136188075 Handbook of Pharmaceutical Generic Development Vol 12 Part 2

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 PHARMACEUTICAL

GENERIC DEVELOPMENT

S E M I

SOLIDS

VOLUME XII Part Two 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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E l e c t r o n i c << H a n d b o o k S e r i e s o fPharmaceut i ca l Gener ic Deve lopment

ISSN 0793 8667 - Electronic VersionHandbook Development 24 Volume Series

ISSN Series Number 0793 761X - Electronic Version

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 Innovative Development Vol. 12 - Semisolids

Handbook 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 Oral DR

Handbook of Pharmaceutical Innovative Development Vol. 15 - Suspensions Oral

Handbook of Pharmaceutical Innovative Development Vol. 16 - Capsules Oral

Handbook of Pharmaceutical Innovative Development Vol. 17 - Master Formula

Handbook of Pharmaceutical Innovative Development Vol. 18 - Master processes

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

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 F

P 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 XII - Part TWOS 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

L o c u m I n t e r n a t i o n a l P u b l i s h e r s

Handbook ofPharmaceuticalG e n e r i cDevelopment

SS e m i

solids

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

A N D A D e v e l o p m e n t

P a r t T w oT w o



SERIAL NUMBER - DO NO REMOVE - REGISTERED WITH

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

HPGD Series - Semisolid Dosage Forms

First 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.

UK Fax: +(44) 207-900 2096US Fax: +(1) 435-408 1665

Fax: +972-97-494 532E-mail: info@locum. co. il

h t t p : / / w w w . l o c u m . c o . i lh t t p : / / w w w . l o c u m e u r o . c o m

h t t p : / / w w w . l o c u m u s a . c o mhandbooks@l o c u m u s a . com

sales@l o c u m u s a . comCurrent Printing (last digit) :10 9 8 7 6 5 4 3

⌦ PRINTED IN USAPRINTED IN ISRAEL

PRINTED IN IRELANDPRINTED IN REPUBLIC OF SOUTH AFRICA



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). 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

p p pLOCUMp p p

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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

Í ° ÎÏ Ð

Í ° Î

HANDBOOK OF GENERIC DRUG DEVELOPMENT ANDA DEVELOPMENT

24 V24 Volume DDrug DDevelopment SSeries Sect: 11.1 ANDA DEVELOPMENT

SECTION I SECTION 1

Application/ Table of Contents

TABLE OF CONTENTS(Overall ANDA Guideline Requirements for this Section).

1.1 Cover Letter - basis for submission of an abbreviated application.

1.2 Signed Application Form (Form FDA 356h or 3439) with original ink signature.

1.3 Executive Summary - Introductory Outline on the organization of this ANDA1

1.4 Table of Contents - to CDER Guide to Industry Format, (February 1999).

Note:Cover Letter:Cover letter should be on the letterhead of the Applicant or the Applicant Agent andshould state:

üü Purpose of Submissionüü Type of Submission

Ü (Original ANDA)

Ü (Supplement)

Ü (Amendment)

Ü (Annual Report)

Ü (Re-submission)

üü Name of Applicantüü Title of Applicantüü Signature of Applicant (original ink)üü Proprietary name (if any)üü Generic name of Drugüü Number of volumes submitted.þþ Methods Validation Post Approval Commitment .þþ Electronic Format Statement (portion or whole submission).þþ Sterility Assurance Data Statement (Indicate that submission contains SAD)

CompareOLD & NEW

Data

þþ - NEW 1999/2000Requirements

Indicate Type:-Change being Effected

Expedited review requestedPreapproval Supplement

SUPAC Supplement

SUPAC Changes:-þ Describe Change

þ Reference Exact SUPAC Guidance& Guidance Sectionþ Cover letter Header

"This Submission is based on aSUPAC DOCUMENT"



SECTION I SECTION 1

Application/ Table of Contents'This Submission is based on a SUPAC Document'

COVER LETTER

Date: ______________

Office of Generic DrugsCDER, Food and Drug AdministrationDocument Control Room - No. 150Metro Park North II7500 Standish PlaceROCKVILLE MD 20855-2773.

ORIGINAL ABBREVIATED NEW DRUG APPLICATION[Generic name] Specific Oral Dosage Form [USP]

Dear Sir,

We submit herewith an ABBREVIATED NEW DRUG APPLICATION for the drugproduct q [Generic name] Semisolid [USP] qcream qOintment qGel [000.0]mg/5g. (delete where appropriate)

Enclosed are the archival and review copies in accordance with the Office ofGeneric Drugs Guidance for Industry dated February 1999. These copies arepresented in a total of nine (9) volumes, FOUR [4] for the archival and FIVE [5] forthe review copy.

We furthermore commit to fully resolve any appropriate post approval issueidentified in the methods validation process.

The Application contains a full report of a topical Bioequivalence study. The Studycompares q [Generic name] Semisolid [USP] qcream qOintment qGel [000.0]mg/5g manufactured by [Generic Manufacturing Co. Inc./ Ltd.] to the reference listeddrug under protocol conditions. This section is submitted in PRINT and theprescribed ELECTRONIC format.

The Application does/does not contain Sterility Assurance Data in section XXIIWe look forward to your review and comment.Yours Sincerely.Our Best Wishes,

Signature Name of Responsible Person. Dated __________________Regulatory Affairs Director

Enclosures - Nine files

Clear BriefIntroductory Statement

Letter HeaderFor SUPAC submissions

only.(Place on envelop as well)

Specify - Type of Bioequivalence

⌦ Results of Study⌦Results of Multiple Dose Study

Dissolution Data Waiver Request



SECTION I SECTION 1


TABLE OF CONTENTSSECTIONS I

1.1 Cover Letter - basis for submission of an abbreviated application.

.2 Signed Application Form (Form FDA 356h or 3439) with original ink signature.

.3 Table of Contents - to CDER Guide to Industry Format, (April 1997).

.4 Executive Summary - Introductory Outline on the organization of this ANDA1

ÜÜÜ TABLE OF CONTENTS IS A REGULATORY REQUIREMENT (CFR 314(50)b.)

SECTIONS II2.1 Section Page (with Color Section TAG) and brief descriptor of the section.

.2 Basis for ANDA Submission

SECTIONS III3.1 Section Page (with TAG) and brief descriptor of the section.

.2 Patent Certification statement - (Paragraph I, II, III or IV)

.3 ‘Little VIII’ Patent statement - i.e. no labeling claims on a new indication.

.4 Exclusivity Statement with reference to the RLD.

.5 Certification Pursuant to the Generic Drug Enforcement Act of 1992.

SECTIONS IV - Generic vs. RLD Comparison4.1 Section Page (with TAG) and brief descriptor of the section.

.2 Comparison between Generic and Reference Listed Drug (RLD).

.3 Tabulate to show proposed product is the same as listed product namely: -Use; Active Ingredients; inactive ingredients: Route: Dosage Form; Strength

.4 Rx or OTC Marketing Statement for proposed Generic Product.

.5 Side-by-side comparison of insert.2

.6 Side-by-side comparison of label. 2

.7 Certification that proposed labeling is the same as listed drug.

.8 Innovators labeling - (obtain latest insert from FDA FOI).



SECTION I SECTION 1


TABLE OF CONTENTS

SECTIONS V - LABELING

5.1 Section Page and cover statement

.2 Innovators labeling - (obtain latest insert from FDA FOI).

.3 Proposed Generic labeling

.4 Side-by-side comparison of insert.

.5 Side-by-side comparison of label.

.6 Certification that proposed labeling is the same as listed drug.

1Strongly recommended - but not a legal or statutory requirement2Strongly recommended to repeat sections 5.4 & 5.5 in section 4 as 4.5 & 4.6 (new reg.)

SECTIONS VI - BIOAVAILABILITY / BIOEQUIVALENCE STUDY

6.1 Title Page and brief summary statement of what this section contains.

.2 Formula Composition of GENERIC product

.3 Percent Composition of Formula

.4 Comparative Ingredients List between Innovator & Generic

.5 Certificates of Analysis of Generic Drug Product - (all strengths)

.6 Certificates of Analysis for Innovator’s Product - (all strengths)

.7 Comparative Diffusion Profile using 6 dosage units each - (all strengths)

.8 Comparative Diffusion Profile (CDP study results, statistics, tables and graphs)

.9 Request for Waiver for Biostudy for other strengths (multiple strength application)

.10 Outline of packaging container closures - proposed marketing packs.

.11 Schematic Trail of all packed units

.12 Topical Bioequivalence protocol and study reports conducted on pivotal batch

*(Biostudy = Bioavailability / Bioequivalence Study required in selected cases)



SECTION I SECTION 1


TABLE OF CONTENTS

SECTIONS VII - Components and Composition7.1 Title Page (with TAG) and brief narrative statement of what this section contains.

.2 List of Components - in order of manufacture (name & grade).

.3 Formula Composition of Generic Product

.4 Percent Composition of Generic Product.

.5 Comparative composition summary by batch size (qualitative & quantitative)

SECTIONS VIII - RAW MATERIAL CONTROL

Active ingredients & Chromatographs

8.1 Title Page (with TAG) and brief narrative statement of what this section contains.

.2 Outlines of SOP for handling Raw Materials including Retest Procedure/Period

.3 VENDORS Certificates of Analysis (CofA) ; Specifications and Test Results

.4 GENERIC FIRM'S Certificates of Analysis (CofA) ; Specifications and Test Results

.5 Disclosure of Active ingredients Source. (Type II DMF Authorization Letter)

.6 DMF of Manufacturer via Letter of Access from Active Manufacturer.

.7 Active Material Monograph, Spectra and Chromatographs for REFERENCE &TEST Samples supplied by GENERIC FIRM'S QC laboratory

SECTIONS VIII - RAW MATERIAL CONTROLInactive ingredients

8.8 Title Page and brief summary statement of what this section contains.

.9 CoA from Generic Firm’s QC laboratory, plus supporting:

- Identification IR or UV spectra of Active

- HPLC chromatograms (Assay - Impurities) - label peaks

- Photocopy of TLC chromatograms (Assay - Impurities)



SECTION I SECTION 1

Application/ Table of ContentsTABLE OF CONTENTS

SECTIONS VIII - CONTINUED

SECTIONS VIII - RAW MATERIAL CONTROLInactive ingredients

.10 CoA from Active Manufacturer, - plus supporting:

- Identification IR or UV spectra of Active

- HPLC chromatograms (Assay - Impurities) - label peaks

- Photocopy of TLC chromatograms (Assay - Impurities)

.11 IR Identification Spectra of Reference Standard (Pharmacopoeial).

Physical Specifications from Active Manufacturer:

- Bulk Density

- Particle Size (note: water insoluble material)

.12 Physical and analytical test methods.

.13 Material Data Safety Sheet - source of data for manufacturing cautions.

.14 Monographs of each non-active from Generic QC lab

.15 Coating Colors and Dyes - US Source with Batch Certification

.16 - Composition of Approved Pigments and Dyes

.17 CoA from Generic QC lab (Applicants Release Certificate)

.18 CoA from Approved Manufacturer (Suppliers Release Certificate)

.19 Routine Testing Protocol and Frequency of tests for Active Material

.20 Routine Testing Protocol and Frequency of tests for Inactive Material

.21 Statement that other suppliers may be used subject to meeting pharmacopoeialstandards.

.22 SOP Outline of vendor qualification requirements (outlines are unsigned)

.23 SOP Outline of retesting procedures and schedule (micro. NMT 12 months)

.24 SOP Outline of RM environmental storage temperatures (15o-25 o (30o C).



SECTION I SECTION 1


SECTIONS IX - Description of Manufacturing Facility9.1 Title Page (with TAG) and brief narrative statement of what this section contains.

.2 Statement of commercial - Site address of Manufacture(s).

.3 Statement of commercial - Packaging & Labeling - site address.

.4 Statement of commercial - Site of Distribution - site address.

.5 Address of Facility for QC and Stability Testing.

.6 Brief description of facilities for MNF testing equipment and stability equipmentand key personnel (no personnel CVs).

