to use; it does not mean that the excipient cannot be used outside this range but it obviates the need for a validation and lengthy justification studies in the submission of NDAs. 14. Expanded section on bioequivalence submission was required to highlight the recent changes in these requirements. New entries include a comprehensive listing of bioequivalence protocols in abbreviated form as approved by the U.S. FDA; these descriptions are provided in each volume where pertinent. To receive approval for an ANDA, an applicant must generally demonstrate, among other things, equivalence of the active ingredient, dosage form, strength, route of administration and conditions of use as the listed drug, and that the proposed drug product is bioequivalent to the reference listed drug [21 USC 355(j)(2)(A); 21 CFR 314.94(a)]. Bioequivalent drug products show no significant difference in 15. 16. 17. 18. 19. the rate and extent of absorption of the therapeutic ingredient [21 U.S.C. 355(j)(8); 21 CFR 320.1(e)]. BE studies are undertaken in support of ANDA submissions with the goal of demonstrating BE between a proposed generic drug product and its reference listed drug. The regulations governing BE are provided at 21 CFR in part 320. The U.S. FDA has recently begun to promulgate individual bioequivalence requirements. To streamline the process for making guidance available to the public on how to design product-specific BE studies, the U.S. FDA will be issuing product-specific BE recommendations (To make this vital information available, an appendix to each volume includes a summary of all currently approved products by the U.S. FDA where a recommendation on conducting bioequivalence studies is made available by the U.S. FDA. When filing an NDA or an ANDA, the filer is faced with the choice of defending the methods used to justify the bioavailability or bioequivalence data. The U.S. FDA now allows application for waiver of bioequivalence requirement; a new chapter on this topic has been added along with details of the dissolution tests, where applicable, approved for various dosage forms. Dissolution testing requirements are included for all dosage forms where this testing is required by the FDA. Surrogate testing to prove efficacy and compliance is getting more acceptance at regulatory agencies; in my experience, a well-designed dissolution test is the best measure of continuous compliance. Coupled with chapters on waivers of bioequivalence testing, this information on dissolution testing should be great value to all manufacturers; it is recommended that manufacturers develop their own in-house specifications, more stringent than those allowed in these listings and the USP. Best-selling products (top 200 prescription products) are identified with an asterisk and a brand name where applicable; in all instances, composition of these products is provided and formulation of generic equivalents. Despite the vast expansion of pharmaceutical sales and shifting of categories of blockbuster drugs, basic drugs affecting gastrointestinal tract, vascular system, and brain remain most widely prescribed. Updated list of approved coloring agents in the United States, Canada, European Union, and Japan is included to allow manufactures to design products for worldwide distribution. Tablet-coating formulations that meet worldwide requirements of color selection are included in the Volume 1 (compressed solids) and Volume 5 (OTC) because these represent the products often coated. Guidelines on preparing regulatory filings are now dispersed throughout the series depending on where these guidelines are more crucial. However, the reader would, as before, need access to all volumes to benefit from the advice and guidelines provided. As always, comments and criticism from the readers are welcomed and these can be sent to me at [email protected] or [email protected] I would try to respond to any inquiries requiring clarification of the information enclosed in these volumes. I would like to express deep gratitude to Sherri R. Niziolek and Michelle Schmitt-DeBonis at Informa, the publisher of Preface to the Series—Second Edition this work, for seeing an immediate value to the readers in publishing the second edition of this book and allowing me enough time to prepare this work. The diligent editing and composing staff at Informa, particularly Joseph Stubenrauch, Baljinder Kaur and others are highly appreciated. Regardless, all errors and omissions remain altogether mine. vii In the first edition, I had dedicated each volume to one of my mentors; the second edition continues the dedication to these great teachers. Sarfaraz K. Niazi, Ph.D. Deerfield, Illinois, U.S.A. Preface to the Series—First Edition erations 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 cGMP compliance specific to the dosage form. Advice is offered on how to scale up the production batches. It is expected that formulation scientists will use this information to benchmark their internal development protocols and 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 close paradigm when it comes to selecting formulations—”not invented here” perhaps reigns in the mind of many seasoned formulations scientists subconsciously when they prefer to choose only a certain platform for development. It is expected that with the 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 that has taken years to compile, and I thank scores of my graduate students and colleagues for their help. A work of this size cannot be produced without errors, although I hope that these errors do not distract the reader from the utility of the book. I would sincerely appreciate if readers point out these mistakes for corrections in future editions. No industry in the world is more highly regulated than the pharmaceutical industry because of potential threat to a patient’s life 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 the 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 where 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 a 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 OTC products. The separation of OTC products, even 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 consid- Sarfaraz K. Niazi, Ph.D. Deerfield, Illinois, U.S.A. viii Preface to the Volume—First Edition nificant 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 The semisolid drugs category is composed of ointments, creams, gels, suppositories, and special topical dosage forms. They 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 sigix x Preface to the Volume—First Edition 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)]. PreIND 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. Although 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 ([email protected]). 