136188028-Handbook-of-Pharmaceutical-Generic-Development-Vol-03-Part-1.pdf

SEMISOLID TOPICAL DOSAGE FORM

HHandbook of PPharmaceutical h a n d b o o k s @ l o c u m u s a . c o m GGeneric DDevelopmenthttp://www.l o c u m u s a . c o m

HANDBOOK OF PHARMACEUTICALGENERIC DEVELOPMENT

S E M ISOLIDS

VOLUME III - Part One Generic Development Topical Dosage Forms

HANDBOOK OF PHARMACEUTICALGENERIC DEVELOPMENT

Handbook o f Pharmaceut ica lGeneric Development 24 Volume Series



H a n d b o o k o f P h a r m a c e u t i c a lG e n e r i c D e v e l o p m e n t S e r i e s

Compiled by :J . D . B L O C K

BSc. MPS. D/PHARM.

Research Director Generic & Innovative Drug Development Division, Locum International Group.Science Editor - International Journal of Generic Drugs & International Journal of Drug Development

School of Pharmacy University of the Witwatersrand and Witwatersrand TechnikonJohannesburg RSA.

Edited:I A G I M S c i e n t i f i c C o m m i t t e e

Review Process :Generic & Innovative Drug Development Division

Research CenterLocum International Research

Handbook of Pharmaceutical Generic Development Vol. 1 - TabletsPart I (Development) & Part II (Model ANDA or EU Dossier)

Handbook of Pharmaceutical Generic Development Vol. 2 - CapsulesPart I (Development) & Part II (Model ANDA or EU Dossier)

Handbook of Pharmaceutical Generic Development Vol. 3 - SemisolidsPart I (Development) & Part II (Model ANDA or EU Dossier)

Handbook of Pharmaceutical Generic Development Vol. 4 - LiquidsPart I (Development) & Part II (Model ANDA or EU Dossier)

Handbook of Pharmaceutical Generic Development Vol. 5 - SG CapsulesPart I (Development) & Part II (Model ANDA or EU Dossier)

Handbook of Pharmaceutical Generic Development Vol. 6 - e-SOPs / SOPs.Part I (Development) & Part II (Model ANDA or EU Dossier)

Handbook of Pharmaceutical Generic Development Vol. 7 - SuspensionsPart I (Development) & Part II (Model ANDA or EU Dossier)

Handbook of Pharmaceutical Generic Development Vol. 8 - Eye & NosePart I (Development) & Part II (Model ANDA or EU Dossier)

Handbook of Pharmaceutical Generic Development Vol. 9 - Aerosols MDIPart I (Development) & Part II (Model ANDA or EU Dossier)

Handbook of Pharmaceutical Generic Development Vol. 10 -Tablets CR/MRPart I (Development) & Part II (Model ANDA or EU Dossier)

Handbook of Pharmaceutical Generic Development Vol. 11 -Capsules ERPart I (Development) & Part II (Model ANDA or EU Dossier)

Handbook of Pharmaceutical Generic Development Vol. 12 - Tablets Oral DRHandbook of Pharmaceutical Generic Development Vol. 13 - AnalyticalPart I (Method Validation) & Part II (Analytical Methods 1994-2003) (Top 50 Generic Assay Methods)Handbook of Pharmaceutical Innovative Development Vol. 14 - Tablets OralHandbook of Pharmaceutical Innovative Development Vol. 15 - Capsules OralHandbook of Pharmaceutical Innovative Development Vol. 16 - Suspensions OralHandbook of Pharmaceutical Drug Development (1-5) Vol. 17 - MF and MMI(Master Formula & Manufacturing Instructions Parts 1 - 5)

Handbook of Pharmaceutical Drug Development (6-10) Vol. 18 - MF and MMI(Master Formula & Manufacturing Instructions Parts 6 - 10)

Handbook of Pharmaceutical Innovative Development Vol. 19 - SOPs/PAI-ChecklistPart I, Part II & Part III.(Development, Manufacturing & Engineering)

Handbook of Pharmaceutical Drug Development Vol. 20 - Sterile Injections

Available either on Online, CD ROM or via electronic mail attachment.Additional Drug Specific Volumes in Preparation. An on-going electronic and print series

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H A N D B O O K O FP H A R M A C E U T I C A LGENERIC DEVELOPMENT

SemisolidT O P I C A L D O S A G E F O R M

VOLUME III - Part ONES E M I S O L I D D O S A G E F O R M

Jeremy D. BlockB.Sc. MPS. D/Pharm.

International Euro Edition. L O C U M P U B L I S H I N G H O U S E

[email protected] / [email protected] Publishing House - Israel Locum Pharmaceutical Publishers - USA Locum International Publishers - Cape Town



Innova t i ve Ser ies

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Handbook ofPharmaceuticalG e n e r i cDevelopment

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Copyright 1994-00 - Locum PublishingHouse Inc. All Rights Reserved.

Neither this book nor any part may bereproduced or transmitted in any form orby any means, electronic or mechanical,including photocopying, microfilming andrecording, or by any information storageand retrieval system, without thepermission of the publishers.A L o c u m H o u s e P u b l i c a t i o n

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LOCUM INTERNATIONAL PUBLISHERS REGISTRATION SERVICESWARNING: THIS ISSUE A IS MULTIPLE PAGE UV CODED PUBLICATION.

HPDD Innovative Series - Semisolid Dosage FormsFirst and Second International Edition - 01/02.First and Second edition published and distributed in UK, US, EU, RSA, Israel and Japan inNovember 1996-9: by Locum International Publishing House (Houston, Israel, South Africa).

Third International Edition - 03 (First Print).Second printing published and distributed in UK, US, EU, Israel, Asia, and Japan inFebruary 2000 by Locum International Publishing House (Houston, Israel, South Africa) inHard Cover; Soft and Spiral Cover; Electronic Diskette; and e-mail attachment versions. Allprint and electronic versions identical in content and format.

Copyright 1995 - 2000, Handbook of Pharmaceutical Generic Development.Text Copyright 1995 - 2000, Handbook of Pharmaceutical Generic Development.Illustration copyright 1995 - 2000, Handbook of Pharmaceutical Generic Development.Locum International Publishing House PO Box 874, 50 Gilad Street Kochav Yair 44864Israel. - All right reserved.ISBN 0793 873XISBN 0793 8748 - Electronic Version (Diskette, CD ROM, and Online version)Handbook Development 24 volume series.General ISSN Series number 0793 7407General ISSN Series number 0793 7792 - Electronic Issue (Diskette, CD ROM andOnline version are identical in size and content to the printed hard or soft coverversion.)

Duplication: No part of this publication may be reproduced, stored in a retrievalsystem or transmitted in any form or by any means, electronic, mechanical,photocopying, microfilming, recording or otherwise, without the prior writtenpermission of the copyright owner or subject to the following conditions:Authorization to photocopy items for internal or personal use or internal or personaluse of specific company personnel, is granted by Locum International PublishingHouse, provided that the base fee of $3 per page is paid directly to the CopyrightClearance Center (CCC) 222 Rosewood Drive, Danvers, MA 01923 USA. Fororganizations that have been granted a photocopy license by CCC, a separatesystem of payment has been arranged.For additional information, contact the Publications Department Locum InternationalPublishing House; PO Box 874, 50 Gilad Street, Kochav Yair, 44864 Israel.

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E D I T O R I A L P R E F A C EHandbook of Generic Drug Development - Semisolid Dosage Forms

his handbook represents the third International Edition for Europe of the ongoing24 volume series of Generic Drug Development and appears under the

cumulative title of the Handbook series of Generic Drug Development. The ongoingseries is updated annually at the end of each year. This is an ongoing process asnew data, specifications and process techniques are added on a continual andexpanding basis. This handbook is fact, never fully complete, as each new annualedition brings an enlarged and extended profile in the drug development process, aswell as new agency rules, guidelines and guidance to industry which continue to beadded year by year as the global product data base expands. Currently over 150scientific publications and drug development conferences are annually referenced inthe 24 volume Handbook series of Generic Drug Development.This mammoth task presents a continual ongoing commitment by the scientificreview committee to the improvement of the technical databases and the productspecific drug development requirements and know-how technology accessedthrough the world wide IAGIM joint ventures and know-how projects currently activein over 15 countries.The Handbook is available in electronic format (Online and CD ROM) and the e-format is up-dated annually to association members of IAGIM.

This third international edition of the Handbook has been redesigned and updatedto meet the January 1999 Guidance for Industry - Organization of an AbbreviatedNew Drug Application and an Abbreviated Antibiotic Application as well as all currentapproved and draft FDA guideline requirements of the Center of Drug Evaluationand Research (CDER) up to June 2000. Editor-in-Chief.

ISSN 0793 873X

A n o n - g o i n g s e r i e sA d d i t i o n a l V o l u m e s i n P r e p a r a t i o n

General Series ISSN 0793 7407Electronic Series ISSN 0793 7792

0793 7407International Print Edition

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AcknowledgmentsI.A.G.I.M. (R&D) Foundation.

I.A.G.I.M. Members (1994 - 2000).Contributions - Generic & Research Firms

Associate Universities, Technicons and Consultants.Handbook Series Coordinating Committee. International Journal of Drug Development.