.7 Statement on the GMP Certification of Compliance for the generic mfg. site

.8 Generic Manufacturing Site - Central File No (CFN)

SECTIONS XOutside Firms & Contract Testing Laboratory

10.1 Title Page (with TAG) and brief narrative statement of what this section contains. .2 Name and Site Address of all Contract Laboratories.

.3 Registration No. of each Contract Laboratory.

.4 List of Test(s) or FUNCTIONS to be Performed by Contract Laboratory.

.5 Certification letter of GMP/GLP Compliance of Contract Laboratory.

.6 Statement on the cGMP Status and Certification of Compliance re:- a contract manufacturing site- a contract labeler or packaging site.- environmental assessment or a claim for categorical exclusion

SECTIONS XIProposed Manufacturing and Processing Instructions


.2 Outlines of Manufacturing, equipment listing and Packaging SOP. .3 Summary of In-process controls and reprocessing statement. .4 Flow Chart of Manufacturing Procedure. .5 Blank forms for Intended Production runs for LARGEST commercial batch size

with processing equipment specified (Note 1:10 pivotal ratio).

.6 Blank forms should include the full manufacturing process such as:- Blank forms - Master Formula (Commercial batch size)- Blank forms - Manufacturing Procedures (English translations)- Blank forms - In-process specifications sheet for final blend.- Blank forms - In-process control sheets (English translations).- Blank production forms for in-process weight controls- Blank forms for production yields and weighing print-outs attachments



SECTION I SECTION 1


TABLE OF CONTENTS

11.7 Finished Product Release Specifications.

.8 Outline Packaging Operations and packaging equipment listing

.9 Blank Packaging Records.

.10 Side-by-side comparison of Pivotal & Production Batches (Formulation,Equipment, QC, Production Operating Personnel, SOPs).

.10 Reprocessing statement.

SECTIONS XIIPivotal Manufacturing and In-Process Controls


.2 Outline of In-process SOPs.

.3 In Process Controls and sampling plan summary.

.4 Executed Manufacturing Procedure Flow Chart.

.5 Pivotal Batch Title page

.6 Pivotal Batch Records.

.7 Executed Batch with signatures .8 - Master Formula for pivotal size

.9 - Executed forms - Master Formula (Commercial batch size).

.10 - Executed forms - Manufacturing Procedures (English translations.)

.11 - Executed forms - In-process control sheets (English translations).Documentation for manufacturing procedures, including production yields).

.12 - Executed forms - In-process manufacturing specifications for bulk material.

.13 - Executed forms - In-process product specifications for bulk material.

.14 - Executed forms - In-process test result sheet of the bulk material

.15 - Certificate of Batch Homogeneity (showing test results.)

.16 - Executed forms - In-process specifications.

.17 - Executed forms - In-process test results sheet.

.18 - FILL weight Verification study and results

.19 - Executed forms for production yields and weighing print-outs attachments.

.20 Executed forms production forms for in-process weight controls (translations)

.21 Finished Product Release Specifications

.22 Manufacturing (Mnf's) Deviation Reports (MDRs) - (translations)



SECTION I SECTION 1


TABLE OF CONTENTS12.23 Executed forms production forms for in-process weight controls (translations)

.24 Finished Product Release Specifications

.25 Manufacturing (Mnf's) Deviation Reports (MDRs) - (translations)

.26 Production Packaging Work Sheets - (translations)

.27 Production Packaging Control Forms - (translations)

.28 Distribution of Pivotal lot into various container-closures systems (Packaging)

.29 Pivotal Batch Packaging Trail - (overall disposition of UNITS i.e. net yield, QCsampling, reserve samples, stability samples, Biostudy, Packaging formats.)

SECTION XIIIDescription & Characteristics of Packaging Components

Packaging and labeling Procedures13.0 Title Page (with TAG) and brief narrative statement of what this section contains.

.1 Outlines for Packaging and Labeling Procedures

.2 Blank Packaging Forms and Packaging reconciliation.

Summary of Container-closure-liner system used for each strength.

CONTAINERS, GLASS OR THERMOPLASTIC

(REQUIREMENTS FOR EACH CONTAINER.)

.3 Description of Packaging Components - pack sizes for each strength.

.4 i. LoA from manufacturer referencing their container DMF #.

.5 ii. LoA from resin mnf. referencing their resin DMF # used in container - (Obtainseparate letters for each resin type used in plastic containers.)

.6 Manufacturer's Container Specifications or Certificate of Conformance, including;

- drawings/diagrams and dimensions

- test protocol and Certificates meeting USP and 21 CFR requirements

- DSC thermal analysis (for thermoplastic containers only)

- Manufacturer’s Container CoA

.7 Testing Specifications / protocol and test results (CoA) of Generic packaging Lab.

.8 CoAs of Containers from Generic packaging Lab.

.9 Batch Compliance Results



SECTION I SECTION 1


TABLE OF CONTENTS

METAL CAPS AND THERMOPLASTIC CLOSURES(PER EACH CLOSURE.)

13.09 LoA from closure manufacturer referencing DMF # of cap (+ GMP statement.)

.10 LoA from resin manufacturer referencing thermoplastic resin DMF #. (Obtainseparate letters for each resin type used in thermoplastic closures)

.11 Mnf's Closure Specifications or Certificate of Conformance, including;

- drawings/diagrams and dimensions

- test protocol and certificates meeting all USP and 21 CFR requirements

- DSC thermal analysis (only for thermoplastic closures)

- Manufacturer’s CoA

.12 Testing Specifications / protocol and test results (CoA) of Generic packaging Lab.

.13 Batch Compliance Results.

INNER CLOSURE LINER:

13.14 Item description and use - meets current CFR and USP requirements.

.15 LoA from manufacturer to applicant referencing their DMF # of inner liner.

.16 Inner liner Specifications or Certificate of Conformance from manufacturers.

.17 Testing Specifications / protocol of Generic packaging Lab.

.18 CoA or test results of inner liner from Generic packaging Lab.

.19 Batch Compliance Statement.

FOAM SEALS, PRESSURE SENSITIVE, TAMPER RESISTANT, ADHESIVE,INNER SEALS:

13.20 Item description and use - meets current CFR and USP requirements.

.21 LoA from manufacturer to applicant referencing their DMF # of foam seal.

.22 Foam seal Specifications or Certificate of Conformance from manufacturers


.24 CoA or test results of Foam seal from Generic packaging Lab.

.25 Batch Compliance Statement.



SECTION I SECTION 1


TABLE OF CONTENTS

TUBES AND NOZZLES/APPLICATORS

13.26 Item description and use - USP requirements.

.27 LoA from manufacturer to applicant referencing their DMF #

.28 Specifications or Certificate of Conformance from manufacturers.


.30 CoA or test results from Generic packaging Lab.

.31 Batch Compliance Statement of incoming packaging materials.

Section XIV - Controls for the Finished Dosage Form14.1 Title Page (with TAG) and brief narrative statement of what this section contains.

.2 State if drug product is:

- Compendial and test methods � used are USP

- Non-Compendial and test methods in-house and validated.

- Non-Compendial and test methods based on � and validated.

14.3 Certificate of Analysis of Pivotal Batch(es), including

- HPLC, TLC, GC, UV chromatograms and spectra e.g.:

- CoA for _______ [product] USP [Strength #1] mg + HPLC chromatograms




� Stability Indicating Assay; Impurity Limit Tests; Dissolution Assay� USPC Inc. Pharmacopeial Forum, � FDA



SECTION I SECTION 1


TABLE OF CONTENTS

Section XV - Analytical Methods


State if drug substance and drug product is:

- Compendial and test methods � used are USP

- Non-Compendial and test methods in-house and validated.

- Non-Compendial and test methods based on� and validated.

Active material

.2 Active Ingredient Test Method

.3 Active Ingredient Test Method Validation

In-process Material

.4 Final Blend Test Methods (especially Uniformity of Content)

Finished Product

.5 Finished Product Test Methods (QC Release

- physical tests

- chemical tests

- microbiological tests

.6 Finished Product Test Methods - (Stability Check)

- stability Indicating Test Methods.

- impurity limit tests.

- Preservative Efficacy Test Method (Validation and stability Studies).

.7 Finished Product Analytical Validation methodology

- stability Indicating Assay.

- impurity limits or specific impurity quantitation and detection levels (LQ & LD).

- microbiological limit tests



RESERVED SECTIONNOT FOR CURRENT USE

SECTION I SECTION 1


Section XVIStability of Finished Dosage Form


.2 Stability Protocol for Post Approval Production Batches (ANDA commitment).

.3 Package Configuration/sizes (largest and smallest) used in stability studies.

.4 Expiration Dating Period Statement.

.5 Stability Protocol used for Pivotal lot.

.6 Stability Reports Results of Pivotal Lot from 3 months accelerated and controlledroom temperature studies.

.7 Stability Data Summary Report (graphs).

Section XVIIReserved

17.0 Title Page (with TAG) and brief statement that section is reserved.

17.1 Reserved

Section XVIIISamples of the drug and articles used as

components18.1 Title Page (with TAG) and brief narrative statement of what this section contains.

.2 Statement on Sample Submission Procedures to FDA on request on

.3 - Submission of Drug Substance

.4 - Submission of Drug Product / Finished Dosage Form

.5 - Submission of Appropriate Reference Standards (where required)



SECTION I SECTION 1

Application/Table of ContentsTABLE OF CONTENTS.

Section XIXENVIRONMENTAL IMPACT ANALYSIS REPORTS

19.1 Title Page (with TAG) and brief narrative statement of what this section contains.19.2 Environmental Exclusion Assessment

- Development Site- Manufacturing Site

19.3 Applicable Environmental Laws (National / State / Local /Foreign):- Development Site- Manufacturing Site- Contract Manufacturers

19.4 Site Environmental Certification:- Development Site- Manufacturing Site- Contract Manufacturers

19.5 Statement on Environmental Compliance:- Development Site- Manufacturing Site- Contract ManufacturersCommercial Plant Manager and QA Director Signatures.

Section XXADDITIONAL INFORMATION


20.1 Certification Pursuant to the Generic Drug Enforcement Act of 1992.

20.2 US Agents Letter of Authorization

Section XXIADDITIONAL INFORMATION


21.2 Reference to previously submitted Information

21.3 Original Data / Literature Publication where English translation is submitted

21.4 Outline of manufacturing re-work study.

21.5 Table of DMF Numbers (with LOA dates).

21.6 Letters of Authorization (LOA) - TWO PHOTOCOPIES1

21.7 Field Copy Certification1 TWO PHOTOCOPIES OF LETTERS OF AUTHORIZATION WITH RECENT DATES (i.e. where possible in the same year as the ANDA submission.)



SECTION I SECTION 1


FDA FORM 3439

or

FDA FORM 356h[REVISED]

Jan 8, 1998

(The FDA revised Form 365h - Federal Register July 8, 1997)The revised "all purpose" form was official from January 8, 1998.

(NOTE: All DMF numbers stated on this form to be exactly the same as shownin Section 21 )

Correct pagination between text and Table of Contents is essential.(Page numbers in the actual application must be placed at bottom center of eachpage and run consecutively to the end of the submission i.e. up to Section 21)



NOTES



SECTION II SECTION 2

Basis for ANDA Submission


2.O Section Page and Title. The information in this section summarizes the fourcritical structures supporting the legal basis for this abbreviated new drug application

2.1.0 Basis for ANDA Submission is submitted as follows and is;

2.1.1 Based on an Abbreviated New Drug Application

or2.1.2 Based on an approved ANDA Suitability Petition

and3.0 Based on Active Ingredient (same as RLD) and current approved labeling

and4.0 Based on Route of Administration, Dosage Form and Strength

and5.0 Based on Bioequivalency Data submitted (Applicant Generic Drug vs. RLD)

NOTE:-MODEL Letters are provided in Section IV highlighting each of four critical structuresand supporting documentation stating the legal basis for this abbreviated new drugapplication

4




Basis for ANDA SubmissionBASIS FOR ABBREVIATED NEW DRUG APPLICATION

[a] Listed Drug.This applications refers to the Reference Listed Drug [NAME] qSemisolidqTablet / qCapsule manufactured by [RLD Company Name Inc. / Ltd.](delete where necessary).