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—including me. Sarfaraz K. Niazi, Ph.D. Deerfield, Illinois, U.S.A. About the Author Sarfaraz K. Niazi has been teaching and conducting research in the pharmaceutical industry for over 35 years. He has authored hundreds of scientific papers, textbooks, and presentations on the topics of pharmaceutical formulation, biopharmaceutics, and pharmacokinetics of drugs. He is also an inventor with scores of patents in the field of drug and dosage form delivery systems; he is also licensed to practice law before the U.S. Patent and Trademark Office. Having formulated hundreds of products from the most popular consumer entries to complex biotechnology-derived products, he has accumulated a wealth of knowledge in the science and art of formulating and regulatory filings of investigational new drugs (INDs) and new drug applications (NDAs). Dr. Niazi advises the pharmaceutical industry internationally on issues related to formulations, cGMP compliance, pharmacokinetics and bioequivalence evaluation, and intellectual property issues (He can be contacted at [email protected] xi Contents Animal Products 13 Species Selection 13 Subject Characteristics 13 Human Food Safety Considerations 13 Bibliography 14 Preface to the Series—Second Edition…. v Preface to the Series—First Edition…. viii Preface to the Volume—First Edition…. ix About the Author…. xi PART I. REGULATORY AND MANUFACTURING GUIDANCE 2. Quality Risk Management 15 I. Introduction 15 II. Scope 15 III. Principles of Quality Risk Management 15 IV. General Quality Risk Management Process 15 A. Responsibilities 16 B. Initiating a Quality Risk Management Process 16 C. Risk Assessment 16 D. Risk Control 17 E. Risk Communication 17 F. Risk Review 17 V. Risk Management Methodology 17 VI. Integration of Quality Risk Management into Industry and Regulatory Operations 18 Glossary 18 Bibliography 19 Annex I: Risk Management Methods and Tools 19 I.1 Basic Risk Management Facilitation Methods 19 I.2 Failure Mode Effects Analysis 19 Potential Areas of Use(s) 19 I.3 Failure Mode, Effects, and Criticality Analysis 19 Potential Areas of Use(s) 19 I.4 Fault Tree Analysis 19 Potential Areas of Use(s) 19 I.5 Hazard Analysis and Critical Control Points 20 Potential Areas of Use(s) 20 I.6 Hazard Operability Analysis 20 Potential Areas of Use(s) 20 I.7 Preliminary Hazard Analysis 20 Potential Areas of Use(s) 20 I.8 Risk Ranking and Filtering 20 Potential Areas of Use(s) 20 I.9 Supporting Statistical Tools 20 Annex II: Potential Applications for Quality Risk Management 21 II.1 Quality Risk Management as Part of Integrated Quality Management 21 Documentation 21 Training and education 21 Quality defects 21 1. Waiver of In Vivo Bioequivalence Study 2 I. Introduction 2 II. The Biopharmaceutics Classification System 2 A. Solubility 5 B. Permeability 5 C. Dissolution 5 III. Methodology for Classifying a Drug Substance and for Determining the Dissolution Characteristics of a Drug Product 5 A. Determining Drug Substance Solubility Class 5 B. Determining Drug Substance Permeability Class 6 1. Pharmacokinetic Studies in Humans 6 2. Intestinal Permeability Methods 6 3. Instability in the Gastrointestinal Tract 9 C. Determining Drug Product Dissolution Characteristics and Dissolution Profile Similarity 10 IV. Additional Considerations for Requesting a Biowaiver 10 A. Excipients 10 B. Prodrugs 10 C. Exceptions 10 1. Narrow Therapeutic Range Drugs 10 2. Products Designed to Be Absorbed in the Oral Cavity 10 V. Regulatory Applications of the BCS 10 A. INDs/NDAs 10 B. ANDAs 11 C. Postapproval Changes 11 VI. Data to Support a Request for Biowaivers 11 A. Data Supporting High Solubility 11 B. Data Supporting High Permeability 11 C. Data Supporting Rapid and Similar Dissolution 11 D. Additional Information 12 1. Excipients 12 2. Prodrugs 12 3. Exceptions 12 xii Contents II.2 II.3 II.4 II.5 II.6 II.7 II.8 Auditing/Inspection 21 Periodic review 21 Change management/change control 21 Continual improvement 21 Quality Risk Management as Part of Regulatory Operations 21 Inspection and assessment activities 21 Quality Risk Management as Part of development 21 Quality Risk Management for Facilities, Equipment, and Utilities 22 Design of facility/equipment 22 Hygiene aspects in facilities 22 Qualification of facility/equipment/ utilities 22 Cleaning of equipment and environmental control 22 Calibration/preventive maintenance 22 Computer systems and computer controlled equipment 22 Quality Risk Management as Part of Materials Management 22 Assessment and evaluation of suppliers and contract manufacturers 22 Starting material 22 Use of materials 22 Storage, logistics, and distribution conditions 22 Quality Risk Management as Part of Production 22 Validation 22 In-process sampling and testing 22 Production planning 22 Quality Risk Management as Part of Laboratory Control and Stability Studies 22 Out of specification results 22 Retest period/expiration date 23 Quality Risk Management as Part of Packaging and Labeling 23 Design of packages 23 Selection of container closure system 23 Label controls 23 3. Pharmaceutical Quality System 24 I. Pharmaceutical Quality System 24 A. Introduction 24 B. Scope 24 C. Relationship of ICH Q10 to Regional GMP Requirements, ISO Standards, and ICH Q7 24 D. Relationship of ICH Q10 to Regulatory Approaches 24 E. ICH Q10 Objectives 24 1. Achieve Product Realization 24 2. Establish and Maintain a State of Control 25 3. Facilitate Continual Improvement 25 F. Enablers: Knowledge Management and Quality Risk Management 25 1. Knowledge Management 25 2. Quality Risk Management 25 II. III. IV. Glossary Annex 1 Annex 2 G. Design and Content Considerations 25 H. Quality Manual 25 Management Responsibility 25 A. Management Commitment 25 B. Quality Policy 26 C. Quality Planning 26 D. Resource Management 26 E. Internal Communication 26 F. Management Review 26 G. Management of Outsourced Activities and Purchased Materials 26 H. Management of Change in Product Ownership 26 Continual Improvement of Process Performance and Product Quality 26 A. Lifecycle Stage Goals 26 1. Pharmaceutical Development 26 2. Technology Transfer 27 3. Commercial Manufacturing 27 4. Product Discontinuation 27 B. Pharmaceutical Quality System Elements 27 1. Process Performance and Product Quality Monitoring System 27 2. Corrective Action and Preventive Action System 27 3. Change Management System 28 4. Management Review of Process Performance and Product Quality 28 Continual Improvement of the Pharmaceutical Quality System 28 A. Management Review of the Pharmaceutical Quality System 29 B. Monitoring of Internal and External Factors Impacting the Pharmaceutical Quality System 29 C. Outcomes of Management Review and Monitoring 29 29 30 31 4. Pharmaceutical Development 32 I. Introduction 32 A. Approaches to Pharmaceutical Development 32 II. Elements of Pharmaceutical Development 32 A. Target Product Profile 32 B. Critical Quality Attributes 32 C. Linking Material Attributes and Process Parameters to CQAs—Risk Assessment 33 D. Design Space 33 1. Selection of Variables 33 2. Defining and Describing a Design Space in a Submission 33 3. Unit Operation Design Space(s) 33 4. Relationship of Design Space to Scale and Equipment 33 xiii