Journal of Pharmaceutical Development.International Journal of Generic Drugs.I.A.G.I.M. Drug Development Archives

Locum International Archives.FDA/OGD/CDER Maryland

Guides and GuidelinesLibrary of Congress.AIC Conferences.Editorial Board.

Pharm. Eur.USP/NF.USPC.

BP.

T o D o r i b e l l e f o r h e r y e a r s o f s u p p o r t a n d h e l p

t o S e a n f o r h i s e x p e r t k n o w l e d g e o n c o m p u t e r i z a t i o nt o D a v i d a n d A r i f o r r u n n i n g t h e p r o j e c t ' s c o m p u t e r s

a n d l a s t l y t o P a t f o r h i s i n e s t i m a b l ec o n t r i b u t i o n .

Third International Edition.2000

L O C U M P U B L I S H I N G H O U S E

CONTENTS.CONTENTS.

HHandbook of PPharmaceutical GGeneric DDevelopment 24 Volume Drug Development [email protected] [email protected]

ContentsP H A R M A C E U T I C A L D E V E L O P M E N T

Table of Contents VIIIAcronyms - Abbreviations XIIIIntroduction XVIPreface XVForward XVI

Chapter 11Regulatory 1.1 - Pre-formulation checklist 1.2Documentation 1.3- SOP Control checklist 1.4Development Notebooks 1.5- Development Notebooks checklist 1.6- SOP Control and Development Notebooks SOPs 1.7

Chapter 22Developing the Formula -an Overview 2.1- Formulation checklist 2.2- Formula Development 2.3Drug Development Checklist 2.4Development formula SOPs 2.5Developing the Formula 2.7Purified Water - an ingredient 2.12Product Development Guide 2.19

Chapter 33Active Ingredients 3.1-Dos and Donts 3.2-Active checklist - Approved suppliers 3.4-Active checklist timeline 3.5-Standard Operating Procedures, actives 3.6-Active Ingredients - Approved suppliers SOP 3.7

CONTENTS.CONTENTS.


ContentsChapter 44Semi active ingredients 4.1-Validating the semi active ingredients, checklist 4.2Non active materials (excipients) 4.3-checklist non active ingredient 4.4Standard Operating Procedures, Non actives 4.5Qualifying the semiactives 4.6Semi active Tabulations 4.7Qualifying of the antioxidant 4.11The Reference Listed Drug 4.14

Chapter 55Container closure systems 5.1-Container-liner-closure systems, Checklist 5.2-Container-liner-closure systems, SOPs 5.5-Container-liner-closure systems - Flowchart 5.8

Chapter 66Manufacturing Instructions 6.1- Manufacturing Instructions; Checklist 6.2- The Manufacturing Instructions and Controls 6.5- The Manufacturing Process 6.9- The Manufacturing Flow Charts 6.16- The Manufacturing Controls 6.21- Packaging Operation 6.25

Chapter 77In-process Quality Controls 7.1-Manufacturing in-process controls; Checklist 7.2-Manufacturing in-process controls; What to Validate? 7.4-In-process Quality Controls; SOPs 7.5

Chapter 88Finished Product Specifications 8.1- Finished Product Specifications; checklist 8.3- Glossary of Terms and Specifications 8.4- Finished Product Specifications; SOPs 8.7

CONTENTS.CONTENTS.


ContentsChapter 99Process Optimization 9.1Qualification of Antioxidant and Preservatives 9.2Qualification of finished Product Specification 9.3Qualification of antioxidant and chelating Agent Limits 9.5Optimization - Stability Studies 9.8

Chapter 1010Scale-up procedures 10.1- Re-mixing & Processing Times 10.3- Scale-up procedures; checklist 10.4- Scale-up procedures; SOPs 10.5

Chapter 1111Cleaning Limits 11.1Cleaning Limits Procedures; Checklist 11.6Cleaning Validation Requirements; SOPs 11.7

Chapter 1212Analytical Validation Requirements 12.1-Analytical Testing Out of Specification 12.21-Analytical Testing Do's and Don'ts 12.23-Ruggedness and Robustness 12.27Analytical Validation Agency Guidelines 12.31

Chapter 1313Process Qualification Batch 13.1-Process Qualification Batch; Checklist 13.2-Process Qualification Batch; SOPs 13.3-Process Qualification - Sampling Bias 13.4-Process Qualification Sampling - Do's and Don'ts 13.6-Process Qualification Protocol 13.8

CONTENTS.CONTENTS.


ContentsChapter 1414Pivotal batch-The Pivotal Batch 14.1-Pivotal batch Checklist 14.2-Pivotal batch SOPs 14.3-Sampling and Testing the Pivotal Batch 14.5-Auditing the Pivotal batch 14.10-Auditing the Pivotal batch Checklist 14.11

Chapter 1515Bioequivalence vs. RLD 15.1Topical Bioequivalence 15.2Biostudy Graphs (Standard) 154.Diffusion Testing 15.7SUPAC SS* 15.9

Chapter 1616Technical Transfer Documentation 16.1-Technical Transfer Documentation; Checklist 16.5-Technical Transfer Documentation; Pharmaceutical Part 16.7-Technical Transfer Documentation; Analytical Part 16.10

Chapter 1717Process Validation batches 17.1-The Process Validation Batches; Checklist 17.3-Process Validation Requirements; SOPs 17.4-Process Validation Master Plan 17.5-Process Optimization Master Plan 17.8

Chapter 1818Pre--Approval Inspections 18.1Pre--Approval Summary Audit 18.8Pre--Approval Team Set-Up 18.9Pre--Approval Team Audit Activities 18.11

CONTENTS.CONTENTS.


ContentsChapter 1919Stability Testing of Drug Substance and Drug Product I 19.1Stability Testing of Drug Substance and Drug Product II 19.15Stability Testing of Drug Substance and Drug Product II 19.21Stability Testing Significant Change 19.24Storage Conditions 19.29Setting up a functional Stability Unit 19.31Stability SOPs Development 19.39

Chapter 2020Development SOPs 20.1Index of Pharmaceutical Standard Operating Procedures 20.5Index of Analytical Standard Operating Procedures 20.9Index of Microbiological Standard Operating Procedures 20.16Index of Stability Standard Operating Procedures 20.21Ready-To-Go Drug Development Series 20.27

ISSN 0793 873X

A n o n - g o i n g s e r i e sA d d i t i o n a l V o l u m e s i n P r e p a r a t i o n

H a n d b o o k o f P h a r m a c e u t i c a lG e n e r i c D e v e l o p m e n t S e r i e s

ISSN 0793 8748 - Electronic VersionsHandbook Development 24 Volume Series

Series ISSN Number 0793 7792 - Electronic Version

CONTENTS.CONTENTS.


H P G DH a n d b o o k o f P h a r m a c e u t i c a l G e n e r i c D e v e l o p m e n t

Drug Development - Part IANDA - Part II

Copyright 1995 -2000 Locum International Ltd.

2000 Update ProgramPart I and Part II: HandBook Generic Development Series

Volume 1 Edition 03 - 2000 Volume 9 Edition 03 - 2000 Volume 2 Edition 03 - 2000 Volume 10 Edition 03 - 2000 Volume 3 Edition 03 - 2000 Volume 11 Edition 03 - 2000 Volume 4 Edition 03 - 2000 Volume 12 Edition 03 - 2000 Volume 5 Edition 03 - 2000 Volume 13 Edition 03 - 2000 Volume 6 Edition 03 - 2000 Volume 14 Edition 03 - 2000 Volume 7 Edition 03 - 2000 Volume 15 Edition 03 - 2000 Volume 8 Edition 03 - 2000 Volume 16 Edition 03 - 2000

Initiation Date : January 2000Expiration Date : January 2003No of Years : Three (3)Update Period : January 2000; to January 2003.

This ANDA Drug Registration program has been updated to January 2000 Office of Generic Drugsrequirements. Handbook clients requiring to continue this annual service need only to becomemembers of I.A.G.I.M. for the period of the update service required by the firm.The ANDA Update Program is renewed in December each year as a function of the firmsrequirements.

Warning: Copyright 1985 -2000 Locum Publishing House Inc. - All Rights Reserved.Neither this information nor any part of the data contained therein may be reproduced, copied or transmitted inany form, modification or merged portion or by any means, electronic or mechanical, including printingphotocopying, microfilming and recording, or by any information storage and retrieval system, without the priorwritten permission of the publishers. Trademark - Locum Corporation, Locum International Group

[email protected]

(See web site for IAGIM Membership Benefits / Application Forms and additional details)[email protected]://www.locumeuro.com

D R U G D E V E L O P M E N T

Hand?20@&?00@BooksDrug Development & Manufacture for Pharmaceutical Technology Professions

SEMISOLIDS Introduction

HHandbook of PPharmaceutical GGeneric DDevelopmentxiv

Introductionhe purpose of the Handbook Series is to illustrate generic drug development from pre-formulation to regulatory submission. The Handbook Series on pharmaceutical dosageforms deals with the US generic drug development process of the ANDA (AbbreviatedNew Drug Application). It is equally suitable to the innovative drug development process

for the Chemistry-Manufacturing-Controls (CMC) Section of an New Drug Application (NDA).