The basis for [Applicant Company Name Inc. / Ltd.] proposed ANDA for FullGeneric Drug Name is the approved reference listed drug as above, the subject ofANDA [#00 0000] held by [RLD Company Name Inc. / Ltd.]. and containing [000.0 /000.0 / 000.0mg] of [Generic Drug Name].

According to the FDA listed information published in the list of approved DrugProducts known as the Orange Book 20th (2000) Edition the listing is enclosedherewith.

[b] Exclusivity.Furthermore according to the FDA listed information published in the list ofApproved Drug Products [Orange Book] 20th (2000) Edition the RLD is entitled to aperiod of marketing exclusivity (under section 505j[4][D] of the Act as a NewChemical Entity until the NCE's expiration period of MM/DD/YY

orFurthermore according to the FDA listed information published in the list ofApproved Drug Products [Orange Book] 20th (2000) Edition, no exclusivity’s forthe listed the RLD applies.

[c] According to the information published in the 20th Edition List (2000),the reference listed drug is covered by [one / two] use patent which isaddressed in Section III of this application.

[d] APPROVED ANDA SUITABILITY PETITIONThe basis for [Applicant Company Name Inc. / Ltd.] proposed ANDA is furtherbased on the approval of the suitability petition pursuant to the 21 Code FederalRegister (CFR) # 505[j][2][c] and 21 CFR 314.93 that requested a change from theabove listed drug in subparagraph 1[a] as above.

Docket No [00000]The basis of this ANDA SUITABILITY PETITION is held and was submitted underDocket No [00000] and approved on MM/DD/YY.

A copy of the FDA letter approving the ANDA SUITABILITY PETITION is attached insection II of this application (page [00])




Basis for ANDA SubmissionBASIS FOR ABBREVIATED NEW DRUG APPLICATION (continued)

ACTIVE INGREDIENT [00000]21 CFR 314.94 [A][5][i]

he active ingredient of [Applicant Company Name Inc. / Ltd.] Genericq Semisolid / qTablet / qCapsule (delete where necessary) is the same as that

of the RLD brand name We refer the reviewer to [Applicant Company Name Inc. /Ltd.] annotated labeling and the current approved labeling of the RLD as shown inSection IV-05 of this ANDA (Refer pages [00] to [00])

ROUTE OF ADMINISTRATION DOSAGE FORM AND STRENGTH

21 CFR 314.94 [A][5][i]he Route of Administration, Dosage Form and Strength [Applicant Company'sName Inc. / Ltd.] of Generic q Semisolid / qTablet / qCapsule (delete where

necessary) is the same as for [RLD brand name]Again we refer the reviewer to [Applicant Company Name Inc. / Ltd.] annotatedlabeling and the current approved labeling of the RLD as shown in Section IV-05 ofthis ANDA (Refer pages [00] to [00])

BIOEQUIVALENCY DATA [00000]21 CFR 314.94 [A][7][i]

[Applicant Company Name Inc. / Ltd.] bioequivalent study on [Genericq Semisolid / qTablet / q Capsule Name] (delete where necessary) wassuccessfully conducted in terms of current approval parameters by Clinical ResearchLaboratories [Name and Address]The Full Bioequivalence Report is attached to Section VI of this ANDA (Refer pages[000] to [000])

[Signature of Responsible Person]------------------------------------------------ -----------------------------------------[Name of Responsible Person] DateRegulatory Affairs Director[Applicant Company Name Inc. / Ltd.][Signature of Responsible Person]

[Two typical examples of this section are given below]

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Basis for ANDA SubmissionEXAMPLE 1:

Listed Drug.This applications refers to the Reference Listed Drug [RLD] Miconazole1 /Miconazole USP2 Generic q Semisolid qTablet / qCapsule (deletewhere necessary) manufactured by [RLD Company Name Inc. / Ltd.]3.A copy of the Orange Book 20th (2000) Edition listing is enclosedherewith.

According to the information published in the 20th Edition List, thereference listed drug is covered by [þþ no / one / two] use patent which isaddressed in Section III of this application.

Exclusivity.There are [ONE] / [two] / þþ [no] exclusivity’s for the listed drug.I-184 - expires Sept 24, 2000I-185 - expires Sept 24, 2000

[Signature of Responsible Person]------------------------------------------------ -----------------------------------------[Name of Responsible Person] DateRegulatory Affairs Director[Applicant Company Name Inc. / Ltd.]


1INNOVATOR NAME COUNTRY US or EU2USA RLD 375 / 500 mg - Application Number 0000003INNOVATOR




Basis for ANDA Submission

EXAMPLE 2:

Listed Drug.This applications refers to the Reference Listed Drug [RLD] Miconazole1 /Miconazole USP2 q Semisolid / qTablet / qCapsule manufactured by[RLD Innovator Company Name Inc. / Ltd.]3. (delete where appropriate)A copy of the Orange Book 20th (2000) Edition listing is enclosedherewith.

According to the information published in the 20th Edition List (2000), thereference listed drug [RLD] is covered by [þþ no / one /two] use patent(s)which is addressed in Section III of this application.

Exclusivity.According to the information published in the 20th Edition of the OrangeGuide (2000), there are [one] / [two] / þþ [no] exclusivity’s for the listeddrug.I-000 - expires MM DD, 2000I-000 - expires MM DD, 2000

[Signature of Responsible Person]

------------------------------------------------ -----------------------------------------[Name of Responsible Person] DateRegulatory Affairs Director[Applicant Company Name Inc. / Ltd.]


1 INNOVATOR2 USA RLD IS REGISTERED AS STRENGTH 0 mg +00 mg INNOVATOR Application Number [00000]3 INNOVATOR




Basis for ANDA SubmissionANDA SUITABILITY PETITION APPROVAL LETTER

Date:

Office of Generic DrugsCDER, Food and Drug AdministrationDocument Control Room - No. 150Metro Park North II7500 Standish PlaceROCKVILLE MD 20855-2773.

ORIGINAL ABBREVIATED NEW DRUG APPLICATION[Generic name] Dosage Form

Dear Sir,

We submit herewith the ANDA SUITABILITY PETITION APPROVAL LETTERfor the drug product [Generic name q Semisolid / qTablet / qCapsule [000 / 000]mg. (delete where necessary)


[ANDA SUITABILITY PETITION APPROVAL LETTERattached in Section XXII]

4



End of Section 2.



SECTION III SECTION 3

Patent Certification / Exclusivity


ection Page (with Color Section TAG) and brief narrative of the section.Enclosed in this sections is a statement of patent certification for [Applicant

Company Name Inc. / Ltd.]new drug application [Drug Name]. Also enclosed (ifapplicable) are the statements concerning the required notices to the patent ownersand NDA holder. These statements are in accord with the FD&C Act as amendedSeptember 24, 1984 and with the final regulations effective November 2 1994.

3.1 Patent Certification statement -

State Paragraph I

State Paragraph II

State Paragraph III

State Paragraph IV

3.2 ‘Little VIII’ Patent Statement - i.e. no labeling claims on a new indication.

3.3 Exclusivity Statement with reference to the RLD.

3.4 Certification Pursuant to the Generic Drug Enforcement Act of 1992.

4

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Patent Certification StatementParagraph I Certification

[21 CFR 314.94(a)(12)(i)]

n accord with the Food, Drug and Cosmetic Act as amended September 24, 1984and with the final regulations effective November 2 1994 Patent certification is

hereby provided for our Abbreviated New Drug Application for [Generic DrugName].

e the undersigned hereby certify to the best of our knowledge and in [GenericCompany Name Inc./Ltd.]’s opinion patent information has not been submitted

to the FDA on Patent No [00-0000-00] which claims the reference listed drug [RLD]DRUG Name [USP] [000.0] mg. NDA # 00-000

his certification is made in accordance with Section 505 (j)(2)(A)(vii)(I) of Title Ithe Food, Drug and Cosmetic Act, as amended September 24, 1984 and

pursuant to 21 CFR 314.94 (a)(12)(i)(A)(1).

[Signature of Responsible Person]------------------------------------------------ -----------------------------------------[Name of Responsible Person] Date

Regulatory Affairs Director[Applicant Company Name Inc. / Ltd.]

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Patent Certification StatementParagraph II Certification



e the undersigned hereby certify that to the best of our knowledge and in[Generic Company Name Inc./Ltd.]’s opinion US Patent No [00-0000-00] held

by [Innovator/RLD Company Name Inc./Ltd.] which claimed the reference listeddrug [RLD] DRUG Name[USP] [000.0] mg. NDA # 00-000 expired on 31 December1999



US. Patent No. 0-0000-0000 expiring Dec 31, 1999US. Patent No. 0-0000-0000 expiring Dec 31, 1999


Regulatory Affairs Director[Applicant Company Name Inc./Ltd.]

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Patent Certification StatementParagraph III Certification



e the undersigned hereby certify that to the best of our knowledge and in[Generic Company Name Inc./Ltd.]’s opinion US Patent No [00-0000-00] held

by [Innovator/RLD Company Name Inc./Ltd.] which claimed the reference listeddrug [RLD] DRUG Name [USP] [000.0] mg. NDA # 00-000 will expire on [31December 1999.]

US. Patent No. 0-0000-0000 expiring MM DD, YYYYUS. Patent No. 0-0000-0000 expiring MM DD, YYYY

n accordance with Section 505 (j)(2)(A)(vii)(III) of the Food, Drug and CosmeticAct, as amended [Generic Company Name Inc./Ltd.] certifies that the Company

will not engage in the commercial manufacture, use or sale of the drug Product untilthis aforementioned patent has expired.


Regulatory Affairs Director

[Applicant Company Name Inc. / Ltd.]

Note the Bolar amendment allows the sale of the bulk active material and thedevelopment manufacture testing of the developed generic product SOLELYfor the purposes and under the condition of getting it approved as an ANDA

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Patent Certification / ExclusivityAlternative Certification

Patent Certification StatementParagraph III Certification

he undersigned hereby certifies to the best of our knowledge and in [GenericCompany Name Inc./Ltd.]’s opinion there is [one] patent which claims the listed

drug [RLD] DRUG Name [USP] [000.0] mg. NDA # 00-000.

US. Patent No. 0-0000-0000 expiring MM DD, YYYYUS. Patent No. 0-0000-0000 expiring MM DD, YYYY

In accordance with Section 505 (j)(2)(A)(vii)(III) of the Food, Drug and Cosmetic

Act, as amended [Generic Company Name Inc./Ltd.] certifies that the Company willnot engage in the commercial manufacture, use or sale of the drug Product until thisaforementioned patent has expired .



Attached:Page Number: [00]The Prescription Drug Product List of the APPROVED DRUG PRODUCTS WITHTHERAPEUTIC EQUIVALENCE EVALUATIONS EDITION 20th - 2000 USDepartment of Health and Human Sciences.

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Patent Certification / ExclusivityPatent Certification StatementParagraph IV Certification



e the undersigned hereby certify that to the best of our knowledge and in[Generic Company Name Inc./Ltd.]’s opinion US Patent No [00-0000-00]

issued on MM DD, YYYY and will expire on 31 December 2004 [will not beinfringed] / [ is invalid] / [is unenforceable]1 by the manufacturer [Generic CompanyName Inc./Ltd.] upon the manufacture use and sale by [Generic] DRUG Name[USP] [000.0]mg. for which this application is submitted

NO INFRINGEMENT STATUS of the following patents.US. Patent No. 0-0000-0000 expiring MM DD, YYYYUS. Patent No. 0-0000-0000 expiring MM DD, YYYY

[Signature of Responsible Person]------------------------------------------------ -----------------------------------------[Name of Responsible Person] DateRegulatory Affairs Director[Applicant Company Name Inc./Ltd.]

1Select the appropriate language that constitutes the basis of the patent challenge namely:

♦ [the patent will not be infringed]

♦ [the patent is invalid]

♦ ♦ [the patent is unenforceable] or♦ ♦ [ANDA applicant hold a licensing agreement for the Patent Holder]1

Special Note of Notification:If the owner of the patent, subject to a paragraph IV Certification, is a person or entity otherthan the registered NDA holder, then the applicant, is required to notify, under separatecover, both parties - namely the Patent Holder and the NDA Holder.(Certified mail return receipt cards often get damaged in the mail - thus avoid use, assystem is ineffective. Where Fedex® , UPS® or DHL® etc. is used to advise of anotification it is essential to obtain the recipient approval to use Fedex® , UPS® or DHL®couriers PRIOR to notification).