xiv Contents 5. Design Space vs. Proven Acceptable Ranges 33 6. Design Space and Edge of Failure 33 E. Control Strategy 34 F. Product Lifecycle Management and Continual Improvement 34 III. Submission of Pharmaceutical Development and Related Information in CTD Format 34 A. Quality Risk Management and Product and Process Development 34 B. Design Space 34 C. Control Strategy 35 D. Drug Substance Related Information 35 Glossary 35 Appendix 1: Differing Approaches to Pharmaceutical Development 35 Appendix 2: Illustrative Examples 36 Example of Use of a Risk Assessment Tool 36 Example of Depiction of Interactions 36 Illustrative Examples of Presentation of Design Space 36 5. Pharmaceutical Development in CTD 39 I. Introduction 39 A. Objective of the Guideline 39 B. Scope 39 II. Pharmaceutical Development 39 A. Components of the Drug Product 40 1. Drug Substance 40 2. Excipients 40 B. Drug Product 40 1. Formulation Development 40 2. Overages 40 3. Physicochemical and Biological Properties 40 C. Manufacturing Process Development 41 D. Container Closure System 41 E. Microbiological Attributes 41 F. Compatibility 41 Glossary 42 6. Scale-Up and Postapproval Changes for Nonsterile Semisolid Dosage Forms: Manufacturing Equipment 43 I. Preservative 43 II. Manufacturing Changes 43 III. Process 44 A. Batch Size (Scale-Up or Scale-Down) 44 IV. Manufacturing Site 44 I. Introdution 44 II. Particle Size Reduction and Separation 45 A. Definitions 45 1. Unit Operations 45 2. Operating Principles 45 B. Equipment Classifications 45 1. Fluid Energy Mills 45 2. Impact Mills 45 3. Cutting Mills 45 4. Compression Mills 45 5. Screening Mills 45 6. Tumbling Mills 45 7. Separators 45 III. Mixing 45 A. Definitions 45 1. Unit Operation 45 2. Operating Principles 46 B. Equipment Classification 46 1. Convection Mixers, Low Shear 46 2. Convection Mixers, High Shear 46 3. Roller Mixers (Mills) 46 4. Static Mixers 46 5. Low-Shear Emulsifiers 46 IV. Transfer 46 A. Definitions 46 1. Unit Operation 46 2. Operating Principles 46 B. Equipment Classification 46 1. Low Shear 46 2. High Shear 46 V. Packaging 46 A. Definitions 46 1. Unit Operation 46 2. Operating Principles 47 B. Equipment Classification 47 1. Holders 47 2. Fillers 47 3. Sealers 47 7. GOOD Manufacturing Practice Guide for Active Pharmaceutical Ingredients 48 1. Introduction 48 1.1 Objective 48 1.2 Regulatory Applicability 48 1.3 Scope 48 2. Quality Management 48 2.1 Principles 48 2.2 Responsibilities of the Quality Unit(s) 49 2.3 Responsibility for Production Activities 49 2.4 Internal Audits (Self-Inspection) 50 2.5 Product Quality Review 50 3. Personnel 50 3.1 Personnel Qualifications 50 3.2 Personnel Hygiene 50 3.3 Consultants 50 4. Buildings and Facilities 50 4.1 Design and Construction 50 4.2 Utilities 51 4.3 Water 51 4.4 Containment 51 4.5 Lighting 51 4.6 Sewage and Refuse 51 4.7 Sanitation and Maintenance 51 5. Process Equipment 52 5.1 Design and Construction 52 5.2 Equipment Maintenance and Cleaning 52 5.3 Calibration 52 5.4 Computerized Systems 52 6. Documentation and Records 53 6.1 Documentation System and Specifications 53 6.2 Equipment Cleaning and Use Record 53 Contents 7. 8. 9. 10. 11. 12. 13. 14. 15. 6.3 Records of Raw Materials, Intermediates, API Labeling and Packaging Materials 53 6.4 Master Production Instructions (Master Production and Control Records) 53 6.5 Batch Production Records (Batch Production and Control Records) 54 6.6 Laboratory Control Records 54 6.7 Batch Production Record Review 54 Materials Management 54 7.1 General Controls 54 7.2 Receipt and Quarantine 54 7.3 Sampling and Testing of Incoming Production Materials 55 7.4 Storage 55 7.5 Reevaluation 55 Production and In-Process Controls 55 8.1 Production Operations 55 8.2 Time Limits 56 8.3 In-process Sampling and Controls 56 8.4 Blending Batches of Intermediates or APIs 56 8.5 Contamination Control 56 Packaging and Identification Labeling of APIs and Intermediates 56 9.1 General 56 9.2 Packaging Materials 56 9.3 Label Issuance and Control 57 9.4 Packaging and Labeling Operations 57 Storage and Distribution 57 10.1 Warehousing Procedures 57 10.2 Distribution Procedures 57 Laboratory Controls 57 11.1 General Controls 57 11.2 Testing of Intermediates and APIs 58 11.3 Validation of Analytical Procedures (see Subsection 12) 58 11.4 Certificates of Analysis 58 11.5 Stability Monitoring of APIs 58 11.6 Expiry and Retest Dating 59 11.7 Reserve/Retention Samples 59 Validation 59 12.1 Validation Policy 59 12.2 Validation Documentation 59 12.3 Qualification 59 12.4 Approaches to Process Validation 59 12.5 Process Validation Program 60 12.6 Periodic Review of Validated Systems 60 12.7 Cleaning Validation 60 12.8 Validation of Analytical Methods 60 Change Control 61 Rejection and Reuse of Materials 61 14.1 Rejection 61 14.2 Reprocessing 61 14.3 Reworking 61 14.4 Recovery of Materials and Solvents 61 14.5 Returns 61 Complaints and Recalls 62 16. Contract Manufacturers (Including Laboratories) 62 17. Agents, Brokers, Traders, Distributors, Repackers, and Relabelers 62 17.1 Applicability 62 17.2 Traceability of Distributed APIs and Intermediates 62 17.3 Quality Management 62 17.4 Repackaging, Relabeling and Holding of APIs and Intermediates 62 17.5 Stability 62 17.6 Transfer of Information 62 17.7 Handling of Complaints and Recalls 63 17.8 Handling of Returns 63 18. Specific Guidance for APIs Manufactured by Cell Culture/Fermentation 63 18.1 General 63 18.2 Cell Bank Maintenance and Record Keeping 63 18.3 Cell Culture/Fermentation 64 18.4 Harvesting, Isolation, and Purification 64 18.5 Viral Removal/Inactivation Steps 64 19. APIs for Use in Clinical Trials 64 19.1 General 64 19.2 Quality 64 19.3 Equipment and Facilities 65 19.4 Control of Raw Materials 65 19.5 Production 65 19.6 Validation 65 19.7 Changes 65 19.8 Laboratory Controls 65 19.9 Documentation 65 Glossary 65 8. Validation of Analytical Procedures 68 I. Introduction 68 II. Types of Analytical Procedures to be Validated 68 Glossary 69 9. Validation of Analytical Procedures: Methodology 70 I. Introduction 70 II. Specificity 70 A. Identification 70 B. Assay and Impurity Test(s) 70 1. Impurities Are Available 70 2. Impurities Are Not Available 70 III. Linearity 71 IV. Range 71 V. Accuracy 71 A. Assay 71 1. Drug Substance 71 2. Drug Product 71 B. Impurities (Quantitation) 71 C. Recommended Data 71 VI. Precision 72 A. Repeatability 72 B. Intermediate Precision 72 C. Reproducibility 72 D. Recommended Data 72 xv xvi Contents VII. Detection Limit 72 A. Based on Visual Evaluation 72 B. Based on Signal-to-Noise 72 C. Based on the Standard Deviation of the Response and the Slope 72 1. Based on the Standard Deviation of the Blank 72 2. Based on the Calibration Curve 72 D. Recommended Data 72 VIII.Quantitation Limit 72 A. Based on Visual Evaluation 72 B. Based on Signal-to-Noise Approach 72 C. Based on the Standard Deviation of the Response and the Slope 73 1. Based on Standard Deviation of the Blank 73 2. Based on the Calibration Curve 73 D. Recommended Data 73 IX. Robustness 73 