Each book is devoted to a specific dosage form e.g. tablets, capsules, liquids, topical semisolids, suspensions, aerosols and so forth. This is an ongoing series that is reviewed andupdated twice annually, as new agency regulations, guides, guidelines and industryprocedures are adopted or regulated.

The Handbook is a basic hands-on working approach to generic drug development and theoverall developmental process. The book ends with the requirements for manufacturing thefirst three commercial product lots for distribution and marketing.

Each Handbook is presented in two volumes referred to as Part One and Part Two. These twoparts are supplementary and should be used and referenced together as they complementeach other. Electronic templates for the full registration process are available for each dosageform. These approximate +300 templates consist of electronically completed ANDA data whereonly the variable facts and figures need to be inserted into the prepared data fields.

Part One covers the development topics from pre-formulation of generic ANDAs to final FDAfiling with the Office of Generic Drugs. Each chapter details key development steps coupledwith a hands-on development checklists that dovetails with a series of SOPs on practicalgeneric issues that the FDA review chemists and inspectors routinely address during an ANDAfile review and during pre-approval site inspections (PAIs).

Agency site inspections routinely cover the product development unit or R&D departments,QC and Analytical Research laboratories, as well as the manufacturing facilities andproduction warehouses. During a product-specific pre-approval inspection there is aconcentration of effort by the inspectorate to thoroughly review and evaluate the drugdevelopment process from pre-formulation to pivotal batch.

Topics covered are real life examples from A (actives) to V (validation). Procedures are keptas simple as possible in order that the checklists and SOPs can be understood by alldepartmental personnel concerned. Repetition in the checklists and SOP is routinely used toemphasize essential procedures or requirements and to restate the aims and objective in atutorial manner. Thus the checklist becomes a first party audit or self-inspection format for theStandard Operating Procedures.

Part Two is a complete real-life dosage form specific working model of a US GenericApplication or commonly known as an Abbreviated New Drug Application (ANDA).

Part THREE is a complete real-life dosage form specific working model of a EU Dossier +Expert Report (the Electronic Handbook exhibits a unique Expert Report Compiler)

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SEMISOLIDS Introduction

HHandbook of PPharmaceutical GGeneric DDevelopmentxv

Preface getting a generic drug to the market place on time.

etting a generic drug to the market place at the right time is no easy task. Thegeneric drug product must be approved by the FDA, close to the latest patentand exclusivity expiration date of the innovator drug, if a firm wants to be thefirst generic drug product on the retail shelves.

Furthermore the three commercial validation batches should be manufactured, filledand packed via a full scale standard production run. The now ready-to-launch genericdrug product must meet all its product specifications and the three commercialvalidation lots should be on real time stability evaluation for at least one to threemonths. Should all this work have been completed on time and the manufacturingfacility is in full GMP compliance with all manufacturing and control documentation inplace - then the generic product has been developed .on time.

Getting to this point is a long training and planning operation. That it can be done hasbeen shown by dedicated and well managed generic innovative and genericcompanies. This handbook is designed to show the key highlights of the essentialtraining and planning along the way.

It is not a manual on how to pre-formulate or formulate a specific dosage form, moreover it is a handbook on how to plan, manage and deliver all the key ingredients of asuccessful generic drug product from pre-formulation to the marketed generic drug -on time and without a delay in the drug product development process.

The length and breath and importance of preparing a successful long life genericproduct for the market place requires much attention to detail. Development must stopif the product fails an essential intermediate, finished product or stability specificationand continue only after the fault has been isolated and corrected - thus the essentialuse of checklists and standard operating procedures in this Handbook. The SOPs aregeneric in content, they simply highlight important principles and way points and aresuitable for editing and customizing for the firms own in-house needs.

The FDA file contents and review expectations of the drug product must be wellunderstood and controlled early in the development process in order to avoid problemswith the approval process and later with the quality and customer acceptance of themarketed product. This Handbook emphasizes first party certification by in-houseauditing and self inspection programs exhibiting a past systematic QC track record thatmay help streamline FDAs enforcement of drug Good Manufacturing Practices(GMPs).

This handbook was designed to produce a rugged generic drug product - to rapidlyfacilitate FDA and pre-approval review and reach the market place on time...

Editor

G

Forward

HHandbook of PPharmaceutical GGeneric DDevelopmentxvi

FORWARDThirteen Key Directives

on Drug Development.

Directive 1. "Write a clear SOP on drugdevelopment". The goal of drugdevelopment is to present a qualityrugged drug in the overall shortestdevelopment time. If your firm hasn'tclear, concise drug developmentprocedures and objectives on file,backed-up with all the necessaryprotocols, from cleaning, to process toanalytical validation - don't start theproject until this is done.Directive 2."Run pilot studies - never uncontrolledstudies" - uncontrolled studies like non-validated assays may seem cheaper atthe time but generally give the wrongguidance. A pilot study to evaluate apotential bioequivalent product with afully validated analytical assay/metabolite/impurity procedure, prior tothe main study - often works out morecost effective than plunging into a highcost study without a pilot evaluation.Never do uncontrolled studies!Directive 3."Write and Report Facts Faithfully"A failed result is a positive endpoint as itmay well highlight a wrong developmentroute. If the result stays 'failed' after afull investigation, then report its impactand conclusions on the study or processfaithfully. Never average results in orderto bring an out-of-spec-result intospecification. That's a GLP violation.

Directive 4."Remember the 5C's of documentationEach documentation page of a report,protocol, method, or submission fileshould be like the 5C's of a flawlessdiamond (cut, clarity, clear, carat, cost.)

Clear statements, aims, objectivesconclusions and results inform thereviewer of where you are going.Concise - a report that is succinct andto the point is all that's needed.Compact, avoid any padding - period!Controlled prospective protocols andprocedures can be written for moststudies or processes and will producewell-controlled documents. Certify & check - review and auditevery document your development unitproduces. Sign, date and stampdocuments that have passed a carefuland thorough audit review process.Directive 5."Be innovative and creative"Get your research department to talk tothe developers, the production people,regulatory affairs and lab. analysts. Donot compartmentalise your personnel.Cross departmental communicationimparts development expertise andbuilds in genuine product value.Challenge SOPs and procedures withthe aim of producing a better product.Documentation can always be mademore attractive and user friendly.Writing procedures using attractive fontsand point sizes often invite readership.Directive 6."Be Open and Direct "Never hide a bad study or cover up apoor result. All test results are validunless an appropriate investigationprocedures proves otherwise. Reviewyour firm's out-of-specificationoperational procedure, and check thatthere are no organization omissionsDirective 7."Investigate all abnormalities"Test results that are out-of-specificationneed formal written investigations basedon a Out-Of-Specification StandardOperating Procedure. The result maywell be a simple sampling or technicianerror. For example - an extraneous peakthat suddenly appeared after manyproduction manufactured lots

Forward

HHandbook of PPharmaceutical GGeneric DDevelopmentxvii

in an HPLC assay spectrum, was foundon investigation to arise from a changein an inactive dye vendor (a newsupplier) and not as was anticipated anew product impurity or degradant.

Directive 8."Run a mock PAI against yourApplication just before submitting."The Drug Application will eventually bejudged on the acceptability of themanufacture, control and testingfacilities as documented in the agencyfile and in-house supporting data. Auditevery facet of the development,manufacture, control and stabilityprocedures of the drug product. Checkand cross-reference each possiblesubmission document against themanufacturing / control and laboratoryfiles and equipment logs. Build inroutine self-inspection checks duringthe development process. Formulatethis quality development routine bySOPs and department audit checklists.

Directive 9."Make your Application really clear,concise and user friendly "Well prepared and assembled print orelectronic files and dossiers are a joy toread, review, and evaluate. Use all thedesk top publishing tools to shape yourfirm's reports as attractive, stimulating,and interesting to read and review.A document can entice or repel a readersimply by its construction - it can also bemade a scientific work-of-art.

Directive 10."Treat regulators like your keypersonnel treat you"Listen to regulators - they too have theirstory to tell and may know regulationsthat you don't. Listen to their concernsclearly - it's in your product's interest.There is no greater achievement insatisfying a PAI inspector's requests inreal-time and in producing thedocumentation/data requested - beforehe leaves the firms' premises.

That regulator won't forget you or yourproduct line up for review!Work with regulators - or they will workagainst you and your product may notget to the market place on time.Treat regulators with respect - as youwould like to be treated. Agency officialare understanding, experiencedprofessionals whose prime concern isproduct quality and safety.

In any regulatory meeting the onlywelcome outcome is a win-win scenario.Both parties get what they want.Remember an agency never looses anargument - the product only suffers andgets delayed due to incomplete data orregulatory requirements.

Directive 11."Talk to the regulators regularly."Allow regulators to review protocolsprior to starting the work. Get theiropinion and express your concernsopenly. Regulators like openness andhonesty - and work well with polite,respectful and professional personnel.