♦ 1Where the generic applicant has an patent holder / innovator Agency Agreement,include the correspondence of the agency licensing agreement, from the RLD Company,as an attachment. (meeting requirement of 21 CFR 314.94(a)(12)(v) (November 2,1994).

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Patent Holder & NDA Holder

Statement Concerning NoticeTo Patent Holder and NDA Holder

21 CFR 314.94(a)(12)(1)(A)(iv) & 21 CFR 314.95

n accordance with Section 505 (j)(2)(B) of the Food, Drug and Cosmetic Act, asamended and 21 CFR 314.94(a)(12)(1)(A)(iv) & 21 CFR 314.95 certifies that

[Generic Company Name Inc./Ltd.] hereby states that our firm, upon receipt fromthe FDA of an acknowledgment letter stating that this ANDA is sufficiently completeto permit a substantive review, will give the notice required by Section 505 (j)(2)(B)of the Food, Drug and Cosmetic Act, as amended, and 21 CFR 314.95 to [RLDCompany Name Inc./Ltd.] the holder of the approved application for the BrandedProduct, [RLD] DRUG Name [USP] [000.0]mg and the owner of US Patent Number[5-0000-00] issued on MM DD, YY.

The notice to the Branded Product [RLD] DRUG Name] shall be sent certified mail,return receipt requested and shall meet the requirements of 21 CFR 314.95 (a) and21 CFR 314.95 (c)

Concurrently with mailing the notice to the [RLD Company Name Inc./Ltd.] thepertaining to the Branded Product - [RLD] DRUG Name] the [Generic CompanyName Inc./Ltd.] will as required by 21 CFR 314.95(b) amend it ANDA for [Generic]DRUG Name [USP] [000.0]mg to include a certification that the notice has beenprovided to each person identified under CFR 314.95(a) and that the notice met thecontents of CFR 314.95(c).



♦ ♦ It has become standard practice for the large RLD (Innovative) Companies to delay for as long aspossible, by means of costly litigation action, the newly applied Generic registration, if submittedunder a Paragraph IV certification, whether or not there is any legal basis for the litigation suite.The spirit and intention of the Act and law to provide suitable cheaper generic drugs for thegeneral public is overridden by the Innovative Companies desire to look for continued extra-legalpatent protection even thought the innovator has indeed received its fair and proper share ofprotection under the law during its full marketing period. The branded RLD Company simplyimmediately sues the generic applicant as a matter of routine practice, using its huge financialleverage to suppress the potentially lesser generic company. (Quote Brussels Conference on PatentCertification Oct. 1999: "if they don't sue - they're brain dead"). In truth, branded RLD Company needto honestly address the overall ethics question of this [now] standard litigation action which isbased purely on the profit and greed motive and is designed to evade, side-step and elude thespirit and intention of the law for the benefit of the general public at large - Editor-in-Chief.

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' No relevant Patent ' Statement21 CFR 314.94(a)(12)(ii)

n accord with the Food, Drug and Cosmetic Act as amended September 24, 1984and with the final regulations effective November 2, 1994. Patent certification

clarification is hereby provided for our submitted Abbreviated New Drug Applicationfor [Generic Drug Name].

his certification is made in accordance with Section 505 (j)(2)(A)(vii)(I) of Title Ithe Food, Drug and Cosmetic Act, as amended, September 24, 1984 and

November 2, 1994 and pursuant to 21 CFR 314.94 (a)(12)(ii).

e the undersigned hereby certify to the best of our knowledge and in [GenericCompany Name Inc./Ltd.]’s opinion there are no patent[s] which claim[s] the

Reference Listed Drug [RLD] DRUG Name [USP] [000.0]mg. NDA #[00-000-00]referred to in this application or that claims a use of the Reference Listed Drug.


Regulatory Affairs Director


BackgroundThis specification is not specifically described under the FD&C Act but appears in the FDA finalregulations dated Nov 2, 1994. The purpose of the "No relevant Patents Statement " appears to bedesigned to aid and help the internal FDA OGD reviewers to assure them that your firm's omission toinclude a patent certification is a deliberate action and not simply a regulatory oversight.

Note: The intention of the regulations and the preamble to the regulations is to provide a positivestatement that the submitted ANDA should not contain any of the FOUR Patent CertificationStatements (i.e. No Paragraph I ; II ; III or IV statement) - Thus, it is necessary to submit a "Norelevant Patents Statement " if and only if, no patent(s) exist that should be the subject of a PatentCertification - i.e. stating the negative condition and thus eradicating the element of an regulatoryoversight.

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Method of Use Patent Statement21 CFR 314.94(a)(12)(iii)



Method of Use Patentn accord with the Section 505 (j)(2)(A)(viii) of Title I the Food, Drug and CosmeticAct, as amended September 24, 1984, [Generic Company Name Inc./Ltd.] hereby

states, with respect to method of Use Patent, US Patent No [000-000-00], submittedby [RLD Company Name Inc./Ltd.] for listing in respect to [RLD Branded DrugName], that of Use Patent No [000-000-00] does not claim a use for which [GenericCompany Name Inc./Ltd.] is seeking approval for [Generic Drug Name]

e the undersigned hereby certify to the best of our knowledge that of UsePatent No [000-000-00] is limited to the following claim (specific therapeutic

use), the use for which [Generic Company Name Inc./Ltd.] now seeks approval inthis ANDA, as evident by the attached proposed labeling (Refer to Page [00]), is foruse indication _________, which is beyond the reach of claims of Patent No [000-000-00] .



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Exclusivity Statement21 CFR 314.94(a)(3)(ii)

[RLD] CAPSULES [000.0] mg. NDA # 00-000

he undersigned hereby certifies to the best of our knowledge and in [GenericCompany Name Inc./Ltd.] opinion the listed drug [RLD] DRUG Name [USP]

[000.0] mg. NDA # 00-000 is not covered by any exclusivity.

ORThe following statement is made if market exclusivity exists under the Waxman-Hatch Actrelative to the Reference Listed Drug - Attach the relevant page of the Orange Book

ccording to the information as published in the 'Orange Book' [Approved DrugProducts with Therapeutic Equivalence Evaluations Edition #20 (2000), US

Department of Health and Human Sciences], the listed drug [RLD] DRUG Name[USP] [000.0mg] is entitled to a three year period of market exclusivity under 505(j)(4)(D) of the F.D.& C Act as a new product which does not expire until Dec 312002.[Generic Company Name Inc./Ltd.] does not intend to introduce its drug productsubject to this ANDA, prior to the expiration of this exclusive marketing period.



Attached:Page Number: [00]The Prescription and OTC Drug Product Patent and Exclusivity Data of theAPPROVED DRUG PRODUCTS WITH THERAPEUTIC EQUIVALENCEEVALUATIONS EDITION 20 (2000) - US Department of Health and HumanSciences.

4End Section III

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24 Volume Drug Development Series Sect: 4.1 Topical SEMISOLID

SECTION IV SECTION 4

Generic and RLD ComparisonTABLE OF CONTENTS(Overall ANDA Guideline Requirements for this Section).

4.1 Section Page (with Color Section TAG) and brief narrative of the section.

4.2 Comparison between Generic and Reference Listed Drug (RLD) / InnovatorTabulate to show proposed product is the same as listed product namely: -

• Conditions of Use

• Active Ingredients

• Inactive ingredients (OGD Interim Inactive ingredient Policy - 'Q&Q'policy of Nov 17 1994 - does not apply to oral dosage forms i.e. tabletscapsules and suspensions)

• Route of Administration & Dosage Form

• Strength

• Inactive Ingredients with supporting data

• Labeling Comparison (Add section V data)4.3 Rx or OTC Marketing Statement for proposed Generic Product.

FDA's Published January 1999 ANDA Guideline requirementsSection IV.

Comparison between Generic Drug and Reference Listed Drug(505(j)(2)(A))

1. Conditions of Use (§ 3l4.94(a)(4))2. Active ingredient(s) and supporting information (§ 3l4.94(a)(5))3. Inactive ingredients as appropriate (§ 314.94(a)(9))4. Route of administration, dosage form, and strength (§ 3l4.94(a)(6))

Note:Until the issue of the FDA Guideline in February 1999 'Guidance for IndustryOrganization of an ANDA' it was appropriate to place the side-by-side labelingcomparison in section V on the ANDA. The new February 1999 'Guide' indicates thatthe side-by-side labeling comparison should appear in Section IV-5. Applicants mayplace the comparison in both section IV-5 and V until the FDA are conversant withthe new guideline

4




Generic and RLD ComparisonInformation required under 314.94 (a)(4) through (6) of the ANDA Regulations finalrule issued April 28 1992 and February 1999 Guidance to Industry.

[RLD] SEMISOLID [Generic name] SEMISOLID

[RLD Company Name] [Generic Co. Name].

Conditions of Use The conditions of useprescribed or recommended orsuggested for [RLD]SEMISOLIDS [USP] may befound in the package insert(see section V).

The conditions of useprescribed, recommended orsuggested for [Generic name]SEMISOLIDS [USP]] are thesame for [RLD] SEMISOLIDS[USP] and may be found in thepackage insert (see SectionV).

Active Ingredient [Active Material] [Active Material]

Dosage Form SEMISOLIDS [USP](Topical dosage form)

SEMISOLIDS [USP](Topical dosage form)

Administration Topical Topical

Strengths

Number ofStrengths

000.0 mg000.0 mg000.0 mg000.0 mg

000.0 mg000.0 mg000.0 mg000.0 mg

Labeling: The labeling proposed for the [Generic Company Name Inc. / Ltd.] drugproduct is the same as the labeling for the listed drug product except for:

1) Changes required because the drugs are produced and distributed by differentmanufacturers and distributors.

2) Product are packed in different size containers.




Rx / OTC Statement

[Generic name] SEMISOLID [USP][All strengths]

Prescription Drug (Rx)This drug is limited in its labeling and by this application to use under theprofessional supervision of a practitioner licensed by law to administer theprescription drug.

or

Over-the-Counter (OTC) DrugThis drug is limited in its prescribed labeling and by this application foruse as an Over-the-Counter (OTC) Drug.





NOTES



SECTION V SECTION 5

Labeling


1. Section Page and cover statement

2. Proposed Generic container panel labeling for each strength & pack size.

3. Proposed Generic Insert / Outsert

4. Innovators Insert / Outsert - (obtain latest insert from FDA FOI).

5. Innovators container panel labeling for each strength & pack size

6. Side-by-side comparison of package leaflet (insert or Outsert.)

7. Side-by-side comparison of label for each strength & pack size

8. Certification that proposed labeling is the same as listed drug (RLD).

4



SECTION V SECTION 5

Labeling

PROPOSED GENERIC CONTAINER PANEL LABELING000 g [Name] SEMISOLID [USP]

Main Panel NDC [0000-0000-00][Generic Name] Semisolid [USP]000 mg per g_________________________Contains:[Active Material] 000 mg per g

Caution: Federal law prohibits dispensing without prescription

000 g Semisolid [USP]


Side Panel Usual dosage : Apply four times a day.See package for full prescribing information.KEEP OUT OF REACH OF CHILDRENKeep tightly closed. Store at controlled room temperature 15º -30º C (59º - 86º F).Protest from exposure to temperatures above 40º C (104º F)and moisture.

KEEP THIS AND ALL MEDICATIONS OUT OF REACH OFCHILDREN6/YY.

MANUFACTURED BY[Generic Company Name Inc. / Ltd.][Address]

Distributed By:[Distributing Company Name Inc. / Ltd.][Address]



SECTION V SECTION 5

LabelingPROPOSED GENERIC CONTAINER PANEL LABELING000 g [Name] SEMISOLID [USP]

Main Panel NDC [0000-0000-00][Generic Name] Semisolid [USP]000 mg per gram_________________________Contains:[Active Material] 000 mg / g


000 g [Name] Semisolid [USP]


Side Panel Usual dosage : Apply four times a day.See package for full prescribing information.KEEP OUT OF REACH OF CHILDREN

Lot NoMfg. Date:Use Before:

Keep tightly closed. Store at controlled room temperature 15º -30º C (59º - 86º F).Protest from exposure to temperatures above 40º C (104º F)and moisture.