X. System Suitability Testing 73 10. Bioequivalence Testing of Topical Drugs 74 I. Inactive Ingredients 74 II. Waiver of Bioequivalence 74 III. Bioequivalence Approaches 74 A. Dermatopharmacokinetic Approaches 74 1. Performance and Validation of the Skin Stripping Technique 75 IV. Sample Pilot Study 75 A. DPK Bioequivalence Study Protocol 76 1. Protocol and Subject Selection 76 2. Application and Removal of Test and Reference Products 76 3. Sites and Duration of Application 76 4. Collection of Sample 76 5. Procedure for Skin Stripping 76 B. Metrics and Statistical Analyses 77 V. Pharmacodynamic Approaches 77 A. In Vitro Release Approaches (Lower Strength) 77 B. In Vitro Release: Extension of the Methodology 78 C. Systemic Exposure Studies 78 11. Good Manufacturing Requirements for Active Pharmaceutical Ingredients 79 I. Introduction 79 II. FDAs Risk-Based, Systems Approach to API Inspections 79 The Quality System 80 12. FDA Active Pharmaceutical Ingredient Manufacturing Facility Inspection 81 Part I—Background 81 General 81 Scope of APIs Covered by This Program 81 Part II—Implementation 82 Objective 82 Program Management Instructions 82 Inspection Planning 83 Profile Classes 83 Types of Inspections 83 Part III—Inspectional 83 Inspection Approaches 84 Full Inspection Option 84 A Full Inspection Is Appropriate 84 Abbreviated Inspection Option 84 Compliance Inspections 84 Selecting Systems for Coverage 84 Preparing the Inspection Strategy 84 Special Inspection Reporting Instructions 85 Special Instructions for Foreign Drug Inspections 85 Part IV—Analytical 85 Part V—Regulatory/Administrative Strategy 86 Part VI—References, Attachments, and Program Contacts 87 Bibliography 87 Part VII—Center Responsibilities 87 Appendix A: Description of Each System and Areas of Coverage 87 Quality System 87 Facilities and Equipment System 88 Materials System 88 Production System 89 Packaging and Labeling System 89 Laboratory Control System 89 Glossary 90 13. Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products: Chemical Substances 94 I. Introduction 94 A. Objective of the Guideline 94 B. Background 94 C. Scope of the Guideline 94 II. General Concepts 94 A. Periodic or Skip Testing 94 B. Release vs. Shelf life Acceptance Criteria 95 C. In-process Tests 95 D. Design and Development Considerations 95 E. Limited Data Available at Filing 95 F. Parametric Release 95 G. Alternative Procedures 95 H. Pharmacopoeial Tests and Acceptance Criteria 96 I. Evolving Technologies 96 J. Impact of Drug Substance on Drug Product Specifications 96 K. Reference Standard 96 III. Guidelines 96 A. Specifications: Definition and Justification 96 1. Definition of Specifications 96 2. Justification of Specifications 96 B. Universal Tests/Criteria 97 1. New Drug Substances 97 2. New Drug Products 97 C. Specific Tests/Criteria 98 1. New Drug Substances 98 2. New Drug Products 99 Glossary 102 References 103 IV. Attachments 104 Contents 14. Skin Irritation and Sensitization Testing of Generic Transdermal Drug Products 115 I. Study Designs 115 A. Recommendations for a Cumulative Skin Irritation Study 115 1. Sample Size 115 2. Exclusion Criteria 115 3. Duration of Study 115 4. Study Design 115 5. Patch Application 115 6. Evaluations 115 7. Data Presentation and Analysis 115 B. Recommendations for a Skin Sensitization Study (Modified Draize Test) 115 1. Sample Size 115 2. Exclusion Criteria 115 3. Duration of Study 115 4. Study Design 115 5. Patch Application 115 6. Data Presentation and Analysis 116 C. Combined Studies 116 Appendix A: Skin Irritation Scoring Systems 116 Appendix B: Adhesion Score 116 Appendix C: Statistics 116 Bibliography 117 15. Impurities in New Drug Substances 118 I. Preamble 118 II. Classification of Impurities 118 III. Rationale for the Reporting and Control of Impurities 118 A. Organic Impurities 118 B. Inorganic Impurities 119 C. Solvents 119 IV. Analytical Procedures 119 V. Reporting Impurity Content of Batches 119 VI. Listing of Impurities in Specifications 119 VII. Qualification of Impurities 120 Glossary 120 16. Impurities in New Drug Products 123 I. Introduction 123 A. Objective of the Guideline 123 B. Background 123 C. Scope of the Guideline 123 II. Rationale for the Reporting and Control of Degradation Products 123 III. Analytical Procedures 123 IV. Reporting Degradation Products Content of Batches 124 V. Listing of Degradation Products in Specifications 124 VI. Qualification of Degradation Products 125 Glossary 125 17. Formulation Factors in Semisolid Dosage Forms 130 I. Potency Uniformity 130 II. Equipment and Production Control 130 A. Mixers 130 B. Filling and Packaging 130 C. Process Temperature Control 130 III. Cleaning Validation 131 A. Detailed Cleaning Procedures 131 B. Sampling Plan for Contaminants 131 C. Equipment Residue Limits 131 IV. Microbiological 131 A. Controls (Nonsterile Topicals) 131 1. Deionized Water Systems for Purified Water 131 2. Microbiological Specifications and Test Methods 132 B. Preservative Activity 132 V. Change Control 132 VI. Transdermal Topical Products 132 A. General Considerations 132 B. The Role of In Vitro Release Testing 133 C. In Vivo Bioequivalence Studies 133 References 134 Glossary 134 18. GMP Audit Template, EU Guidelines 136 Glossary 155 19. Dissolution Testing of Semisolid Dosage Forms 158 20. Approved Excipients in Semisolid Dosage Forms 159 PART II. MANUFACTURING FORMULATIONS Regulatory and Manufacturing Guidance 182 Aceclofenac Gel Cream 182 Acetaminophen Suppositories 182 Acetaminophen Suppositories 183 Acetaminophen Suppositories 183 Acetaminophen Suppositories 183 Acetaminophen Suppositories 184 Acetaminophen Suppositories 184 Acetylsalicylic Acid Suppositories 184 Acne Cover Cream 185 Acne Treatment Cream 185 Acyclovir Cream 186 Acyclovir Ointment 186 Adapalene Cream 187 Alclometasone Dipropionate Cream and Ointment 187 Aloe Vera Gel 187 Alum Cream 187 6-Aminonicotinamide Ointment 188 6-Aminonicotinic Acid Methyl Ester Ointment 188 6-Aminonicotinic Acid Ointment 188 Aminacrine Hydrochloride Cream 188 Amoxicillin Lotion 188 Ampicillin Lotion 189 Analgesic Clear Gel 189 Analgesic Cream 189 Analgesic Lotion 190 Anthralin Cream 190 Antiacne Gel 190 Antifungal Foot Powder 190 Antifungal Topical Cream 191 xvii xviii Contents Antiseptic Cream 191 Antiseptic Lotion 191 Antiseptic Lotion 192 Arginine and Oleoresin Capsicum Cream 192 Arginine Cream 192 Arginine–Aspartate Cream 193 Atropine Opthalmic Ointment 193 Azelaic Acid Cream and Gel 194 Baby Cream, Benzalkonium Chloride, and Zinc Oxide 194 Baby Lotion 195 Baby Lotion 195 Baby Shampoo 196 Bacitracin Zinc and Polymyxin B Sulfate Opthalmic Ointment 196 Base Cream 197 Base Ointment 197 Base Ointment 197 Base Ointment 198 Base Ointment 198 Becaplermin Gel (0.01%) 199 Benzalkonium Chloride and Zinc Oxide Cream 199 Benzalkonium Chloride Contraceptive Gel 200 Benzocaine Cream 200 Benzoyl Peroxide and Alpha-Bisabolol Gel 200 Benzoyl Peroxide Antiacne Microemulsion 201 Benzoyl Peroxide Cream 201 Benzoyl Peroxide Gel 202 Benzoyl Peroxide Lotion 