Directive 12."Take a hard look a your cGMP's "

The absence of GMP compliance simplyadulterates your drug developmentpipeline. GMP compliance is targeted toplay a more dynamic role in the drugreview and PAI process.(Establishment Evaluation System - FDA Drug Center andOffice of Regulatory Affairs electronic data sharing)

Directive 13."Audit everything enthusiastically".Leave no audit stone unturned.Establish consistent in-house audit self-inspection programs effective at eachstage of the drug development pathway.At the end of every development reportsubmission stage, (refer to the DevelopmentChecklist), audit the department andrelevant steps concerned.End-of-study auditing is quite ineffectiveas early errors or omissions can not becorrected promptly and on-time 2

SEMISOLIDS D O C U M E N T A T I O ND O C U M E N T A T I O N CHAPTER 1

HHandbook of PPharmaceutical Chapter: 1.11 GGeneric DDevelopment

Regulatory S i t a n d r e v i e w w i t h y o u r r e g u l a t o r y d e p a r t m e n t b e f o r e y o u s t a r t

eveloping successful generic drugs in the least possible time and withoutexpensive mistakes, requires significant pre-planning with the regulatory affairs

department. Successful generic project managers can visualize all the key sectionsof the ANDA or EC submission file, before pre-formulation work has actually beeninitiated.

The regulatory department must insure that the innovators drug or the referencelisted drug (RLD) is suitable for generic manufacture and marketing.This purpose of this Handbook is to allow the reader to visualize the completegeneric development pathway in a concentrated rational picture.

Review the checklist titled Initial Regulatory Check Prior to Pre-formulation in order to obtainan initial overview of the forensic regulatory elements.An early decision on all the pack sizes is required from the marketing and salesdepartment in order to initiate reverse engineering of all the product specifications.

Part TwoPart Two of the Handbook of Pharmaceutical Generic Development Series providesa full scale model of a current US abbreviated new drug application (ANDA) for theselected dosage form chosen (e.g. tablets, capsules, semi-solids, liquids etc.)

In the model ANDA, the right hand side pages provides an example of each andevery document required to compile and assemble a complete regulatory file forsubmission to the FDAs Office of Generic Drugs (OGD).

The left hand side pages are designed for notes, summaries and explanations on thesubmitted data forms and tables. These pages are designed for side-by-sidecomparisons and ease of viewing. Essential tips and potential traps are explainedin the notes and summaries as well as the common dos and donts regularlyaddressed by the agency review chemists in a ANDA / AADA file submission.

Summary:

Review the ANDA requirements with the Regulatory Affairs Department

Know all the twenty one (21) ANDA sections in the registration file impacting onthe development, formulation, manufacturing procedures, all intermediate andfinal product specifications, pivotal batch, stability requirements, as well as keyregulatory ANDA dos and donts.

Complete the pre-formulation regulatory checklist and discuss and review allthe paperwork required to complete this section successfully.

D



SECTION ISection One of the ANDA file consists of three documents. A drug developer needsto understand the information required to accurately compile these three documentsas the information impacts upon the development timeline. These three parts are:.

Cover Letter and Field Letter Table of Contents Signed Application Form

Cover LetterThe cover letter should be on the letterhead of the Applicant or the Applicant's Agentand should state the following particulars:

1. Purpose of Submission2. Type of Submission

(Original ANDA / AADA) (Supplement) (Re-submission) (Amendment)

3. Name of Applicant4. Title of Applicant5. Signature of Applicant (ink)6. Proprietary name (if any)7. Generic name of Drug8. Number of volumes submitted.

A foreign company will have either a US agent or US subsidiary company to act asthe applicant, especially if the finished drug product is developed and manufacturedoutside the US. There is nothing special about this application letter, which isrequired on a standard applicant letterhead. An exact representation of the coverand field letters are presented in Part II of the Handbook.

Table of ContentsTable of Contents laid-out to the FDA's CDER Guide to Industry Format, (April 1997Overall ANDA Guideline Requirements) needs to provide rapid access to the twentyone (21) sections of the ANDA submission file. A drug developer needs tounderstand all 21 sections, in detail, as they contain the overall development,manufacturing and control data that makes up the entire drug development project.Careful review of each section and its required contents will aid significantly in thepre-formulation to final pivotal processes. The overall development report can bestructured on each CMC section highlighting the choices made and work carried outto fulfill each sectional requirement. The development report is a real-time ongoingseries of procedural reports that culminates in the final collated development report.

SIGNED APPLICATION FORM:Signed Application Form (Form FDA 356h or 3439) with original ink signaturerequires all DMF numbers of materials and containers used in the final productpresentation. Also no test results, analysis, or stability results may be submitted froma QC / QA or R&D laboratory that has not received a FDA Plant DMF number (Note:- New Revised Form FDA 356h became official from January 8, 1998).Obtaining DMF numbers from suppliers on time requires advanced pre-planning (upto three months or more) and scrupulous care should be taken that no Agencydeficiencies or FDA concerns of a recent or overdue nature are outstanding on thematerials or container components being used in the firm's generic formulation.



C H E C K L I S T CL # HPGD-03-01YY

INITIAL REGULATORY CHECK PRIOR TOPRE-FORMULATION

m o d e l e x a m p l e s o f e a c h f o r m , r e p o r t a n d d o c u m e n t a r e p r e p a r e di n P a r t T w o o f t h e H a n d b o o k o f G e n e r i c D r u g d e v e l o p m e n t

1. Submission Cover Letter reviewed and draft prepared? qqYes qNo

2. Revised Form FDA 356h reviewed (NB: all DMF #s clearly noted.) qqYes qNo

3. Basis for ANDA Submission prepared and reviewed? qqYes qNo

4. Is the Patent Certification clear for a generic product development? qqYes qNo

5. Patent Certification statement prepared? qqYes qNo

6. Exclusivity period has expired and statement prepared? qqYes qNo

7. Comparison of your Generic Drug with the chosen Reference ListedDrug (Select from FDA Orange Book) or original Innovator's product ?

qqYes qNo

8. Innovators package insert obtained via FOI (insure latest edition)? qqYes qNo

9. Innovators package insert has no exclusive indications? qqYes qNo

10. Labeling statement on number of strengths and package sizes? qqYes qNo

11. Proposed draft labeling for carton prepared (main & side panel) qqYes qNo

12. Innovators Insert converted to a generic package insert (remove anyexclusive indications)?

qqYes qNo

13. Proposed ANDA Package Insert OK (your firm's details added)? qqYes qNo

14. Side-by-Side comparison of your firm's and innovator's insert? qqYes qNo

15. Repeat check that Innovators Insert is the latest edition and date?(review FDA Web Site for model insert, check immediately beforeANDA file is submitted to OGD.)

qqYes qNo

16. Obtain a full set of Jacket Covers (specific colors for file types) fromFDA OGD Offices and review all FDA guidelines for specific dosageform (i.e. Topical Semisolids)

qqYes qNo

17. Review and list all DMF #'s required for early vendor implementation(Active material suppliers, special excipients, all container-closures specification)

qqYes qNo

Footnote : Bold letter in first word indicate that this work must be checked and approved before pre-formulationwork starts.

qqYes qNo

SEMISOLIDS D o c u m e n t a t i o n CHAPTER 1


Documentation I f t he re i s no documen ta t i on i t s a

r u m o r ;I f i t s w e l l d o c u m e n t e d - i t s a f a c t .

SOP CONTROLStandard operational procedures for ageneric development unit are the firstessential documentation requirements.

Without a functional set of standarddevelopment procedures, developinggeneric drugs will follow a haphazard non-reproducible process. SOPs are efficientand useful instructional and working tools.

Standard Operating Procedures shouldmeet six basic and functional requirements

SOP Index system an intelligent numbering system standardized format approval signatures a rapid distribution procedure Annual or biannual reviews

The SOP index is a list consisting of a SOPreference numbers and the procedure titles.The SOP number ideally has fourcomponents, the department code (P forpharmaceutics etc.), the SOP number e.g.(001 to 999), the edition number (01, 02)and the last review or the editorial date.(e.g. P-000-01-0199).

DosDos andand DontsDonts

Do - make the SOP index an actualStandard Operating Procedure and changethe edition # for each new SOPmodification during the course of the year.

Do - have a SOP manual in a spiral boundbook form for all key departments e.g.Pharmaceutical, Analytical, Stability,Microbiology, Quality Assurance andRegulatory Affairs, for ease of updatingand removing superseded (old) editions.

Do - write brief and to the point SOPs sothat they can be read and understoodquickly.Use forms or checklists for extrainformation and attached to the SOP.Dont - have loose lying SOPs gatheringdust on the shelf.Dont - write a SOP that can not befollowed - routinely, by all concerned.Dont - write long SOPs (about 1 to 3pages is sufficient for the average SOP).

Dont - write SOPs just to comply withGMP - use them frequently as operationaland training tools.

Dont - allow SOPs to become staticdocuments - review and amend themregularly as procedures are optimized.

DEVELOPMENT SOPsA development SOP is a protocol orsummary of the overall generic drugdevelopment process. It acts as a guidelineor road map for the development team tofollow to ensure complete productdevelopment.

Development SOPs are not a CFRrequirement. They are designed for rapidand complete generic drug developmentand are significant aids to agency staffduring pre-approval inspections (PAIs).

DEVELOPMENT NOTEBOOKSSimilar to printed SOPs or better stillelectronic SOPs, numbered and boundprinted development notebooks (noelectronic workbooks) are essential toolsfor a structured generic or innovativedevelopment program to succeed.