KEEP THIS AND ALL MEDICATIONS OUT OF REACH OFCHILDREN

6/YY.

MANUFACTURED BY[Manufacturing Company Name Inc. / Ltd.].[Short Address]

Distributed By:[Distributing Company Name Inc. / Ltd.][Short Address]



SECTION V SECTION 5

Labeling

PROPOSED GENERIC PACKAGE INSERT LABELING

SIDE-BY-SIDE COMPARISON

GENERIC PACKAGE INSERT INNOVATIVE PACKAGE INSERT

Present full Generic package insertidentical to innovators (cautionrestrictions on indications still on patent- these may not be included )

Use point size 7 and highlight thedifferences in the GENERIC PACKAGEINSERT - use line side bars wheredifferences appear as shown:

NOTE:-The differences in the package insertshould be restricted to Generic productname and different addresses forApplicant Manufacturer, Distributor andProduct reference Numbers.

Present full Innovative package insert ofinnovators (restrictions on indicationsstill on patent are included and shownas a difference ) - latest edition ofpackage insert must be used - obtainfrom FOI services

Use point size 7 and highlight thedifferences in the INNOVATIVEPACKAGE INSERT - use line side barswhere differences appear.

NOTE:-The differences in the package insertshould be restricted to Innovativeproduct name and different addressesfor Applicant Manufacturer, Distributorand Product reference Numbers

NOTE:Examine innovators labeling carefully and reproduce wording meeting all regulatoryrequirements. Note: the FDA provide a significant number of the latest packageinserts for Generics - on the Internet - See FDA Website



SECTION V SECTION 5

Labeling

PROPOSED GENERIC CONTAINER LABEL LABELING

SIDE-BY-SIDE COMPARISON

GENERIC CONTAINERLABEL

INNOVATIVE CONTAINERLABEL

Present full Generic CONTAINERLABEL identical to innovators (cautionrestrictions on indications still on patent- these may not be included )

Use point size 12 and highlight thedifferences in the GENERIC PACKAGECONTAINER LABEL - use line side barswhere differences appear as shown:

NOTE:-The differences in the CONTAINERLABEL should be restricted to Genericproduct name and different addressesfor Applicant Manufacturer, Distributorand Product reference Numbers.

Present full CONTAINER LABEL ofinnovators (restrictions on indicationsstill on patent are included and shownas a difference ) - latest edition ofpackage CONTAINER LABEL must beused - obtain from FOI services

Use point size 12 and highlight thedifferences in the INNOVATIVECONTAINER LABEL - use line side barswhere differences appear.

NOTE:-The differences in the CONTAINERLABEL should be restricted toInnovative product name and differentaddresses for Applicant Manufacturer,Distributor and Product referenceNumbers

NOTE:Examine innovators labeling carefully and reproduce wording meeting all regulatoryrequirements



SECTION V SECTION 5

Labeling

PROPOSED GENERIC CONTAINER ADHESIVE LABELING

000 g [GENERIC Name] Semisolid [USP]

(Show ALL dosage and fill sizes)

NDC [0000-0000-00]

[GENERIC Name] Semisolid [USP]000 mg per g.

Each gram contains:[Active Material] [000] mg


000g [GENERIC Name] Semisolid [USP]

Keep tightly closed. Store at controlled room temperature 15º - 30º C (59º - 86º F). Protest fromexposure to temperatures above 40º C (104º F) and moisture. KEEP THIS MEDICATION OUT OFREACH OF CHILDREN.

[Applicant Company Name Inc. / Ltd.]Distributed By:[Distributing Company Name Inc. / Ltd.]

NOTE:Examine innovator's carton and container labeling carefully and reproduceinstructions to meet all regulatory requirements. Obtain the latest printing of theinnovator's product labeling.

4



SECTION V SECTION 5

Labeling

INNOVATIVE CONTAINER ADHESIVE LABELING

000 g [GENERIC Name] Semisolid [USP]

(Show ALL dosage and fill sizes)

NDC [0000-0000-00]

[INNOVATIVE Semisolid [USP]000 mg per g

Each gram contains:[Active Material] [000] mg


000 g [RLD Name] Semisolid [USP]

Keep tightly closed. Store at controlled room temperature 15º - 30º C (59º - 86º F). Protest fromexposure to temperatures above 40º C (104º F) and moisture. KEEP THIS MEDICATION OUT OFREACH OF CHILDREN.

[Innovative (RLD) Company Name Inc. / Ltd.]

NOTE:Examine innovators labeling carefully and reproduce meeting all regulatoryrequirements

4



SECTION V SECTION 5

Labeling Certification Statement

[GENERIC Name] Semisolid [USP][000] mg per g

Certification.Generic Drug's proposed labeling same as Reference Listed Drug.

The undersigned hereby certifies to the best of our knowledge and in[Generic Company Name Inc. / Ltd.]’s opinion the proposed labeling isthe same as listed drug [RLD] SEMISOLID [USP] - NDA # 00-000.



444


SECTION VI SECTION 6

Bioavailability / Bioequivalence



• Title Page and brief summary statement of what this section contains.

• Formula Composition of Generic product

• Percent Composition of Formula

• Comparative Ingredients List between Innovator & Generic (all strengths)

• Certificates of Analysis of Generic Drug Product - (all strengths)

• Certificates of Analysis for Innovator’s Product - (all strengths)

• Biostudy Waiver Request for other strengths (multiple strength applications).

• Outline of packaging container closures - proposed marketing packs.

• Packaging trail of all packed units.

• Biostudy protocol & Biostudy Study Reports1 (conducted on pivotal batch).1(Biostudy = Bioavailability / Bioequivalence/Topical Bioequivalence Study)

NOTETopical corticosteriods are a specific class of topical semisolids that have apublished FDA guidance procedure (June 1992) on in-vivo bioequivalence using avasoconstrictor bioassay and include guidelines on a Franz cell diffusion test.

4





HIS section contains the Biostudy reports of the Topical Bioequivalence studyconducted against the selected RLD. The lot numbers of test product andreference product compared in this study are listed in Table 1:

Generic Product Chosen:

[Generic name] Semisolid [USP] [000.0] mg/g. Lot: 000 was manufactured at[Generic Company Name Inc./Ltd.] [Address] facility, utilizing the production areaand incorporating standard production staff, procedures and equipment.

The Batch size was: Batch size: 150 Kg equal to [150 000] one gram dosageapplications of the Semisolid Dosage Form

Reference Product Chosen:

[RLD Company Name Inc./Ltd.], [RLD] Semisolid Dosage Form [USP] [000.0] mg/gLot: AA000 Expiry Date: Month Year.

This Section contains:♦ Statement of composition of the Generic Product strengths - [Generic Name]

Semisolid [USP] [000.0] mg/g

♦ Percent composition of the Generic Product [Generic Name] Semisolid [USP] [000.0] mg/g - (give all strengths where appropriate.)

♦ Qualitative comparative Ingredient List of the Reference Listed Product (RLD)and Generic Product - (give all strengths where appropriate.)

♦ Certificates of Analysis for both products used in the Topical Bioequivalence.

♦ Certificates of Analysis for both products requested in the waiver

T





Products used in Topical Biostudy:Table 1

PRODUCT Strength

Batch No: C o A No:

REFERENCE [RLD] Semisolid [USP] [000.0] mg/g

Lot: AA000 R000

GENERIC [Generic name] Semisolid [000.0] mg/g

Lot: OO0 G000

Products in Study Waiver Request:Table 2

PRODUCT Strength

Batch No: C o A No:

REFERENCE [RLD] Semisolid[USP] [000.0] mg/g

Lot: AA000 R001

REFERENCE [RLD] Semisolid[USP] [000.0] mg/g

Lot: BB000 R002


Lot: OO0 G001


Lot: OO0 G002

ATTACHED The Packaging and Disbursement Summary for [Generic Company Name Inc./Ltd.] Topical Biostudy pivotal Lot: OO0.





FORMULA COMPOSITIONComposition of the drug, stating the name and amount of each ingredient, whether active ornot, contained in a stated quantity of the drug, in the form in which it is to be distributed.

PERCENT COMPOSITION OF THE PRODUCTPERCENT COMPOSITION OF THE PRODUCT[Generic name] FORM [USP]

Table 3.

FORMULA

INGREDIENTS

Amount in mg

per gram

mg PURPOSE

Miconazole USP Micronized

Pegoxol 7 Stearate [Tefose 63™]

Heavy Mineral OIL NF

Benzoic Acid USP

Butylated Hydroxyanizole

Peglico 5 Oleate [LABRAFIL M 1944™]

Edetate Disodium USP

Purified Water USP

20.00

180.00

44.80

2.00

000.05

30.00

1.50

721.65

ACTIVE1

EMULGENT

OIL BASE

PRESERVE

ANTIOXIDANT

EMULGENT

CHEALATE

AQ. PHASE

TOTAL 1000.00

1 The weight of the ACTIVE may alter according to the potency of active raw material

4





QUALITATIVE COMPARATIVE

INGREDIENTS LIST

Table 4.

[Generic name] Form [USP]

[Active Material]

[Generic Company Name Inc. / Ltd.]

[RLD] Form [USP]

[Active Material]

[RLD Company Name Inc. / Ltd.]*




Benzoic Acid USP




Purified Water USP

Miconazole USP



Benzoic Acid USP


Peglico 5 Oleate


Purified Water USP

* Reference Source - PDR 1998/1999

Note:Qualitative comparative ingredients list are identical for all dosage strengths.





CERTIFICATES OF ANALYSISREPRESENTING THE DRUG PRODUCTS USED IN BIOEQUIVALENCY STUDY

The analytical results of the Certificates of Analysis for [Generic Company Name Inc. / Ltd.] and[RLD Company Name Inc. / Ltd.] Drug Product lots were obtained from the Analytical ResearchLaboratories at [Generic Company Name Inc. / Ltd. & Address].

Generic Product: Attached Certificate of Analyses in support of waiver:(3 Batches for antibiotics)Certificate of Analysis No: A01 Lot: A00 [000.0] mg/g Date: MM DD YYCertificate of Analysis No: A02 Lot: A00 [000.0] mg/g Date: MM DD YY

Certificate of Analysis No: B01 Lot: B00 [000.0] mg/g Date: MM DD YYCertificate of Analysis No: B02 Lot: B00 [000.0] mg/g Date: MM DD YY

Certificate of Analysis No: C01 Lot: C00 [000.0] mg/g Date: MM DD YYCertificate of Analysis No: C02 Lot: C00 [000.0] mg/g Date: MM DD YY

Innovative Product (1 Batch)Certificate of AnalysesCertificate of Analysis No:AA01 Lot: AA02 [000.0] mg/g Date: MM DD YYCertificate of Analysis No:AA01 Lot: AA02 [000.0] mg/g Date: MM DD YY

FDA GUIDELINE NOTE:The evidence available at this time for the in vitro-in vivo correlation of release testsfor semisolid dosage forms is not as convincing as that for in vitro dissolution as asurrogate for in vivo bioavailability of solid oral dosage forms. Therefore, the FDA'scurrent position concerning in vitro release testing is as follows:

Ü In vitro release testing is a useful test to assess product “sameness” undercertain scale-up and post-approval changes for semisolid products.

Ü The development and validation of an in-vitro release test is not required forapproval of an NDA, ANDA or AADA nor is the in vitro release test required as aroutine batch-to-batch quality control test.

Ü In vitro release testing, alone, is not a surrogate test for in vivo bioavailability orbioequivalence.

Ü The in vitro release rate should not be used for comparing different formulationsacross manufacturers.





CERTIFICATE OF ANALYSISChromatogram part only.