202 Benzoyl Peroxide Lotion 202 Betamethasone and Cinchocaine Suppositories 203 Betamethasone and Neomycin Gel Cream 203 Betamethasone and Salicylic Acid Lotion 203 Betamethasone Cream 204 Betamethasone Cream 204 Betamethasone Dipropionate Cream, Lotion, and Ointment 204 Betamethasone Dipropionate Ointment 205 Betamethasone Gel 205 Betamethasone Opthalmic Ointment 205 Betamethasone Valerate and Cinchocaine Ointment 206 Betamethasone Valerate Cream 206 Betamethasone Valerate Foam 207 Betamethasone Valerate Ointment 207 Betamethasone Valerate Ointment 207 Bifonazole Cream (1%) 208 Bisacodyl Suppositories 208 Bisacodyl Suppositories 208 Biscarboxychromonyloxy Propanol Ointment 209 Bleaching and Antimicrobial Dentifrice 209 Breast Care Cream 209 Budesonide Cream 210 Budesonide Ointment 210 Buprenorphine Hydrochloride Suppository 211 Burn Cream 211 Burn Cream 211 Butenafine Hydrochloride Cream 212 Butesin Picrate and Metaphen Ointment 212 Butesin Picrate Ointment 213 Butoconazole Nitrate Vaginal Cream 214 Calamine and Diphenhydramine Hydrochloride Lotion 214 Calamine and Pramoxine Hydrochloride Lotion 215 Calamine Cream 215 Calamine Cream 215 Calamine Lotion 216 Calcipotriene Cream 216 Calcipotriene Cream 216 Calcium Carbonate Ointment 216 Camphor, Eucalyptus Oil, and Menthol Ointment 217 Carbamazepine Cream 217 Carbamazepine Gel 217 Carbamazepine Ointment 217 Carbamide Peroxide Chewing Gum 217 2-Carbamoylpyrazinamide Ointment 218 Castor Oil Ointment 218 Cefaclor and Benzoyl Peroxide Gel 218 Cefaclor and Benzoyl Peroxide Lotion 218 Cetrimide Antiseptic Cream 219 Cetrimonium Bromide Cream 219 Chloramphenicol Opthalmic Ointment 219 Chlorhexidine and Cetrimonium Bromide Cream 219 Chlorhexidine Gel 220 Chlorpromazine Suppositories 220 Ciclopirox Cream, Lotion, and Gel 220 Ciclopirox Nail Varnish 220 Ciclopirox Nail Varnish 220 Ciprofloxacin Hydrochloride Opthalmic Ointment 221 Clindamycin Gel 221 Clindamycin Lotion and Gel 221 Clindamycin Phosphate Suppository 221 Clindamycin Phosphate Topical Gel 221 Clindamycin Phosphate Vaginal Cream 221 Clindamycin Phosphate Vaginal Suppository 221 Clobetasol Propionate Cream 222 Clobetasol Propionate Cream, Ointment, and Gel 223 Clobetasol Propionate Ointment Gel 223 Clotrimazole and Betamethasone Cream and Lotion 223 Clotrimazole Cream 223 Clotrimazole Lotion 224 Clotrimazole Lotion 224 Clotrimazole Vaginal Cream 225 Clotrimazole Vaginal Cream 225 Clotrimazole Vaginal Cream Inserts 225 Clotrimazole and Clindamycin Cream 225 Clotrimazole and Clindamycin Suppositories 226 Clotrimazole and Clindamycin Suppositories 226 Coal Tar and Allantoin Cream 226 Coal Tar and Allantoin Cream 227 Coal Tar Cream 227 Collagenase Ointment 227 Conjugated Estrogens Vaginal Cream 227 Cyanocobalamin Gel 227 DBcAMP Ointment 227 Desonide Cream, Ointment, and Lotion 228 Desoximetasone Emollient Cream, Gel, and Ointment 228 Dexamethasone Sodium Phosphate Ointment 228 Dexpanthenol Cream 228 Dexpanthenol Gel Cream 229 Diclofenac Diethylamine Gel 229 Contents Diclofenac Diethylammonium Gel 230 Diclofenac Sodium Suppositories 230 Diclofenac Sodium Suppositories 230 Diclofenac Sodium Suppositories 231 Diclofenac Sodium Suppositories 231 Dichlorobenzyl Alcohol Tooth Gel 231 Dienestrol Vaginal Cream 232 Diethylamine Salicylate Cream 232 Diflorasone Diacetate Cream and Ointment 232 Dimethicone and Zinc Oxide Ointment 232 Dinoprostone Cervical Gel 232 Dinoprostone Vaginal Insert and Suppositories 233 Diphenhydramine Hydrochloride and Zinc Acetate Ointment 233 Docosanol Lotion 233 Econazole Nitrate and Benzoyl Peroxide Cream 233 Econazole Nitrate and Benzoyl Peroxide Lotion 234 Eflornithine Hydrochloride Cream 234 Enzyme Extract Ointment 234 Erythromycin and Neomycin Ointment 235 Erythromycin Gel 235 Erythromycin Ointment 235 Erythromycin Ointment 236 Estradiol and Norethindrone Acetate Transdermal System 236 Estradiol Transdermal System 236 Estradiol Vaginal Cream 236 Estradiol Vaginal Cream 237 Ethylenediamine Tetracetate Ointment 238 Eucalyptus and Mint Ointment 238 Foot Freshener Cream 239 Foot Mousse 239 Fluocinonide Cream 240 Fluocinonide Cream, Ointment, and Gel 240 Fluorometholone Opthalmic Ointment 240 Fluorouracil Cream 240 Flurandrenolide Lotion 241 Flurandrenolide Topical Film 241 Fluticasone Ointment 241 Fluticasone Propionate Ointment 241 Fluticasone Propionate Cream 242 Fluticasone Propionate Cream 242 Folic Acid Suppository 242 6-Formylaminonicotinamide Ointment and Lotion 242 Foscarnet Cream 243 Gamma Benzene Hexachloride Lotion 243 Gentamicin Sulfate Cream 244 Gentamicin Sulfate Ointment 244 Gentamicin Sulfate Ointment 245 Glycerin Suppositories 245 Glycerin Suppositories 245 Glycolic Acid Cream 246 Gramicidin, Neomycin, Nystatin, and Triamcinolone Ointment 246 Halobetasol Propionate Cream and Ointment 247 Hemorrhoid Cream 247 Heparin Gel Cream 247 Hexachlorophene Cream 248 Hydrocortisone Acetate and Pramoxine Hydrochloride Cream and Lotion 249 Hydrocortisone Acetate Suppositories 249 Hydrocortisone and Nitrofurazone Cream 249 Hydrocortisone Butyrate Cream and Ointment 250 Hydrocortisone Cream 250 Hydrocortisone Cream 251 Hydrocortisone Cream 251 Hydrocortisone Cream and Ointment 252 Hydrocortisone Gel 252 Hydrocortisone Gel 252 Hydrocortisone Gel 253 Hydrocortisone Ointment 253 Hydrogen Peroxide and Carbamide Peroxide Bleaching Oral Dentifrice 253 Hydrogen Peroxide Bleaching Dentifrice Paste 254 Hydrogen Peroxide Ointment 254 Hydrophilic Ointment USP 255 Hydroquinone Cream 255 Hydroquinone Cream and Gel 256 Hydroquinone Gel 256 Ibuprofen and Domperidone Maleate Suppository 257 Ibuprofen Cream 257 Ibuprofen Gel 257 Ibuprofen Gel 258 Ibuprofen Gel 258 Ibuprofen Gel Cream 258 Ibuprofen Gel Cream 259 Ibuprofen Gel Cream 259 Imiquimod Cream 259 Indomethacin Gel 259 Indomethacin Gel 260 Indomethacin Gel 260 Indomethacin Suppositories 261 Indomethacin Suppositories 261 Indomethacin Suppositories 261 Insect Bite Cream 262 Keratolytic Cream 262 Ketoconazole Cream 263 Ketoconazole Cream 263 Kojic Dipalmitate Cream 263 Lactic Acid Cream 264 Lanolin Cream 264 Lidocaine Adhesive System Gel 264 Lidocaine and Prilocaine Topical Adhesive System Cream 264 Lidocaine and Tribenoside Cream 265 Lidocaine and Tribenoside Ointment 265 Lidocaine and Tribenoside Suppositories 266 Lidocaine Anorectal Cream 266 Lidocaine, Eugenol, and Menthol Dental Ointment 266 Lidocaine Gel 267 Lidocaine Gel 267 Lidocaine Ointment 267 Lindane Lotion 268 Mafenide Acetate Cream 268 Malathion Lotion 268 Mandelic Acid Cream 268 Medicated Foot Cream 269 Menthol, Methyl Salicylate, and Menthol Cream and Ointment 269 Mercuric Oxide Ointment 269 Mesalamine Suppository 269 Methotrexate Cataplasms 270 Methotrexate Cream 270 xix xx Contents Methotrexate Gel 270 Methotrexate Lotion 271 Methoxsalen Lotion 271 Methyl Salicylate and Menthol Cream 271 Methyl Salicylate and Menthol Gel 272 Methyl Salicylate and Menthol Lotion 272 Methyl Salicylate and Menthol Ointment 272 Methyl Salicylate Clear Gel 273 Methyl Salicylate Cream 273 Methyl Salicylate Cream 274 