C H E C K L I S T CL # HPGD-02-01YY

SOP CONTROLSOP CONTROL .. f a i l u r e t o f o l l o w y o u r S O P s a d u l t e r a t e s t h e p r o d u c t

1. Is there an Index for all the Pharmaceutical Development SOPs ? qqYes qNo

2. Is this Index a Standard Operational Procedure itself ? qqYes qNo

3. Are SOPs correctly organized according to this Index ? qqYes qNo

4. Are the SOPs available in the community language(s) ? qqYes qNo

5. Do the SOPs have a logical, intelligent SOP numbering system ? qqYes qNo

6. Are all SOPs signed and is each signature dated ? qqYes qNo

7. Check, if the circulation of SOPs is effective and on-time ? qqYes qNo

8. Check that no SOP has a date older than two (2) years ? qqYes qNo

9. Check that superseded SOP editions have all been removed ? qqYes qNo

10. Check that all department personnel have signed the Agreement toComply with SOPs?

qqYes qNo

11. Is the effective date of the SOP about 21 days after the last signature- to allow for SOP training ?

qqYes qNo

12. Has the SOP been signed by all authorizing parties within 14-21days of the first signature?

qqYes qNo

13. Are the department SOPs - brief, concise and to the point? (selectand review three examples.)

qqYes qNo

14. Are the responsible persons clearly indicated in the SOP'sResponsibility section?

qqYes qNo

15. Has a product specific Development SOP been prepared for eachdosage form under development (i.e. SOP for Topical Semisolids etc.)?

qqYes qNo

16. Do these Development SOPs acts as a blue print for thedevelopment team to follow to ensure complete product development?

qqYes qNo

17. Does the development team regard Development SOPs as valuableworking tools and fail-safe procedural mechanisms?

qqYes qNo

Footnote : Bold letters in checklist indicate that this work must be checked and approved before pre-formulation work starts.



D E V E L O P M E N TD E V E L O P M E N TN O T E B O O K S R e c o r d e v e r y t r i a l f o r m u l a , e v e r y

m e t h o d u s e d , e v e r y r e s u l t o b t a i n e da n d e v e r y f a i l u r e .

DEVELOPMENT NOTEBOOKSPharmaceutical development notebooks areessential tools for successful generic drugdevelopment. The Development notebooksare bound, numbered, 100 page, hard covernotebooks suitable for a developmentlaboratory environment.

The issue and control of the developmentnotebooks and the signing procedures aftereach work section is complete is animportant control check.

The development notebooks are used torecord all pre-formulation and productdevelopment procedures. All failedprocedures must be recorded. No productwas ever developed without a number ofreject lots.Key data recorded in notebooks include :

All ingredient lot # and expiry dates Active and excipient sources (supplier) all pre-formulation formula all manufacturing methods used Equipment used, speeds and times All in-process controls all results and observations all tentative specifications All finished product controls proposed stability specifications all failed data, and abnormal results investigations and conclusionsEach stage and page of the notebook issigned by a supervisor and then dated.

Corrections to notebooks follow theCorrection SOP. All deletions must bereadable and no correction fluids (TipexFluid or White-out) are permissible.

All ingredient weights and measuresrequire a check signature at the time ofmeasurement. Late signatures are invalidand are neither GMP or professional.

Development of pre-formulation anddevelopment lots do not require strict GMPprocedures, however good GMPdevelopment practices enhance thescientific validity of results obtained.

Non-calibrated equipment and poorprocess techniques produce questionabledevelopment reports and generic products.ANDAs derived from inadequatedevelopment procedures may certainly failin the market place.

Development Quality AssuranceA well documented, and controlled genericdevelopment unit permits for rapid genericdrug development at the lowest cost.

Meticulously prepared developmentdocumentation aids in the timelyproduction of rugged generic productswithin the allocated development timeframe.

Good documentation is a cost-and-timesaver and allows for rapid data reviewduring pre-approval inspections (PAIs), ablessing for agency inspectors, as well as aproven training record for furthersuccessful generic product development.

The development notebook is the raw datasource for the Development Report and isan important review document from a pre-approval and regulatory viewpoint.Up to 10% of development and researchtime should be allocated to fine-tuningdevelopment SOPs, notebooks, correctdocumentation and team training in theircorrect use. 3



CHECK LISTCL # HPGD-02-01YY

D E V E L O P M E N T N O T E B O O K SD E V E L O P M E N T N O T E B O O K S ..

S i g n e v e r y s t a g e n o t e v e r y p a g e - c h e c k e v e r y p a g e a n d e v e r y s t a g e .

1. Does the Development Unit have bound & page numbered notebooks ? qqYes qNo

2. Are the printed development notebooks signed on every stage & page ? qqYes qNo

3. Has each completed section been signed with a check signature ? qqYes qNo

4. Has correcting fluid been used to cover up data ? qqYes qNo

5. Are data corrections performed according to the SOP ? qqYes qNo

6. Are all pre-formulation and development formula numerically recorded ? qqYes qNo

7. Do the notebooks record successful and failed development product formula ? qqYes qNo

8. Do all calculations have check signatures which are dated. qqYes qNo

9. Has the Product Development SOP been complied with during the productdevelopment phase ?

qqYes qNo

10. Is a process of formula, specifications and process optimization evident ? qqYes qNo

11. Do all specifications have an appropriate range, where absolutely needed? qqYes qNo

12. Have critical upper and lower range limits been qualified ? qqYes qNo

13. Are out-of-specification results investigated and documented ? qqYes qNo

14. Are the lot #s, expiration dates and source of each active and non-activeingredient used during routinely recorded in workbooks ?

qqYes qNo

15. Does the development notebook appear suitable as a scientific basis for thegeneric drug product Product Development Report?

qqYes qNo

16. The Product Development Report comprises of both pharmaceutical andanalytical development reports.

qqYes qNo

Footnote : Bold letters in checklist indicate that this work must be checked and approved before pre-formulation work starts.



STANDARD OPERATINGP R O C E D U R E

Page 1 of 1

SOP # HPGD-02-01YY

SOP CONTROL AND DEVELOPMENTSOP CONTROL AND DEVELOPMENTNOTEBOOKSNOTEBOOKS

The following Standard Operating Procedures are recommended for a genericdevelopment unit and should be in place prior to initiating product development:Electronic, computer based, SOPs are rapidly becoming a common placephenomena in pharmaceutical environments.Electronic updating and distribution and removal of superseded SOPs is greatlysimplified by using an internal network system (intranet) for SOP distribution andviewing. An appropriately signed 'Master SOP' collection is held by the firms archiveor library system, while electronic copies for staff use displayed in a PDF formatare viewable on firms numerous internal desk computer screens.

SOP CONTROL# HPGD-02-01YY Indexing procedure for pharmaceutical development SOPs

# HPGD-02-01YY Index for pharmaceutical development SOPs

# HPGD-02-01YY Signing procedures of pharmaceutical development SOPs

# HPGD-02-01YY Standard Operating Procedures - number and format

# HPGD-02-01YY Circulation of pharmaceutical development SOPs

# HPGD-02-01YY Annual review of pharmaceutical development SOPs

# HPGD-02-01YY List of FDA guides and Guidelines impacting on productdevelopment dosage form and type (IR)

DEVELOPMENT NOTEBOOKS# HPGD-02-01YY Issue and use of pharmaceutical development notebooks.

# HPGD-02-01YY Signing procedures for development notebooks.

# HPGD-02-01YY Development notebooks - review and audit procedures.

# HPGD-02-01YY Standard procedures in generic product development.

# HPGD-02-01YY Pharmaceutical development notebooks - disposition.

ED. N0: 01Replaces NEW

Effective Date: APPROVED:

Ed. Status : 01

DD / MM / YY

Department R&D RA QC / QA

SEMISOLIDS D E V E L O P M E N T CHAPTER 2


A N O V E R V I E W

Developing the Formula p l a n t h e d e v e l o p m e n t s t a g e s i n t o a D e v e l o p m e n t S O P- t h e n c a r e f u l l y w o r k t h e p l a n o f w h a t y o u a r e g o i n g t o d o

THE DEVELOPMENT SOPhe development SOP is adocument that contains each stage

of the development process of thegeneric drug up to and including thepivotal batch (submission batch).

This document brings all theinteracting departments, i.e.pharmaceutical, analytical and stabilityunits together to form onedevelopment program.

The overall development procedurerequires that the product formula,manufacturing process and controlsand final product specifications(including stability) are formulated,optimized and qualified through aseries of upper and lower limitspecification qualifications during theoverall product development phase.

These validation qualifications aredemonstrated again for regulatorypurposes as a final single continuousprocess during the manufacture of thepivotal batch and demonstrated in thethree validation batches.

The validation process shows that allthe ranges and limits in amanufactured batch, produce thedesired drug product according to thewritten specifications.

Optimizations and qualification ofspecification limits and processparameters are developed before thepivotal batch manufacture in adevelopment batches namely theprocess optimization and qualificationbatch (PQ). The PQ batch is in fact thereal end point of product development.