RLD: Lot No: Exp. Date: Analysis Date: Fill Size

Standard ChromatogramBarr spec.15 14/2/98 12:03Assay Innovator 000mgSampleD-3400method SI- 00-00 Tabs. Tag 44 CH: 1 Vial : 8File 15 Calc-Method: AREA HEIGHT Conc. BC No: RT AREA HEIGHT Conc. BC No:3.63 445 56 0.0008 BB 17.61 5553456 588456 99.995 BB 214.63 645 66 0.0011 BB 315.93 445 96 0.0008 BB 4Total

Lab book Ref.

GENERIC: Lot No: Exp. Date: Analysis Date: Fill Size

Standard ChromatogramBarr spec.16 14/2/98 13:43Assay Generic 000mgSampleD-3400method SI- 00-00 Tabs Tag 45 CH: 1 Vial : 11 File 15 Calc-Method: AREA HEIGHT Conc. BC No: RT AREA HEIGHT Conc. BC No:3.63 445 56 0.0008 BB 17.62 5553456 588456 99.995 BB 214.63 445 66 0.0008 BB 315.93 445 96 0.0008 BB 4

Lab book Ref.





REQUEST FOR WAIVER OFIN-VIVO BIOAVAILABILITY STUDIES

STATUS OF EACH STRENGTH:[Generic Product] Semisolid 000 mg/g - Bioequivalence Study Submitted in thisANDA.

[Generic Product] Semisolid 000 mg/g - Waiver hereby being requested.



WAIVER REQUEST[Generic Firm] hereby request a waiver of evidence for a topical bioequivalency withrespect to [Generic Product] Semisolid 000 mg/g USP as listed in Table 2.

A topical bioequivalency study was conducted on [Generic Product] Semisolid 000mg/g (Table 1) and a full report of the biostudy is included in Section VI of thisANDA.

The [Generic Product] Semisolid 000 mg/g which is the subject of this application,has the same geometric proportional formulation as the [Generic Product] Semisolidmg strengths per gram given in Table 3.

MULTI-STRENGTH PREPARATIONSThe milligrams per gram Semisolid and comparative percent compositions of the[one/two/three] strengths are shown for purposes of similarity in Table 5 (not shown).

44





Biostudy Section of Packaging and DisbursementSummary for Pivotal Lot: 000

Product: [Generic name] SEMISOLID [USP] [000] mg/g - Batch No: 000

60g HDPE Collapsible Tube with cap/nozzle [00 mm]


Refer to Section 12 for complete Packaging and Disbursement summary ofPivotal Lot: 000

4

200 units x 60 g

Packaging date: Month DD, 1999

Nov.28, 1996

5 units x 60 gQC Testing

Month DD, 1999

60 units 60 gBiostudy (European Market)

Month DD, 1999

80 units 60 gBalance stored in

Pivotal Warehouse

55 units x 60 gRelease & Stability Testing

Month DD, 1999

300 units x 30 g


Nov.28, 1996

10 units x 30 g

QC Testing & Reserve units

Month DD, 1999

25 units x 30 g

Release & Stability Testing

Month DD, 1999

65 units x 30 g

Biostudy & Retained Samples

Month DD, 1999

200 units x 30 g

Balance stored in

Pivotal Warehouse

BIOSTUDY

BIOSTUDY





FINAL TOPICALBIOEQUIVALENCE REPORT

(Summary Report Here)

FULL BIOEQUIVALENCE PRESENTED INSEPARATE BINDINGS AS STAND ALONE

VOLUME(S) USING FDA BIO JACKETCOVERS (RED).

4



Bioavailability/ Bioequivalence

HANDBOOK OF GENERIC DRUG DEVELOPMENT Sect: 6.11 Topical SEMISOLID

FINAL REPORT

TITLEBIOEQUIVALENCE Evaluation

of two Topical [Active Material] Preparationsin [00] Healthy Volunteers

SPONSOR [Applicant Company Name Inc. / Ltd.][Address]

INVESTIGATION SITE [CRO Company Name Inc. / Ltd.][Address]

ANALYTICAL CENTER(S) [CRO Testing Lab Name Inc. / Ltd.][Address]

BIOMETRICAL CENTER [CRO Biometrics Center Name Inc./Ltd.][Address]

PRINCIPAL INVESTIGATOR [Name of Principal Investigator][Principal Investigator Qualifications]

CLINICAL STUDY DATESStart Date Month DD, 200YCompletion date Month DD, 200YDATE OF COMPLETION Month DD, 200YOF FINAL REPORT

Report Code No S00000





TABLE OF CONTENTSVOLUME ONE1. Section : Project Summary

2. Section : Rationale for [topical] study.

3. Section : Summary of Statistical Analysis

4. Section : Study protocol, Protocol amendments, Informed Consent, IRB Approval, and Clinical Report.

5. Section : Summary of Bioequivalent Data.

6. Section : Individual Linear and Semi-log graphs

7. Section : Statistical report on [Active Material]

8. Section : Analytical Report for[Active Material]

9. Section : Results of [Active Material]

10. Section : Statistical Data of Standards and Quality Control Samples for [Active Material]

11. Section : Chromatograms of [Active Material]

VOLUME TWO1. Appendix : Validation of [Active Material]

2. Appendix : Validation Report for [Active Material]

3. Appendix : Chromatograms of [Active Material]

4. Appendix : Statistical Data of Standards and Quality Control Samples

5. Appendix : Short description of Testing FacilitiesTesting Facilities in USTesting Facilities in EuropeBIOMETRICAL Center in US

VOLUME THREE1. Appendix : Case Records Forms.





STATEMENT OF STUDY FACILITY

STATEMENT ON STUDY FACILITYThis report is respectfully submitted to [Applicant Company Name Inc. / Ltd.][Address]

The signature below attests to the content and accuracy of the clinical part of this finalreport based on the aspects of the investigation performed at the facilities of [TestingFacilities Inc. in US] situated [Address].

Month DD, 1999

[Signature of Responsible Person] -----------------------------------------

[Name of Principal Investigator] DatePrincipal Investigator





STATEMENT OF TESTING FACILITY

STATEMENT ON STUDY FACILITY STATUSThe undersigned hereby conforms that our testing facility in [Address]operates in compliance with all regulatory requirements of the US Food andDrug Administration.

[CRO Testing Facilities in US] [Address] guarantees that at the time of theanalysis of biological samples performed in the Study No [0000] the [TestingFacilities in US] had no current outstanding deficiencies as cited by the FDAor other government agency and that the facility fully met the performancerequirements for current Good Laboratory Practice (cGLP) of the US Foodand Drug Administration and US Code 21 Federal Register.

[Signature of Responsible Person]------------------------------------------------ ---------------------------------[Name of CEO / President] Date

CEO / President





STATEMENT OF BIOMETRICAL FACILITY

This report is respectfully submitted to [Applicant Company Name Inc. / Ltd.][Address]

The signature below attests to the content and accuracy of the biometrics part of thisfinal report based on the aspects of the investigation performed at the facilities of[Testing Facilities in US] [Address].

Month DD, 1999

[Signature of Responsible Person]------------------------------------------------ - -----------------------------------------[Name of Principal Investigator] DatePrincipal Pharmacokeneticist





PROJECT SUMMARYThis report is respectfully submitted to [Applicant Company Name Inc. / Ltd.][Address].

The objective to determine the bioequivalence of [Generic name] Semisolids [USP][000.0] mg/g in comparison to a registered preparation of [Innovator name] Semisolids[USP] marketed by [Innovator] in [Country]

This project was designed as a randomized, single application, two way, crossovercomparative study for evaluating topical bioequivalence / pharmacokinetics of thefollowing test preparations:

[Generic name] Semisolid [000.0] mg / g Lot: 000 versus the [RLD] Semisolid [000.0]mg /g. Lot: AA000

THE Study was performed in [00] healthy volunteers who received a [000] mg singleapplication of [Active Material] under controlled study conditions.

DETERMINATION of [Active Material] were performed according to SOP 00 on thesamples collected, following application of the topical forms. [Active Material]concentration was determined by a validated [GC-MS] / [HPLC] method.

BASED on the results of the study the test product is comparable in rate and extent ofabsorption for the reference product for [Active Material]

THE clinical observations were unremarkable. No significant or unexpected changes invital signs, ECGs, physical examinations or clinical laboratory tests were observed.Only one subject showed a mild adverse reaction.

[Signature of Responsible Person] -----------------------------------------

[Name of Principal Investigator] DatePrincipal Investigator





TITLE

BIOEQUIVALENCE Evaluationof two Topical [Active Material] Preparations

in [00] Healthy Volunteers

Volume OneSTUDY DATA

VOLUME ONE

1. Section : Project Summary

2. Section : Rationale for [topical] study according to FDA Guidelines.

3. Section : Summary of Statistical Analysis

4. Section : Study protocol, Protocol amendments, Informed Consent, IRB Approval, and Clinical Report.

5. Section : Summary of Bioequivalent Data.

6. Section : Individual Linear and Semi-log graphs

7. Section : Statistical report on the [Active Material]

8. Section : Analytical Method Report for [Active Material]

9. Section : Analytical Method Validation for the [Active Material]

10. Section : Test Results of [Active Material]

11. Section : Analytical Chromatograms of the [Active Material]

12. Section : Statistical Data of Standards and Quality Control Samples for the [Active Material]





TITLE

BIOEQUIVALENCE Evaluationof two TOPICAL [Active Material] Preparations in

[00] Healthy Volunteers

Volume TwoAPPENDIXES

1. Appendix :: Validation of [Active Material]

2. Appendix :: Validation Report for [Active Material]a

3. Appendix :: Chromatograms of [Active Material] in Plasma

4. Appendix :: Statistical Data of Standards and Quality Control Samples

5. Appendix :: Short description of Testing Facilities

Testing Facilities in US [Address]

Testing Facilities in Europe [Address]

BIOMETRICAL Center in US [Address]





TITLE

BIOEQUIVALENCE Evaluationof two TOPICAL [Active Material] Preparations in

[00] Healthy Volunteers

Volume ThreeCase Records Forms

1. Appendix :: Case Records Forms (format - electronic on disk).

(Consideration as to presenting the Case Records Forms for review via an electronicformat - i.e. Digital or Scanned Case Records Forms, where possible)




HANDBOOK OF GENERIC DRUG DEVELOPMENT Sect: 6 Topical SEMISOLID

BRIEF OVERVIEW

TYPES OF BIOEQUIVALENT STUDIES FORSEMISOLIDS

IN VIVO BIOEQUIVALENCE STUDIESThe design of in vivo bioequivalence studies for semisolid dosage forms variesdepending on the pharmacological activity of the drug and dosage form. A briefgeneral discussion of such tests follows.

Objective:To document the bioequivalence of the drug product for which the manufacture hasbeen changed, is defined in SUPAC-SS, compared to the drug productmanufactured prior to the change or compared to the reference listed drug (RLD).

Design:The study design is dependent on the nature of the active drug. The bioequivalencestudy can be a comparative skin blanching study as in:

Ü Glucocorticoids (FDA, Topical Dermatological Corticosteroids: In VivoBioequivalence, June 2, 1995.) Ü Comparative clinical trial or any other appropriate validated

bioequivalence study (e.g., dermatopharmacokinetic study) for thetopical dermatological drug product.

Analytical Method:The assay methodology selected should ensure the followingÜ SpecificityÜ AccuracyÜ Inter-day precision (ruggedness)Ü Intra-day precision (ruggedness)Ü Linearity of standard curvesÜ Adequate sensitivityÜ RecoveryÜ Stability of the samples under the storage and handling conditions associated

with the analytical method.