Methyl Salicylate Heat Rub Lotion 274 Methyl Salicylate Lotion 275 Methyl Salicylate, Thyme, Pine, and Menthol Foot Cream 275 Metoclopramide Suppositories 276 Metoclopramide Suppositories 276 Metoclopramide Suppositories 277 Metoclopramide Suppositories 277 Metronidazole Cream 277 Metronidazole Gel Solution 278 Metronidazole Lotion 278 Metronidazole Vaginal Gel 278 Miconazole Cream 278 Miconazole Mouth Gel 279 Miconazole Nitrate Cream 279 Miconazole Nitrate Vaginal Suppositories 280 Miconazole Nitrate Vaginal Suppositories (400 mg) 280 Minoxidil Gel 281 Minoxidil Gel 281 Minoxidil Gel 281 Minoxidil Gel 282 Mometasone Furoate Cream 282 Mometasone Furoate Lotion 282 Monobenzone Cream 283 Multivitamin Oral Gel Veterinary 283 Multivitamin Oral Gel with Linoleic and Linolenic Acid 284 Mupirocin Calcium Cream 284 Mupirocin Ointment 284 Mupirocin Ointment 285 Naftifine Hydrochloride Cream 285 Naftifine Hydrochloride Cream 285 Nanoxynol Suppository with Bacterial Culture 286 Neomycin and Bacitracin Ointment 287 Neomycin Gel 287 Neomycin, Polymyxin B Sulfate, and Bacitracin Zinc Opthalmic Ointment 288 Nicotine Polymer Gel 288 Nitrofurazone Cream 288 Nondetergent Neutral Dry Skin Cream 289 Nystatin Cream 289 Nystatin Ointment 290 Nystatin, Neomycin Sulfate, Gramicidin, and Triamcinolone Acetonide Cream 291 Nystatin, Neomycin Sulfate, Gramicidin, and Triamcinolone Acetonide Ointment 292 Octyl Methoxycinnamate, Octyl Salicylate, and Oxybenzone Gel 292 Olibanum Gum Cream 292 Oxiconazole Cream and Lotion 293 Oxymorphone Hydrochloride Suppositories 293 Oxytetracycline Ointment 293 Panthenol and Chlorhexidine Lotion 293 Panthenol Ointment 294 Panthenol Lotion 294 Pantoprazole–Cholesterol Complex Suppository 295 Papain Chewing Gum 295 Papain Ointment 295 Penciclovir Cream 295 Peppermint Cream 295 Permethrin Cream and Lotion 296 Petrolatum and Lanolin Ointment 296 Phenylephrine Ointment, Cream, Suppositories, and Gel 296 Piroxicam Ointment 296 Piroxicam and Dexpanthenol Gel 296 Polymyxin, Bacitracin, Hydrocortisone, and Zinc Ointment 297 Povidone–Iodine and Lidocaine Gel 297 Povidone–Iodine Bar Soap 297 Povidone–Iodine Bar Soap 298 Povidone–Iodine Bar Soap 298 Povidone–Iodine Cream 298 Povidone–Iodine Cream 299 Povidone–Iodine Cream 299 Povidone–Iodine Gel 299 Povidone–Iodine Gel 300 Povidone–Iodine Gel 300 Povidone–Iodine Gel Cream 300 Povidone–Iodine Gels 301 Povidone–Iodine Glucose Ointment 301 Povidone–Iodine Glucose Ointment 301 Povidone–Iodine Mastitis Cream for Cattle 302 Povidone–Iodine Soft Gel 302 Povidone–Iodine Transparent Ointment 302 Povidone–Iodine Vaginal Ovule 303 Povidone–Iodine Vaginal Ovule 303 Povidone–Iodine Vaginal Ovules 303 Povidone–Iodine Vaginal Ovules 303 Pramoxine Cream 304 Pramoxine Hydrochloride and Zinc Acetate Lotion and Ointment 305 Pramoxine Suppositories 305 Pramoxine Suppositories 305 Pranoprofen Ointment 306 Prednicarbate Emollient Cream 306 Prochlorperazine Suppositories 306 Progesterone Gel 306 Promethazine Hydrochloride Suppositories 306 Promethazine Suppository 306 Psoriasis Cream 306 Psoriasis Cream 307 Resorcinol Acne Cream 307 Rubefacient Analgesic Ointment 307 Salicylic Acid Cream 308 Salicylic Acid Cream 308 Salicylic Acid Gel 309 Scopolamine Transdermal Therapeutic System 309 Selenium Sulfide Detergent Lotion 310 Selenium Sulfide Lotion 311 Silicone Cream 311 Silver Sulfadiazine Cream 311 Silver Sulfadiazine Cream 311 Sodium Chloride Ointment 312 Sodium Sulfacetamide Lotion 312 Contents Spermatocidal Effervescent Suppository 313 Squalene Cream 313 Starch Ointment 313 Sucralafate and Hyaluronic Acid Ointment 313 Sucralafate Ointment 314 Sucralafate Opthalmic Ointment 314 Sulfacetamide Ointment 314 Sulfacetamide Sodium and Prednisolone Acetate Opthalmic Ointment 314 Sulfanilamide Suppositories 314 Sulfathiazole Cream 315 Sulfur Ointment 315 Tacrolimus Ointment 315 Terconazole Vaginal Cream 315 Terconazole Vaginal Suppositories 315 Testosterone Gel 315 Testosterone Transdermal System 316 Tetracaine Gel and Cream 316 Tetracycline Hydrochloride Ointment 316 TGF Alpha-Ointment 316 Therapeutic Skin Lotion 317 Tolnaftate and Undecylenate Cream 317 Tretinoin and Alpha-Bisabolol Gel 318 Tretinoin and Dexpanthenol Gel 318 Tretinoin Cream 319 Tretinoin Cream 319 Tretinoin Gel 319 Tretinoin Gel Microsphere 320 Triacontanol Ointment 320 Triclosan Foot Care Cream 320 Triclosan Foot Cream 321 Tridax procumbens Ointment 321 Trolamine Salicylate Cream 322 Ulinastatin Suppository 322 Ultrasonic Adhesive Gel 322 Vitamin A Ointment 323 Vitamin A Suppositories 323 Vitamin C Vaginal Ointment 323 Vitamin E Gel Cream 324 Wound Debriding Ointment 324 Zinc Oxide and Vitamin E Cream 324 Zinc Oxide Lotion 325 Zinc Oxide Ointment 325 Zinc Oxide Ointment 325 Zinc Oxide Ointment with Vitamin E and Aloe 326 Zinc Pyrithione Detergent Lotion 326 Zinc Undecylenate Cream 326 Zirconium Oxide Lotion 327 Commercial Pharmaceutical Formulations 327 Index…. 335 xxi Part I Regulatory and Manufacturing Guidance 1 Waiver of In Vivo Bioequivalence Study I. INTRODUCTION This guidance provides recommendations for sponsors of investigational new drug applications (INDs), new drug applications (NDAs), abbreviated new drug applications (ANDAs), and supplements to these applications that wish to request a waiver of in vivo bioavailability (BA) or bioequivalence (BE) studies for immediate-release (IR) solid oral dosage forms. These waivers apply to Bioavailability and bioequivalence studies are expensive to conduct and given the need for multitude of these studies in the development of an NDA or ANDA, there had always existed a need to justify these needs on scientific grounds. This is particularly important for the generic drug industry since the generic competitors must keep their cost of regulatory approval to as low a level as possible. Recently, guidelines have emerged that would allow waiver of both BA and BE studies in some situations. There are also provisions available for the sponsor to challenge the requirement and if the basic criteria set are met, there is a very good possibility of receiving waivers. These waivers are intended to apply to the following: 1. subsequent in vivo BA or BE studies of formulations after the initial establishment of the in vivo BA of IR dosage forms during the IND period and 2. in vivo BE studies of IR dosage forms in ANDAs Regulations at 21 CFR Part 320 address the requirements for bioavailability (BA) and BE data for approval of drug applications and supplemental applications. Provision for waivers of in vivo BA/BE studies (biowaivers) under certain conditions is provided at 21 CFR 320.22. This guidance explains when biowaivers can be requested for IR solid oral dosage forms based on an approach termed the biopharmaceutics classification system (BCS). r Subsequent in vivo BA or BE studies of formulations after the initial establishment of the in vivo BA of immediaterelease (IR) dosage forms during the IND period. r In vivo BE studies of IR dosage forms in ANDAs. Regulations at 21 CFR part 320 address