THE DEVELOPMENT REPORTThe development report documents allthe results of the development processas highlighted from pre-formulation tothe pivotal batch filing in the ANDA

The development notebooks andreports provide the basic raw data/results to the development report.The development report is completedafter the pivotal batch has beenpacked, tested and placed onaccelerated stability.All product specifications andprocedures and qualifications arecompleted prior to the start of thepivotal batch. Major development stopsat the conclusion of this batch.

This batch is the ANDA demonstrationbatch for filing with the FDA thatdemonstrates a well developedproduct formula and process.Scale-Up and Post Approval Changes(SUPAC) are permissible after thepivotal batch but MUST follow theSUPAC rules for each change made.

The three validation batches, - sold ascommercial products - demonstratethat the formula and processconsistently give the same productspecifications and are comparable tothe bioequivalency batch (i.e. pivotal).

The development process simplyestablishes the ruggedness orrobustness of the formula, themanufacturing process, the productspecifications and the type ofequipment used. The pivotal andvalidation batches demonstrate andthen prove the consistency of theoverall drug product and process.

T



C H E C K L I S T CL # HBGD-01-01YY

DEVELOPING THE FORMULA c o m b i n e t h e d e v e l o p m e n t s t a g e s i n t o a n o v e r a l l ' D e v e l o p m e n t R e p o r t '

- wha t d i d you rea l l y do?

1. Is a Development SOP for the dosage form available? qYes qNo

2. Does a SOP specifying the contents of a Development Report? qYes qNo

3. Are non-soluble active ingredients characterized for particle size for eachapproved supplier (special significance in eye preparations)?

qYes qNo

4. Are the source and supply of the excipients characterized? qYes qNo

5. Is the source and supply of the container / closure characterized qYes qNo

6. Does the SOP indicate that non-compendial active material assays requires avalidation and stability indicating assay ?

qYes qNo

7. Does the SOP required full analysis of the reference listed drug (RLD), itsimpurity profile and stability ?

qYes qNo

8. Is an historical listing and summary of all experimental batches manufacturedrequired ?

qYes qNo

9. Are the in-actives qualitatively and quantitatively compatible with the RLD fortopical use (same composition and strength)?

qYes qNo

10. Do the manufacturing procedures, process parameters and in-process controlsrequire optimization and limit challenges ?

qYes qNo

11. Is a process of tightening / qualifying the product specifications, (based onbatch analysis) evident as the development process undergoes optimization?

qYes qNo

12. Does the development process identify the critical processing steps for thevalidation protocol with the potential to affect the product?

qYes qNo

13. Has the preservative efficacy of the RLD been evaluated to assess thesuitability of the RLD preservative system?

qYes qNo

14. Does the analytical development require a final validated assay and stabilityindicating (SI) assay well before running the pivotal batch?

qYes qNo

15. Are stability study assays of the PO and PQ batch required to be tested by thevalidated assay procedure and SI analysis?

qYes qNo

Footnote : Bold numbers in checklist indicate that this work must be checked and approved before formulation work starts.

SEMISOLID D e v e l o p m e n tD e v e l o p m e n t CHAPTER 2


Formula Development r e s e a r c h a n d e v a l u a t e t h e r e f e r e n c e l i s t e d d r u g t h o r o u g h l y '

ANDA Topical PreparationsThe development of a semisoliddosage requires six key decisions.Choosing the : - reference listed drug (RLD) active material (source/supply) non-active ingredients (source/supply) container-closure system (as RLD) Hanson diffusion procedure In-vitro similarity to the RLDThe RLD is chosen from the FDA'Orange Guide' (now on the Internet).(Approved Drug Products with TherapeuticEquivalence Evaluations - current 18th Edition1998).

Active substanceThe active drug substance is chosenaccording to standard criteria. Correctchoice of active ingredient is criticaland time consuming. Key selectionparameters include :-

Analytical profile - similar to RLBunder normal and stress conditions.

Impurity profile - similar to RLBunder normal and stress conditions.

Approved supplier must meet allANDA regulatory documentationrequirements.

Active Material specificationsremain constant - batch-to-batch(not a R&D lot or non-commercialbatch)

Able to supply for the next 8-10years at the similar specificationsafter ANDA (pivotal) batchmanufactured.

Using the RLD's Active MaterialIdeally the same supplier of the activedrug substance as used by the RLD, isthe most cost-effective in the longterm, as stability, impurity, and aging

profiles are similar.In-active ingredients (excipients)The product formula of the genericsemisolid topical should contain thesame in-active ingredients at the samequantities as the RLD (5 % variationallowed).The qualitative ingredients arerequired to be in the OGD InactiveIngredient Guide (IIG).The FDA publish the InactiveIngredient Guide. Inactive ingredientsfound in approved semisolid drugproducts in the US are listed in the IIG.The strength (i.e. quantity) of theinactive ingredient in the productformula must not be greater than thehighest concentration previouslyapproved in an approved drug productfor the same route of administration(i.e. topical route)

Semisolids development needsspecific development SOPs to clarifythe choice of inactive ingredients forformulation development.

The choice of a well known excipientmanufactures with an establishedexcipient range is very important aslong term stability, microbiological andaging problems are minimized oravoided. Thus source and supply ofinactive ingredients for topical semi-solids are paramount

Container closure systemsThe drug product container-closuresystem should be a similar materialcomposition as the RLD container-closure system.The degree of product protection bythe container-liner-closure systemmust prevent physical, chemical andmicrobiological changes on storageand during customer-consumer use.



C H E C K L I S T CL # HBGD-01-01YY

FORMULA DEVELOPMENT

S y s t e m a t i c a l l y c o m p a r e y o u r d e v e l o p i n g p r o d u c t t o t h e c h o s e n R L Da t a l l k e y s t a g e s '

1. Has the Reference Listed Drug (RLD) been chosen from the OrangeGuide?

qYes qNo

2. Has the RLD been purchased in all the proposed marketing sizes ? qYes qNo

3. Have different batch numbers (3 lot #s) of the RLD been purchased? qYes qNo

4. Confirm if the RLD is of recent manufacture (analyze new samples)? qYes qNo

5. Conform that at least 10-20 samples of each RLD lot # and pack sizesare available for physical, chemical (assay/impurities), and stabilitytesting?

qYes qNo

6. Confirm if the RLD has been placed on stability at 40o C for 3 monthsfor evaluating potential degradation and impurity levels?

qYes qNo

7. Confirm if the impurity profile of the RLD has been evaluated? qYes qNo

8. Has reverse engineering of the RLD formula been performed? qYes qNo

9. Have the chosen inactive and maximum strength been crossedchecked in the IIG? (for unique or unusual excipients)?

qYes qNo

10. Are the in-actives qualitatively compatible with the RLD for topicaluse (composition and strength)?

qYes qNo

11 Have the RLD formula been reviewed in the International DrugCompendia (Italian, French, Swiss) for formula composition data?

qYes qNo

12. Has the FOI system been used to gather data on the Innovativedrug?

qYes qNo

13. Has a full analytical profile range been determined from analysis ofthe various batch lots of the RLD (at least 3 lots #s for Assay; ContentUniformity)?

qYes qNo

14. Has the chosen RLD undergone stress testing to establish the levelof its degradation products?

qYes qNo

15. Has a diffusion profile of several RLD batch lots been evaluated toassess the consistency of the RLD diffusion parameters?

qYes qNo

16. Has the preservative efficacy of the RLD been evaluated to assessthe suitability of the RLD preservative system ?

qYes qNo

Footnote : Bold numbers in checklist indicate that this work must be checked and approved before formulation work starts.



STANDARD OPERATINGSTANDARD OPERATINGPROCEDURESPROCEDURES

Page 1 of 1.

SOP # HBGD-01-01YY

FORMULA DEVELOPMENT

The following selected model Standard Operating Procedures are recommended fora generic development unit : Models of selected SOPs are provided.

DEVELOPMENT SOPP-000-01-01YY Setting up a General Development SOP.P-000-01-01YY Setting up a Product Specific Development SOP.P-000-01-01YY Contents of a Development SOP - Semisolids.

DEVELOPMENT FORMULAP-000-01-01YY Vendor Certification Requirements for Product Development.P-000-01-01YY Formulation of ANDA Semisolids PreparationsP-000-01-01YY Formulation of ANDA to Q & Q Status (Semisolids).P-000-01-01YY Standard Procedures for Generic Product Development

DEVELOPMENT REPORTP-000-01-01YY SOP for Development Reports.P-000-01-01YY Contents of a Development Report - Semisolids.P-000-01-01YY Parameters for Process Optimization and Process Qualification.

NOTE ON DEVELOPMENTThe intent and purpose of the pivotal batch is as a final demonstration that theformula, process and controls are well developed and tested during developmentstages and really need no significant changes or further process qualification.However scale-up changes can take place within the SUPAC rules after

manufacturing the pivotal batch. These SUPAC rules govern the Scale-Up frompivotal (10% or more) to commercial (100%) and Post-Approval Changes i.e.changes after registration approval has been given.