HANDBOOK OF GENERIC DRUG DEVELOPMENT Sect: 6 Topical SEMISOLID

NOTES



SECTION VII SECTION 7

Components and Composition


7.1 Section Page (with Color Section TAG) and brief descriptor of the section. Acomplete statement of components and composition is provided in this section. Acomparison 7.2 List of Components - in order of manufacture (name & grade)7.3 Formula Composition of Generic Product7.4 Percent Composition of Generic Product

This section contains:

• List of components

• Formula Composition

• Percent Composition

FDA's Published January 1999 ANDA Guideline requirements

1. Components and Composition Statement

4





LIST OF COMPONENTS

Following is a full list of the articles used as components of the drug product:

SEMISOLIDS [USP] [000.0] mg per g(equivalent to [000.0] mg [Active Material]

1. Miconazole USP Micronized

2. Pegoxol 7 Stearate [Tefose 63™]

3. Heavy Mineral OIL NF

4. Benzoic Acid USP

5. Butylated Hydroxyanizole

6. Peglico 5 Oleate [LABRAFIL M 1944™]

7. Edetate Disodium USP

8. Purified Water USP

4





FORMULA COMPOSITION

Composition of the drug, stating the name and amount of each ingredient, whether active ornot, contained in a stated quantity of the drug in the form in which it is to be distributed.

[Generic name] Semisolids [USP]

FORMULA

INGREDIENTS

Amount in mg

per gram

MATERIALS mg PURPOSE




Benzoic Acid USP




Purified Water USP

20.00

180.00

44.80

2.00

000.05

30.00

1.50

721.65

ACTIVE

EMULGENT

OIL BASE

PRESERVE

ANTIOXIDANT

EMULGENT

CHEALATE

AQ. PHASE

TOTAL 1000.00

* The weight of the ACTIVE may alter according to the potency of active raw material

4





PERCENT COMPOSITION OF THE PRODUCT

[Generic Name] Semisolids [USP]

Formula

Ingredients

Amount in %

per gram


[Pegoxol 7 Stearate Tefose 63™]


Benzoic Acid USP




Purified Water USP

2.000

18.000

4.480

0.200

0.005

3.000

0.150

72.165

TOTAL 100.000 %

4


24 V24 Volume DDrug DDevelopment SSeries Sect: 8.1 Topical SEMISOLID

SECTION VIII SECTION 8

Raw Material Control


Active Ingredient(s)8.1 Title Page and brief summary statement of what this section contains8.2 Outlines of SOPs for handling Raw Materials (Retest procedure max. 12

months)- Outlines of SOP for Qualification of Vendors- Outlines of SOP for Acceptance Criteria- Outlines of SOP for Retesting Schedules- Outlines of SOP for Raw Materials storage

8.3 Disclosure of Active ingredients Source8.4 DMF of Manufacturer via Letter of Access from Active Manufacturer (Type II)8.5 Active Monograph supplied by QC laboratory8.6 CoA from Generic Firm’s QC laboratory, plus supporting

- Identification IR or UV spectra of Active - HPLC chromatograms (Assay - Impurities) - label peaks- Photocopy of TLC chromatograms (Assay - Impurities)

8.7 CoA from Active Manufacturer, - plus supporting- Identification IR or UV spectra of Active- HPLC chromatograms (Assay - Impurities) - label peaks- Photocopy of TLC chromatograms (Assay - Impurities)

8.8 IR Identification Spectra of Reference Standard (Pharmacopoeial)8.10 Physical Specifications from Active Manufacturer

- Bulk Density,- Particle Size (note: water insoluble material)- Physical and analytical test methods

8.11 Outline of Material Data Safety Sheet (MDSS)(source of data for manufacturing instructions precautions).

Inactive Ingredients8.12 Testing Specifications (ID and characterization)8.13 Suppliers Certificate of Analysis (Specifications and Test Results)

4






• Outline of the Standard Operating Procedures for Raw Materials

• Summary of Lot Numbers of Active and Inactive Ingredients

• Disclosure of Active Ingredient Source (approved supplier)

• Active Ingredient DMF Authorization Letter

• Active Ingredient Certificates of Analysis

• Active Ingredient Supporting Data (Spectra)

• Outline of Material Data Safety Sheet (MDSS)

• Inactive Ingredient Testing Monographs & Test Procedures

• Inactive Ingredient Certificates of Analysis

• Routine Testing Protocols - retest schedules

FDA's Published January 1999 ANDA Guideline requirements:-Section VIII.

Raw Materials1. Active ingredient(s).a. Synthesis listing manufacturer/supplier (Type II DMF authorization letters)b. Certificates of analysis specifications and test results from drug substancemanufacturersc. Testing specifications and data from drug product manufacturer(s)d. Spectra and chromatograms for reference standards and test samplese. Retesting period

2. Inactive ingredients (§ 3l4.94(a)(9))a. Testing specifications (including identification and characterization)b. Suppliers' certificates of analysis (specifications and test results)c. Retest schedule

4





OUTLINE OF STANDARD OPERATING PROCEDURES FORHANDLING RAW MATERIALS AND PACKAGING MATERIALS

1. Vendors Approval

All chemical raw materials used in the manufacturing of commercial products andprimary stability batches, must be supplied by approved vendors.The approval of vendors is a shared responsibility of the QA Department of the plantand the Purchasing Department. For pilot batches, the R&D Department isresponsible.

The Purchasing Dept. submits an application to approve a vendor to the QADepartment, specifying the full details of the vendor and samples identified by themanufacturer, including the Certificates of Analysis of the manufacturer. Themanufacturer must have a DMF (Drug Master File) submitted to the FDA.The QC Laboratory tests must confirm that the Certificate of Analysis, which mustaccompany the raw material, meets the raw material requirements.In the absence of a pharmacopoeia monograph, compliance to an approved in-house monograph is required. The in-house monograph forms part of therequirements.

The use of an alternative active raw material from a new vendor, not stated in theANDA, is subject to the prior approval of the FDA.

After obtaining satisfactory results, and if required the approval of the appropriatehealth authority, the QA Unit approves the new vendor.

2. Acceptance CriteriaAll raw materials are quarantined after receipt at the firms warehouse, pending testsand analysis.With the arrival of raw materials, the existence of a purchase order is checked,including the line number of the order. The status of the vendor and the condition inwhich the goods arrived is full examined.All lots are sampled. Each lot must have a manufacturer’s Certificate of Analysis forthe QC department review.The initial batches of an approved vendor are tested according to the fullmonograph. When the reliability of the vendor’s Certificate of Analysis isestablished and the vendor is approved, the use of an abbreviated monograph isevaluated.A full compendial monograph is performed every 6 months on all incoming rawmaterial lots.On receipt, each sample undergoes at least one (1) identification test. Furtherroutine tests are performed as required by the respective testing program.





Rejected Batches:Raw materials samples not approved for use by the laboratory will be marked by alaboratory issued red Rejected label, affixed to the sample by a quality assuranceunit, and transferred to the Rejected area of the warehouse.

Rejected materials will remain in the Rejected area until a final decision is reachedwhether to return them to the supplier or to destroy them.

3. Retest Schedule

Each lot of raw material remaining in the inventory is retested based on the previousdate of analysis.Retest period for highly sensitive materials (actives and excipients) and materialsrequiring microbiological testing, is 12 months.All other active and excipient materials are retested after 24 months, or as stipulatedin the laboratory documents. [Active Material] (Approved Supplier) will be retestedafter 12 months.

4. Storage

Quarantine Storage

1. Raw materials shall be stored in controlled environmental areas under monitoredenvironmental storage temperatures, held between 15o to 25oC. 2. Raw materials received shall be marked with identification labels QUARANTINE -Do Not Use! Materials shall be sampled and then transferred, for holding in thequarantine area, pending QC release. 3. The quarantine for raw materials requiring cooling or freezing shall be stored incontrolled and routinely monitored refrigerators or deep freezers, capable ofmaintaining the correct temperature conditions for the appropriate raw material. 4. The raw materials shall be stored, off the floor, on a shelf, on a palette, in cagesor in appropriate refrigerated units. 5. The raw materials shall remain in the quarantine area throughout the QCAnalytical Laboratory material acceptance testing.

Release from Quarantine 1. Raw materials released by the QC laboratory for use in production, shall receive agreen Released label. The label is printed by the QC Lab computer and attachedover the orange part of the label marked QUARANTINE - Do Not Use!. 2. The expiration dates for the released raw materials are printed on the labels bythe QC lab computer. Materials having a green Released label will be transferredto the released materials storage area. 3





Summary of Batch Numbers of Active& Inactive Raw Materials Used in theExecuted (Pivotal) Batch - Lot: 000

Raw Material Raw Material Batch Numbers

Used for MNF of Lot:

Lot: 1002

Representative

Certificate of Analysis(a)

Miconazole USP [micronizedmaterial]

Lot # CoA #

Pegoxol 7 Stearate[Tefose 63™]

Lot # CoA #

Butylated Hydroxyanizole Lot # CoA #

Benzoic Acid USP Lot # CoA #

Peglico 5 Oleate[LABRAFIL M 1944™]

Lot # CoA #

Heavy Mineral OIL NF Lot # CoA #

Edetate Disodium USP Lot # CoA #

Purified Water USP Lot # CoA #

(a) A Certificates of Analysis is provided for each ingredient lot used in the manufactureof the Executed Pivotal batch - Lot: 002.

In cases where full monograph testing has not been performed on the specified lot usedin the pivotal batch, a representative Certificate of Analysis (that is, within a six monthperiod from date of batch manufacture) is provided to confirm full monograph testingresults.

• A Letter of Authorization to reference the DMF and Certificates of Analysis areenclosed.

• Each lot received by THE COMPANY will be fully tested in accordance with themethods and limits stated in this application.

• Any batch lot of ACTIVE MATERIAL remaining in warehouse stock for a periodexceeding 12 months shall be fully re-tested to a full monograph prior to manufacture.




Active Material Control

The manufacturer and approved supplier of the active ingredient

[Active Material] (Approved Supplier) is:

Approved Supplier: [Name] Pharmaceutical and Chemical Company

Address:

[Name] Pharmaceutical and Chemical Company

Street

Town State Zip Code

Country

A Letter of Authorization to DMF and Certificates of Analysis are attached.

Commitment to Compendial Requirement TestingTHE COMPANY commits to perform future pharmacopoeial analyses in accordancewith all compendial testing (or otherwise approved testing) at the time the activematerial are used in the manufacture of [Generic name] SEMISOLIDS [USP] [000.0]mg per g containing the [Active Material] from (Approved Supplier name.)

Any batch lot of [Active Material] which remains in stock for a year will be fullyretested prior to use.3





Physical Specifications of Active Materials

TEST

METHODS

PHYSICAL SPECIFICATIONS

[ACTIVE MATERIAL]

SPECIFICATIONS TEST

RESULTSTEST METHOD

Bulk DensitySuppliers CoA - C0000

06-07g/cc Complies SI-A076-01

Particle SizeSuppliers CoA - C0000

d90 < 250µ Complies SI-A076-02

Bulk DensityIn-house CoA - C0000

06-07g/cc Complies SI-A076-01

Particle SizeIn-house CoA - C0000

d90 < 250µ Complies SI-A076-02

Notes: Active Material Full Monograph from QC laboratory indicating all chemical, Physicaland microbiological tests is attached.

CERTIFICATE OF ANALYSISIncluded (ref. page [00-00]) are the drug substance manufacturers certificate ofanalysis, specifications and test results including identification and assay IR andHPLC specta and chromatograms as used in Lot # [00-0000] used by the applicant to manufacture the ANDA batch used in the bioequivalent study supporting thisANDA.LETTER OF AUTHORIZATIONA letter of authorization to access DMF# [00-00] for the active material is attached tosection XXI (ref. page [00). Please refer to DMF for the complete description of thedrug substance including physical, chemical ,microbiological and stabilityparameters, where appropriate.




Active Material Control Certificate of Analysis and Spectra of Active and Reference Materials

Active Material Certificate of Analysis and Spectra Numbers.

Document Material

Supplied by:

Certificate

number

Remarks

[Active Material]CoA

Approved

Supplier ý# [C076-98] In-house CoA


Approved

Supplier ý# [C076-98] Suppliers CoA


ý ý In-house Ref.Material

[Active Material]I R Spectra (or UV)

Approved

Supplier ý# [C076-98] In-house I R


Approved

Supplier ý# [C076-98] Suppliers I R


Approved

Supplier ýRef. F In-house Ref.

material

[Active Material]Typical HPLC Spectra

Approved

Supplier ý# [C076-98] In-house HPLC


Approved

Supplier ý# [C076-98] Suppliers HPLC


In-house Ref.material

Ref. G In-house HPLC

[Active Material]Typical TLC Photocopy

Approved

Supplier ý# [C076-98] In-house TLC


Approved

Supplier ý# [C076-98] Suppliers TLC


In-house Ref.material

Ref. G In-house TLC





Attachments.Page No. ___ to Page No: ___ .