the requirements for bioavailability (BA) and BE data for approval of drug applications and supplemental applications. II. THE BIOPHARMACEUTICS CLASSIFICATION SYSTEM Provision for waivers of in vivo BA/BE studies (biowaivers) under certain conditions is provided at 21 CFR 320.22. Waiver for bioequivalence testing therefore becomes a topic of great interest worldwide. Several consortiums have debated this topic for years and a consensus has begun to develop on this topic. A large number of policy documents address this topic and include the published FDA and ICH guidelines, Health Canada’s Guideline on Preparation of DIN Submissions, WHO document (1999) entitled “Marketing Authorization of Pharmaceutical Products with Special Reference to Multisource (Generic) Products: a Manual for Drug Regulatory Authorities, Multisource (Generic) Pharmaceutical Products: Guidelines on Registration Requirements to Establish Interchangeability,” Note for Guidance on the Investigation of Bioavailability and Bioequivalence, Committee for Proprietary Medicinal Products (CPMP), 26 July 2001 (CPMP/EWP/QWP/98), and Pan-American Network on Regulatory harmonization: Bioavailability and Bioequivalence working group 2004. The requirement for the in vivo bioequivalence study may be waived for certain generic products [21 USC 360 b (n) (1) (E)]. Categories of products which may be eligible for waivers include, but are not limited to, the following: The BCS is a scientific framework for classifying drug substances based on their aqueous solubility and intestinal permeability. When combined with the dissolution of the drug product, the BCS takes into account three major factors that govern the rate and extent of drug absorption from IR solid oral dosage forms: dissolution, solubility, and intestinal permeability. According to the BCS, drug substances are classified as follows: Class 1: High solubility—high permeability Class 2: Low solubility—high permeability Class 3: High solubility—low permeability Class 4: Low solubility—low permeability In addition, IR solid oral dosage forms are categorized as having rapid or slow dissolution. Within this framework, when certain criteria are met, the BCS can be used as a drug development tool to help sponsors justify requests for biowaivers. There are several factors that affect classification of drugs in different classes. Table 1.1 expands this classification to include a more detailed description including the effect of transporter efflux factors. Observed in vivo differences in the rate and extent of absorption of a drug from two pharmaceutically equivalent solid oral products may be due to differences in drug dissolution in vivo. However, when the in vivo dissolution of an IR solid oral dosage form is rapid in relation to gastric emptying and the drug has high permeability, the rate and extent of drug absorption is unlikely to be dependent on drug dissolution and/or gastrointestinal transit time. Under such circumstances, demonstration of in vivo BA or BE may not be necessary for drug products containing Class 1 drug r Parenteral solutions intended for injection by the intravenous, subcutaneous, or intramuscular routes of administration. r Oral solutions or other solubilized forms. r Topically applied solutions intended for local therapeutic effects. Other topically applied dosage forms intended for local therapeutic effects for nonfood animals only. r Inhalant volatile anesthetic solutions. 2 Waiver of In Vivo Bioequivalence Study Table 1.1 3 The Biopharmaceutics Classification System (BCS) as Defined by the FDA and Modified by Recent Findings High permeability (e.g., absorption >90% compared to intravenous dose) (drug + metabolite). Low permeability High solubility (e.g., when the highest dose strength is soluble in 250 mL or less of aqueous media over a pH range of 1–7.5 at 37◦ C) Low solubility Class 1: (generally about 8% of new leads) Class 2: r r r r r r r r r High solubility High permeability Rapid dissolution for biowaiver Route of elimination: metabolism, extensive. Transporter effects: minimal Low solubility High permeability Route of elimination: metabolism, extensive. Transporter: efflux transporter effects predominant Examples: Abacavir; Acetaminophen; Acyclovirb ; AmilorideS, I ; AmitryptylineS, I ; Antipyrine; Atropine; Buspironec ; Caffeine; Captopril; ChloroquineS, I ; Chlorpheniramine; Cyclophosphamide; Desipramine; Diazepam; DiltiazemS, I ; diphenhydramine; Disopyramide; Doxepin; oxycycline; Enalapril; Ephedrine; Ergonovine; Ethambutol; Ethinyl estradiol; FluoxetineI ; Glucose; ImipramineI ; Ketoprofen; Ketorolac; Labetalol; LevodopaS ; LevofloxacinS ; LidocaineI ; Lomefloxacin; Meperidine; Metoprolol; Metronidazole; MidazolamS, I ; Minocycline; Misoprostol; NifedipineS ; Phenobarbital; Phenylalanine; Prednisolone; PrimaquineS ; Promazine; PropranololI ; QuinidineS, I ; Rosiglitazone; Salicylic acid; Theophylline; Valproic acid; VerapamilI ; Zidovudine Examples: AmiodaroneI ; AtorvastatinS, I ; AzithromycinS, I ; CarbamazepineS, I ; Carvedilol; ChlorpromazineI ; CiprofloxacinS ; CisaprideS ; CyclosporineS, I ; Danazol; Dapsone; Diclofenac; Diflunisal; DigoxinS ; ErythromycinS, I ; Flurbiprofen; Glipizide; GlyburideS, I ; Griseofulvin; Ibuprofen; IndinavirS ; Indomethacin; ItraconazoleS, I ; KetoconazoleI ; LansoprazoleI ; LovastatinS, I ; Mebendazole; Naproxen; NelfinavirS, I ; Ofloxacin; Oxaprozin; Phenazopyridine; PhenytoinS ; Piroxicam; RaloxifeneS ; RitonavirS, I ; SaquinavirS, I ; SaquinavirS, I ; SirolimusS ; SpironolactoneI ; TacrolimusS, I ; TalinololS ; TamoxifenI ; TerfenadineI ; Warfarin Class 3: Class 4: r High solubility r Low permeability r Route of elimination: renal and/or biliary r Low solubility r Low permeability r Route of elimination: renal and/or biliary elimination of unchanged drug; metabolism poor r Transporter: absorptive effects predominant elimination of unchanged drug; metabolism poor r Transporter: absorptive and efflux transporters can be predominant Examples: Acyclovir; AmilorideS, I ; AmoxicillinS, I ; Atenolol; Atropine; Bidisomide; Bisphosphonates; Captopril; Cefazolin; Cetirizine; CimetidineS ; CiprofloxacinS ; Cloxacillin; DicloxacillinS ; ErythromycinS, I ; Famotidine; FexofenadineS ; Folinic acid; Furosemide; Ganciclovir; Hydrochlorothiazide; Lisinopril; Metformin; Methotrexate; Nadolol; Penicillins; PravastatinS ; RanitidineS ; Tetracycline; TrimethoprimS ; Valsartan; Zalcitabine Examples: Amphotericin B; Chlorothiazide; Chlorthalidone; CiprofloxacinS ; Colistin; Furosemide; Hydrochlorothiazide; Mebendazole; Methotrexate; Neomycin Notes: The compounds listed in italic are those falling in more than one category by different authors, which could be a result of the definition of the experimental conditions. The compounds listed in bold are primarily CYP3A substrates where metabolism accounts for more than 70% of the elimination; superscript I and/or S indicate P-gp inhibitors and/or substrate, respectively. The Class 1 and Class 2 compounds are