[End of Document]

Edition No. 01 Effective Date:

APPROVEDAPPROVED:

Ed. Status :New

DD/MM/YY ___________ ____________ ____________ _________/_________ Department RD RA QC / Q A

SEMISOLIDS D E V E L O P M E N TD E V E L O P M E N T CHAPTER 2


D e v e l o p i n g t h e F o r m u l aD e v e l o p i n g t h e F o r m u l a r e s e a r c h a n d e v a l u a t e t h e g e n e r i c f o r m u l a t h o r o u g h l y

Product Development Stages for a US Generic

Literature search:reliminary activities in a drugdevelopment project start with acomprehensive review of

authoritative reference books on thepharmaceutical and analyticalparameters and attributes of the chosendrug. Reference works such as the USPharmacopoeia, (and supplements)B.P., (and addenda) Ph. Eur.;Pharmacopoeial Forum, Physician'sDesk Reference; Martindale; Merck;Florey; and Vidal are thoroughlyreviewed on physical and chemicalsaspects of the active ingredient andpotential formulations. An extensivecomputerized online search relating tothe specific drug substance and thedrug product is conducted.

The USP Supplements and BPAddenda are carefully screened for newmonographs at regular intervals duringthe ongoing drug developmentprogram, as a new active monographmay be published during the actualproduct development stages.Finally the Innovator's Summary Basisof Approval is obtained via the Freedomof Information Services for data review.

Patent Evaluation:The Innovator's overall patent situationis thoroughly evaluated with specialreference to product and use patents.Exclusivity and Patent data is reviewedin the FDA's Orange Book "ApprovedDrug Products with TherapeuticEquivalence Evaluations " Edition 20

(2000) Under the section titled'Prescription and OTC Drug Products -Patent and Exclusivity Data', the patentnumber and patent and exclusivityexpiration dates are obtained. Thelatest cumulative index to the OrangeBook may be viewed on the FDA homepage.Use patents (i.e. therapeutic uses) areindicated with the symbol "U" followedby a number representing a specifictherapeutic use. A corresponding list oftherapeutic uses are given.Exclusivity information for a specificcategory is indicated by an abbreviationfollowed by the date on which theexclusivity actually expires (NCE - Dec30, 1999) NCE = New Chemical Entity.

Sourcing of Raw Material:Sourcing for a potential suppliers of theactive material.At least two approved suppliers ofactive material should be qualified.Request samples from potentialsuppliers. Exercised care that the activematerial samples received, alwaysrepresent a production batch and arenot from an experimental batch lotwhere the specifications, physical (bulkdensity and particle size) and chemical(impurity profile), may change with time.Once a suitable active supplier hasbeen located sufficient material shouldbe ordered to allow for preliminary pre-formulation development to begin priorthe full analytical testing of thesuppliers sample. This is a time savingdevice as a full analytical profile (with

P



[BET], polymorphism evaluation etc.)may take one or two months to fullyappraise.

Testing of Active MaterialSample:Initiate chemical evaluation with theanalytical development laboratory asper official pharmacopoeia monograph(Pharmacopoeial Forum proposedmethod, if present at time), oralternatively by the supplier's testmethod or a modified in-houseanalytical method based on thesupplier's method and specifications,where no official monograph exists.

Marketing input requirements:Based on the Innovator's productobtained from the market place thefollowing product presentationinformation is acquired;

color - (possible special color) odor - Specific odor for (each)

dosage strength

proposed packaging sizes (smallest;intermediate and largest pack sizes)

Specific application nozzles Custom applicators / spreaders Container - closure types. (Aluminum

epoxy coated, plastic squeeze tube.)

Innovator's Product Testing:Physical TestingPhysical tests evaluating theinnovator's product for odor, color, SG,viscosity range, pH, preservativeefficacy etc. as well as an evaluation ofthe delivery mechanism such as thenozzle diameter and length (viscosityrelated - nasal applicators) are nowundertaken.

Inactive Ingredient IdentificationEvaluation of inactive ingredients asused in innovator's product areobtained from the package insert, and /or the PDR with supporting analytical

and microscopic tests confirming,where possible, the identification of theingredients formulated.

Microscopic observation, althoughmainly used for emulsion composition,can give valuable information on non-soluble particle size and crystal shapes(i.e. in pastes).Information on the presence of specificexcipients in pastes can be obtainedfrom microscopic observation.

Hanson P/N 57 or Franz Cell Profile

Perform a cell diffusion profile usingReference Product with appropriate in-house methods for soluble actives.

First batch of Active Material:Active Material Release

This initial active material lot isreleased by the Development (or plantQC laboratory if the material is intendedfor pivotal batches), according topharmacopoeia, (or in-house methodsand specifications in the absence of apharmacopoeia monograph).

Release of material without fullmonograph testing is allowable if thematerial is not intended for a ProcessQualification (PQ) and pivotal batch.

Physical Characterization ofActive:A full analytical evaluation of theapproved supplier active material isnow undertaken that will finally end in acomprehensive Analytical DevelopmentReport.

Standard physical parameters forevaluation. Where the active isinsoluble and held in suspension in thesemi solid matrix;

Polymorphism (in pastes)

Particle size distribution (in pastes)

Microscopic observation (in pastes)



Chemical characterization: Optical rotation Enantiomeric purity (if required) O.V.I. testing (organic volatiles) Impurity profile

Evaluation of raw materialsupplier: DMF availability Compliance with USP monograph

Impurity profile and stability profile

Commitment to maintain writtenphysical / chemical specifications

Statement of non-patent infringement

Interim analytical and pre-formulation development report:The findings of the initial developmentwork are summarized and tabulatedinto an interim development report,covering the analytical and pre-formulation findings that will eventuallyform part of the overall comprehensiveproduct development report.

DEVELOPMENT LOTSDeveloping the formula through aseries of mini experimental trialsinvolves evaluating the type of mixingprocess and the physical properties ofthe globules / emulsion formed. Stepsfor the choice of a suitable process are:

Evaluation of suitable excipients. Evaluation of suitable antioxidants /

preservatives.

simple mixing, phase mixing, vacuummixing.

Time, Temperature and Vacuumrequirements.

Emulsifying at specific phasetemperatures (low / high shear units.)

Determination of target pH and targetviscosity (re: container orifice.)

Physical properties of semisolid: Appearance / Color

Viscosity (Rheology)

pH

Emulsion Stability.

Chemical properties of semisolid:

Assay Uniformity of Content (three points) Preservative Efficacy Microbial Limit Tests.

Choosing Tube & Applicator Set:Ordering of tubes (+applicator nozzles).The Pivotal Batch as well as theProcess Qualification batch should befilled on a production (or productiontype) filling and capping machines.

Production supervisors are consultedregarding the choice of the fillingmachine. Avoid any manufacture withworn-out filling heads or old tubing(microbial hazard).

The Supervisor initiates the ordering ofthe filling heads suitable for theproposed marketed product. Nozzlescapable of extruding the semi-soliduniformly is an important aspect. Nozzleshape and length can affect the flowparameters.

Analytical assay testing:Assay, pH & viscosity tests versusinnovator's product. Uniformity ofContent and crystallization studies forlow solubility drug active concentrationsare critical development parameters.Refer to Pharmacopoeial requirementsfor Uniformity of Content testing.

Active Stability:Ordering of raw material for ProcessQualification (PQ) and Pivotal Batches.On accepting the stability profile datafrom the active material evaluation,coupled with the results the from thedevelopment lots, the active supplier isnow approved. Order sufficient materialfor the PQ and Pivotal Lot manufacture.



It is important to use same batch ofactive material for the PQ and Pivotalbatch, as these two batches aresomewhat complementary to each otherand form the culmination of the formulaand process development.An average of 2-3 months may berequired from date of order to receipt ofapproved active material, during thisperiod process optimization batch(es)and scale-up work is performed.PROCESS OPTIMIZATIONProcess optimization is the process offine tuning the manufacturing processand making minor adjustments to theformula or process. It should beperformed on a larger batch size so thatthe potential problems of scale-up canbe addressed, as they arise with largersize manufacturing equipment that usethe same operating principle. Fine tunethe effects of mixing and coolingparameters may include; mixing speeds (i.e. blade speeds (i.e.

in high speed mixers)

number of mixing stages (one or twofor high shear mixing)

mixing times and total overall mixing phase amounts and rate of addition In-process cooling rates. Re-mixing steps and its effect on

viscosity and flow properties (flow,extrusion, and ability to spread).

Cooling times (shortest) - the effecton content uniformity, and producthomogeneity (any crystal growth?).

Effect of pH on aging (re: assay,content uniformity or phaseseparation).

Qualify the preservative efficacy andMicrobial Limits (bacteria & fungi.)

Final evaluation of stability profile.Process Optimization Report:The findings of the process optimizationwork are summarized in an interim

process report, outlining theoptimization data for final presentationin the product development report.PROCESS QUALIFICATION(The PQ Batch)

The process qualification batch ismanufactured in order to detect anyproblems that may arise during themanufacture of production size batches,permitting a timely solution before themanufacture of a pivotal batch.

The process qualification team andproduction personnel should discussformula and process instructions anddecide on optimum batch size, and thendefine critical processing steps and testparameters to be evaluated.Master Documentation:The project researcher finalizes theBatch Formula and ManufacturingInstructions documentation package forsigning by the authorizing personnel.

The process qualification teamprepares the PQ Protocol and consultwith the analytical coordinator withrespect to the analytical testingrequirements of the many PQ samples.