eliminated primarily via metabolism, whereas Class 3 and Class 4 compounds are primarily eliminated unchanged into the urine and bile. 4 Handbook of Pharmaceutical Manufacturing Formulations: Semisolid Products substances, as long as the inactive ingredients used in the dosage form do not significantly affect absorption of the active ingredients. The BCS approach outlined in this guidance can be used to justify biowaivers for highly soluble and highly permeable drug substances (i.e., Class 1) in IR solid oral dosage forms that exhibit rapid in vitro dissolution using the recommended test methods [21 CFR 320.22(e)]. Several generalizations can be made about the interplay of transporters and the BCS classification. a. Transporter effects are minimal for Class 1 compounds. The high permeability/high solubility of such compounds allows high concentrations in the gut to saturate any transporter, both efflux and absorptive. Class 1 compounds may be substrates for both uptake and efflux transporters in vitro in cellular systems under the right conditions [e.g., midazolam and nifedipine are substrates for Pglycoprotein (P-gp)], but transporter effects will not be important clinically. It is therefore possible that some compounds that should be considered Class 1 in terms of drug absorption and disposition are not Class 1 in BCS due to the requirement of good solubility and rapid dissolution at low pH values. Such pH effects would not be limiting in vivo where absorption takes place from the intestine. Examples of this include the NSAIDs diclofenac, diflunisal, flurbiprofen, indomethacin, naproxen, and piroxicam; warfarin is almost completely bioavailable. In contrast, ofloxacin is listed as Class 2 because of its low solubility at pH 7.5. b. Efflux transporter effects will predominate for Class 2 compounds. The high permeability of these compounds will allow ready access into the gut membranes and uptake transporters will have no effect on absorption, but the low solubility will limit the concentrations coming into the enterocytes, thereby preventing saturation of the efflux transporters. Consequently, efflux transporters will affect the extent of oral bioavailability and the rate of absorption of Class 2 compounds. c. Transporter-enzyme interplay in the intestines will be important primarily for Class 2 compounds that are substrates for CYP3A and Phase 2 conjugation enzymes. For such compounds, intestinal uptake transporters will generally be unimportant due to the rapid permeation of the drug molecule into the enterocytes as a function of their high lipid solubility. That is, absorption of Class 2 compounds is primarily passive and a function of lipophilicity. However, because of the low solubility of these compounds, there will be little opportunity to saturate apical efflux transporters and intestinal enzymes such as cytochrome P450 3A4 (CYP3A4) and UDPglucuronosyltransferases (UGTs). Thus, changes in transporter expression and inhibition or induction of efflux transporters will cause changes in intestinal metabolism of drugs that are substrates for the intestinal metabolic enzymes. Note the large number of Class 2 compounds in Table 1.1 that are primarily substrates for CYP3A (compounds listed in bold) as well as substrates or inhibitors of the efflux transporter P-gp (indicated by superscripts S and I, respectively). Work in our laboratory has characterized this interplay in the absorptive process for the investigational cysteine protease inhibitor K77 (28, 32) and sirolimus (29), substrates for CYP3A and P-gp, and more recently for raloxifene (33), a substrate for UGTs and P-gp. d. Absorptive transporter effects will predominate for Class 3 compounds. For Class 3 compounds, sufficient drug will be available in the gut lumen due to good solubility, but Table 1.2 Model Drugs to Establish Permeability of Drugs Drug Permeability Class Antipyrine Caffeine Carbamazepine Fluvastatin Ketoprofen Metoprolol Naproxen Propranolol Theophylline Verapamil Amoxicillin Atenolol Furosemide Hydrochlorthiazide Mannitol Methyldopa Polyethylene glycol (400) Polyethylene glycol (1000) Polyethylene glycol (4000) Ranitidine High (potential IS candidate) High High High High High (potential IS candidate) High High High High (potential ES candidate) Low Low Low Low Low (potential IS candidate) Low Low Low Low (zero permeability marker) Low an absorptive transporter will be necessary to overcome the poor permeability characteristics of these compounds. However, intestinal apical efflux transporters may also be important for the absorption of such compounds when sufficient enterocyte penetration is achieved via an uptake transporter. Table 1.2 lists model drugs suggested for use in establishing suitability of a permeability method. The permeability of these compounds was determined based on data available to the FDA. Potential internal standards (IS) and efflux pump substrates (ES) are also identified. For application of the BCS, an apparent passive transport mechanism can be assumed when one of the following conditions is satisfied: r A linear (pharmacokinetic) relationship between the dose (e.g., relevant clinical dose range) and measures of BA (area under the concentration-time curve) of a drug is demonstrated in humans. r Lack of dependence of the measured in vivo or in situ permeability is demonstrated in an animal model on initial drug concentration (e.g., 0.01, 0.1, and 1 times the highest dose strength dissolved in 250 mL) in the perfusion fluid. r Lack of dependence of the measured in vitro permeability on initial drug concentration (e.g., 0.01, 0.1, and 1 times the highest dose strength dissolved in 250 mL) is demonstrated in donor fluid and transport direction (e.g., no statistically significant difference in the rate of transport between the apical-to-basolateral and basolateral-to-apical direction for the drug concentrations selected) using a suitable in vitro cell culture method that has been shown to express known efflux transporters (e.g., P-gp). To demonstrate suitability of a permeability method intended for application of the BCS, a rank-order relationship between test permeability values and the extent of drug absorption data in human subjects should be established using a sufficient number of model drugs. For in vivo intestinal perfusion studies in humans, six model drugs are recommended. For in vivo or in situ intestinal perfusion studies in animals and for in vitro cell culture methods, 20 model drugs are recommended. Depending on study variability, a sufficient Waiver of In Vivo Bioequivalence Study number of subjects, animals, excised tissue samples, or cell monolayers should be used in a study to provide a reliable estimate of drug permeability. This relationship should allow precise differentiation between drug substances of low- and high-intestinal permeability attributes. For demonstration of suitability of a method, model drugs should represent a range of low (e.g.,.

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