Production personnel are presentduring the process qualification batchrun, as this process usually mimicsproduction conditions and acts as aprecursor to the upcoming pivotalbatch. The suitability of the processdocumentation package is evaluatedduring this run. Amendments are addedwhere necessary to effect practicaldocumentation for the pivotal batch.Upon completion of the processqualification batch testing, a ProcessQualification Report is formulated.TEST METHODS FINALIZED

A fully validated stability indicatingassay (and impurity profile) is finalizedprior to executing the pivotal batch. Theanalytical methods need to beauthorized and signed prior to the dateof the actual pivotal manufacture.



PIVOTAL LOTSBased on the PQ batch results andamended documentation, the pivotal lot isnow prepared. In the manufacture of thePivotal Batch, a minimum of 100 000(net) dosage units are required. Somefirms prepare documentation for 100 000dosage units gross, ignoring that theremay well be 3% to 5% production losses.The net batch yield turns out to be 95 000/ 98 000 dosage units which is below the100 thousand net required by FDAsOffice of Generic Drugs (OGD).Semisolids may have a greatermanufacturing loss than solid dosageforms - thus it is prudent to scale thepivotal batch for at least 120 000 dosageunits.Note: the pivotal batch may range from10% net to 100% (i.e. full size) of theproposed commercial batch size.Experienced Generic firms who do notanticipate any problems with the pivotaldocumentation often target the pivotalquantity to 70-100% of the proposedcommercial lot thus achieving appropriatescale-up and pivotal in a single batch.

Packing the pivotal batch.The Pivotal batch needs to be fullypacked in the proposed marketing packs(OGD rules). Frequently the pivotal batchis packed into 2 or 3 different pack typesand several different pack sizes andclosure combinations. (combinations of,HDPE Jars, Aluminium epoxy-coatedsqueeze tubes, plastic caps, nozzles etc.)The packaging trail documentationidentifies the exact quantity packed intoeach container-closure system. Theoverall packaging should total to 100% ofthe net pivotal batch.At least 15-20% of the exhibition (pivotal)batch should be packed into eachcontainer-closure category.

IN-VITRO STUDYBioequivalence /Comparison evaluationsThe pivotal batch samples are used toperform a comparison study, if needed.The FDA guidelines on topical productsare included, and highlight the agency

topicals proposals. The FDA CDER homepage from time to time adds furtherprotocols to their established Internet list.Where possible consult these protocolsand the FDA Topical Division prior to anysimilarity evaluation or comparison.

Pivotal Sampling & TestingThe sampling and testing procedures forthe pivotal batch hold a special regulatorysignificance. The pivotal batch representsthe documented batch that is filed withthe FDA's Office of Generic Drugs, as wellas being the batch representing thetherapeutic equivalence of the drugproduct when compared against thereference listed drug / the innovator's owndrug. Evaluate carefully, if such acomparison study is actually required.

Under these circumstances, the need fora representative sampling and testingprocedure, as required by GMP, isachieved by a specific written 'samplingand testing' protocol. This special batchhas both legal and regulatory aspects inthe eyes of the FDA - sampling must notonly be done but seen to be done (i.e. viaa well written protocol).

DEVELOPMENT REPORTSFirms should have a well structured andassembled Product Development Report.Although not a FDA 21 CFR regulatoryrequirement, a functional DevelopmentReport will certainly go a long way toconvince the reviewers of a fully justifiedoverall process that consistently producesthe desired end-product.The Development Report is the basis onwhich the validation protocol is designedand structured, without it validation maywell be incomplete or officially queried.

Development reports are reviewed by thesite inspectors at the product specific pre-approval inspection (PAI visit). Thepreparation of a Product DevelopmentReport should be based on all theinterim reports prepared during thedevelopment work, including analyticalreports and where well prepared,assembled, and structured - oil the officialreview process - immeasurably.



P u r i f i e dW a t e r

A K e y I n g r e d i e n ti n t h e D o s a g e F o r m

D e v e l o p m e n t .

develop al l experimentalbatches with Purif ied Water USPor Ph. Eur. - s imilar or identical

to the proposed commercialproduction qual i ty.

he use of appropriate water qualityas a critical non-active ingredient in

the development of pharmaceuticaldosage forms, especially topicalsemisolid presentations is oftenrealized at a late development stage -occasional too late in the productsoverall development.

This section deals with the pitfalls offailing to establishing strict criteria forwater quality both during pre-formulation, formula development anddesigning the cleaning validationprotocol. Much of what is valid forsensitive topical semisolid dosageformulations, applies equally to thedevelopment cleaning limits creamsointments and gels forms.

Take a second look at

water as a key

non-active ingredient

for topical semisoliddevelopment

Equivalent Commercial QualityThe development units water qualityshould be equivalent to the waterquality that is available for themanufacture of the proposedcommercial product. Wheredevelopment is separated frommanufacture (in an overseas facility) theproblem becomes more acute.The optimum scenario is for the R&Ddepartment or development unit to beconnected, where possible to the samewater supply system as the commercialproduction unit or alternatively install apurified water system that mimics theproposed production quality, scheduledfor use in the full-size commercial lots.

This implies that the experimentalbatches, the scale-up lots, the processqualification, pivotal and the initial threevalidation batches will all be preparedand manufactured with commercialproduction quality water.

The cleaning validation protocoldeveloped during the R&D phaseshould use the same water quality.

Changing thewater quality during

product developmentmay compromise

earlier resultsWater quality for product developmentshould be at least purified water ofPharmacopeial grade (USP/Pharm Eur)and used from the very onset of thedevelopment studies.The research or development waterspecifications should not change as theproduct develops and as the awarenessgrows, that microbial parameters andpH are significant formula parameters,to be evaluated in the developmentprocess.

T




Avoid changing specificationsChanging the water quality half waythrough the product development stagewhen microbial parameters are beingaddressed may well invalidate the earlyformula development results, especiallythe overall preservative package,notable the individual preservativeconcentrations chosen.

Water-soluble semiactives used (i.e.preservatives, anti-oxidants andchelating

Using a higher than proposed water

quality during product development

will simply biastest results

agents) require formulation in a stableaqueous phase with standard andconsistent specifications. Using a lowerwater quality, which will have a higherTOC (total organic carbon) level, willnot necessary produce a more ruggedproduct by providing a greaterchallenge vis--vis preservative efficacyand microbial limit testing. To thecontrary the opposite holds true.

The test results will simply be non-comparable with future, down-the-line,test results where the water quality hasbeen upgraded to a production quality,for the manufacture of the exhibition(pivotal) batch(es) required forgovernment agency registrationpurposes.

To evaluate the products ruggednessin order to withstand unusual bioburdenlevels that may result, when the

commercial water quality increasing inbioload at the manufacturers site,reaches warning levels - may beeffected by challenging thedevelopment product with alert /warning level microbial bioloads in theformula ingredient water for PET studyevaluation- i.e. spiking the water phase.

PET testing using common organismsfound at the commercial sites watersupply system (such as pseudomonascepacia - a common NY/NJ organism)needs to be included in the PETprogram, as well as a standard indicatormicrobe such as, the rarely pathogenic,gram negative, Pseudomonas statzeri.

Indicator microbes may highlight thepossible presence of pathogenicorganism that are more commonlyfound - for example the gram negative,pathogen, Pseudomonas aeruginosaethat is required to be regulated in theproduction water and end-productrelease specifications.

Therefore the specific organism, that isidentified as an on-site contaminant in adrug product (liquids / suspensions),may not be as significant as to theactual class and type of organism, itactually represents in the manufacturingprocess or equipment configuration-layout that allows for its continualsurvival, and growth.

Pharmaceutical development units, whoupgrade water quality as the productnears final formation, may not realizethat the initial results based on a lowerwater quality may have skewed theearly test results that now becomeunsuitable for formula-to-formulacomparisons.

Development Pointers: Initiate development with plant quality

water. Preservative Efficacy Testing conducted

with specific organisms found incommercial plant - as well.




Eventually the firm may not have aproper basis for developing a fullyvalidated and optimized drug product orfor that matter, an appropriatevalidation protocol without the need ofrepeating some of the initialdevelopmental batch lots with theapplicable standardized commercialwater quality.

Similarly the use of a higher waterquality, (during the development stagesi.e. WFI) than the proposed plantcommercial quality available, will resultin a commercial product with distortedmicrobial parameters, as well as abiased stability profile. This, indeed, isthe more serious case.

These products are prone to developsevere production problems resulting ingreater microbial bioburdens or OOSchemical pH shifts that frequently failthe product release specifications orworse still, fail the annual commercialstability tests resulting in a drug productrecall.

In such cases the Preservative EfficacyTest results as well as the TotalMicrobial Count (TMC) and theMicrobial Limit Tests (MLT) arepresented optimistically during the end-development stages, which are notactually seen in the commerciallymanufactured lots.

Many firms simply wonder why there islittle correlation in the product quality,as was so clearly demonstrated duringthe development, scale-up or pivotalbatch lots. The answer lies partly inrandom ad-hoc water quality changesthat took place during the developmentand scale-up procedures.These development lots will almostcertainly exhibit changes in theirmicrobial specifications, especially the

PET study results, as the product isrefined and optimized in the enddevelopment stages.

Documents

136188028-Handbook-of-Pharmaceutical-Generic-Development-Vol-03-Part-1.pdf