Active Ingredients:

CoA and supporting Graphs/Spectra • Three (3) active material Certificates of Analysis attached as per table.

• Three (3) active material - I R Spectra - as per table.

• Three (3) active material - Typical UV Spectra - as per table.

• Three (3) active material - Typical HPLC Spectra - as per table.

• Three (3) active material - Typical TLC Spectra - as per table.

(Presented in the order of tabulation).

Supporting Documentation • Active Ingredient DMF Authorization Letter

• Active Material Full Monograph from QC laboratory.

• Bulk Density and Particle Size test methods

Outline of Material Data Safety Sheet (MDSS)





BULK MANUFACTURERSSTATEMENT OF GMP

[Active Material Company Name Inc. / Ltd.]

[Active Material Company Name Inc. / Ltd.] certifies that the methods used in, andthe facilities and controls used for, the manufacture, processing, packaging andstorage of drugs at our [Active Material Company Name Inc./Ltd.] manufacturingplant conform to Current Good Manufacturing Practice in accord with 21 CFR Parts210 and 211.Central File Numbers (CFN) for all facilities used in the manufacture, processing,labeling and packaging and quality control are CFN [00-0000-00]Last inspection date was MM/DD/YYY

and/or

[Active Material Company Name Inc. / Ltd.] certifies that the methods used in, andthe facilities and controls used for, the manufacture, processing, packaging andstorage of actives/intermediates at [Third Party Company Name Inc. / Ltd.] plantconform to Current Good Manufacturing Practice in accord with 21 CFR Parts 210and 211.Central File Numbers (CFN) for all facilities used in the manufacture, processing,labeling and packaging and quality control are CFN [00-0000-00]Last inspection date was MM/DD/YYY


Plant General ManagerPharmaceutical Manufacturing Division[Active Material Company Name Inc. / Ltd.]


QA ManagerPharmaceutical Manufacturing Division[Active Material Company Name Inc. / Ltd.]

(Signed GMP statement required for all processing, warehousing and testing sites.)




Raw Material ControlNon active Ingredients

CERTIFICATES OF ANALYSIS

he following section contains Certificates of Analysis for the lots of inactiveingredients used to produce the pivotal batch. In the case where the lot used inmanufacture was not tested to a full monograph (refer to list of routine tests in

this section) the Certificates of Analysis for the most recent full monograph tested lotof the ingredient is provided as a representative CoA.

Hence, in some cases there are more than one set of THE COMPANY’SCertificates of Analysis for the same raw material ingredient. The first column in thetable (below) represents the routine testing procedure CoA and the second columnrepresents the full compendial or in-house monograph CoA.

The attached raw material testing procedures, in some instances, the Authorizationdate may post-date the Certificates of Analysis supplied. These raw material testingprocedures are updated to agree with subsequent compendial monographs.

Commitment to Compendial Requirement Testing

THE COMPANY commits to perform future analyses in accordance with allcompendial testing or otherwise approved testing at the time such raw materials areused in the manufacture of [Generic name] SEMISOLID [USP] [000.0] mg per g.

THE COMPANY may use other raw material suppliers subject to meeting in-houseapproved supplier requirements and pharmacopoeial standards.

T




Raw Material ControlSummary of Certificate of Analysis Numbers of Non-active Raw Materials

Used in the Executed (Pivotal) Batch.

RAW MATERIAL Certificate of Analysis (CoA) Numbers.

Approved

Suppliers

Used in MNF.

Lot: [ICA00-00]

Representative

C of A’s

1. Pegoxol 7 Stearate[Tefose 63™]

[COMPANY] [CA0326-98] [CA388-98]

2. Butylated Hydroxyanizole [CA0526-98] [CA237-98]

3. Benzoic Acid USP [CA0136-98] [CA0637-98]

4. Peglico 5 Oleate[LABRAFIL M 1944™]

[CA0325-98] [CA0224-98]

5. Heavy Mineral OIL NF [CA0024-98] -

6. Edetate Disodium USP [CA0076-98] [CA0572-98]

7. Purified Water USP [CA0126-98] [CA0637-98]

Note:Where excipients manufacturers have more than one plant the name of theapproved excipient is followed by the country in which the plant is situated.Representative Certificates of Analysis are FULL monograph Certificates testedwithin a six (6) months period of the actual pivotal manufacturing date.

Date Checks

- all Representative Certificates of Analysis in date þþYes q No.

- all Routine Certificates of Analysis precede pivotal MNF dateþþYes q No.

Note : Approved NON ACTIVE Suppliers are not an FDA OGD requirements at the time of publishing(December 1999), but is strongly recommended.

NON ACTIVE SUPPLIERSList non-active suppliers only




Raw Material Control -Non active Ingredients

Attachments.

CoAs

• Seven (7) Certificates of Analysis attached as per table.

(Presented in the order of tabulation).

Supporting Documentation

• • Seven (7) Testing Monographs of non-active materials

• Seven (7) Routine Testing Protocols

(List of Routine tests Performed on non-active materials)

Page References:CoAs Page No. ___ to Page No: ___ .

Testing Monographs Page No. ___ to Page No: ___ .

Routine Testing Protocols Page No. ___ to Page No: ___ .

Special Note:Where inactive ingredient testing methods are non-compendial AND do not appear on the FDAInactive Ingredient List (IIG) - the applicant is required to submit a 505 B2 Application. Thus allinactive ingredients should appear on the FDA's IIG.




Raw Material Control - Non active Ingredients

ROUTINE TESTINGRoutine testing performed on each batch of inactive ingredients.

PEGOXOL 7 STEARATE(Trade Name™)DescriptionIdentification TestViscosityMicrobial Limits

BUTYLATED HYDROXYANIZOLE(Trade Name™)DescriptionIdentification Test

BENZOIC ACID USPDescriptionIdentification Test

PEGLICO 5 OLEATE(Trade Name™)DescriptionIdentification TestViscosityMicrobial Limits

HEAVY MINERAL OIL NFDescriptionIdentification TestViscosityMicrobial Limits

EDETATE DISODIUM USP(Trade Name™)DescriptionIdentification Test

PURIFIED WATER USPPer week - Microbial TestingPer month - Full USP Monograph

LIBRARY OF USP XXIII TESTSDescriptionSolubilityIdentification TestAssayImpuritiesRelated substancesAsh value USP < >Loss on Drying USP < >K-Value USP < >Microbial Limits USP < >Microbial Testing USP < >Preservative efficacy USP < >pH USP < >Organic volatile Imp. USP < >Residual Solvents USP < >Viscosity USP < >USP Monograph (Full) USP < >Apparent Viscosity USP < >Water (KF) USP < >

CONTINUE LIBRARY OFUSP XXIII / NF

TESTS RELEVANT TOTHIS APPLICATION

Where absent from USP / NFadd

BP or Pharm Eur.Tests



SECTION IX SECTION 9

Description of Manufacturing Facility


Section Page (with Color Section TAG) and brief descriptor of the section. Themanufacturer of the final dosage form of the new drug for which this application issubmitted is [Generic Company Name Inc. / Ltd.]. The applicant performs all of themanufacturing, packaging, testing and stability test functions of the submitted drugproduct.[Generic Company Name Inc. / Ltd.] does not manufacturer the active drugsubstance, the excipients or the container closure system used in the manufacturingand packing operations for the finished dosage forms. Details concerning the bulkactive drug substance appears in section VIII as those of the excipients while detailsfor the container closure system appear in section XIII.No / [One / Two] contract firms are involved in the finished [product testing],[packaging components] or [stability testing] requirements as filed in this ANDA(Delete where required)

9.1 Statement of commercial site address of Manufacture(s)

9.2 Statement of commercial packaging & Labeling site address

9.3 Statement of commercial site of Distribution site address

9.4 Address of Facility for QC and Stability Testing

9.5 Brief description of facilities for MNF, testing and stability (no personnelCV’s).

9.6 Statement on the GMP Certification of Compliance Central File Number(CFNs) at manufacturing site.

FDA's Published January 1999 ANDA Guideline requirementsSection IX.

Description of Manufacturing Facility1. Full address(es) of the facility(ies) for the manufacturing process,testing, and stability testing2. Brief description of the facility.3. For description of the facility sterile products, see Section XIV.4. CGMP certification5. Central File Number (CFNs)

4





This section contains:-Addresses of RESEARCH Facilities


• Description of Facility

• Responsible Personnel (Key Staff)

• List of Production Equipment

• Blueprint of Facility

• GMP Certification Statement

Addresses of Scale-up Facilities


• Description of Facility

• Responsible Personnel (Key Staff)

• List of Production Equipment

• Blueprint of Facility

Addresses of Manufacturing Facilities


• List of Responsible Personnel (Key Staff)

• Blueprint of Facilities

• GMP Certification Statement

• Drug Establishment Registration No [#00-00-00-00]

NOTE:Applicant facilities with more than one site who perform special functions at thespecific site (such as analytical or stability testing) need to describe these facilities insection VIII and X. A separate GMP certificate for that specific site needs to beincluded in the application.

4




Description of Research Facility

Research & Scale-up Facilities

LIST OF RESPONSIBLE PERSONNEL

(A) List of research facilities key personnel in the situationwhere the ANDA research site is geographically separated fromthe proposed manufacturing site (i.e. in another city, state orcountry.)

List of Small Scale Manufacturing Equipment

(B) List of research and small scale facilities equipment in thesituation where the pivotal batch was manufactured at a siteother than the proposed manufacturing site (e.g. Another city,state or country).

Blueprint of Research & Scale-up Facilities.

Note: The first three commercial batch lots manufactured at theproposed manufacturing site are required to be validated. [Inaddition - to the above OGD's requirements, lot validation maybe initialized¡ at the remote or foreign site].

¡ Process Qualification Batch and/or Pivotal Batch

4




Description of Manufacturing FacilityLIST OF RESPONSIBLE PERSONNEL

1. Management 11. Weighing Center

2. Validation Unit 12. Granulation Department

3. Stability Unit 13. Drying Department

4. Packaging Materials Lab. 14. Milling Department

5. Physical Lab. 15. Sieving Department

6. Microbiology Lab. 16. Blending Department

7. QC Lab. / QA Lab. 17. Slugging Department

8. Development (R&D) Lab. 18. Compression

9. Warehousing 19. Coating Department

10. Housekeeping 20. Other Departments

LIST OF PRODUCTION EQUIPMENT

+ [Type of Equipment] [Equipment ID. Number] [Equipment Document No.]

1. Scale-up Department 11. Weighing Center

2. Validation Unit 12. Granulation Department

3. Stability Unit 13. Drying Department

4. Packaging Materials Lab. 14. Milling Department

5. Physical Lab. 15. Sieving Department

6. Microbiology Lab. 16. Blending Department

7. QC Lab. / QA Lab. 17. Slugging Department

8. Development (R&D) Lab. 18. Compression

9. Warehousing 19. Coating Department

10. Housekeeping 20. Packaging Department

4




Description of Manufacturing FacilityBLUEPRINT OF MNF FACILITY

Manufacturing, Testing and Storage Areas blueprints - showing facilities layout.

ADDRESSES OF FACILITIES

Manufacturing, processing, bulk packaging, bulk labeling, handling and storage ofthe bulk [Generic name] DRUG [USP] [000.0] mg. will take place at thepharmaceutical manufacturing facility identified below:

[Generic Company Name Inc. / Ltd.]Pharmaceutical Manufacturing DivisionIndustrial Area [Street][Town] [State] [Zip Code] [Country]. and/or

Unit packaging, labeling and handling of all packed [Generic name] DRUG[USP][000.0] mg. will take place at the manufacturing and packaging facility identifiedbelow:

[Generic Company Name Inc. / Ltd.]Pharmaceutical Packaging DivisionIndustrial Area [Street][Town] [State] [Zip Code] [Country].

The packaged and labeled product will be distributed through the [Address]warehouse located at:

[Generic Company Name Inc. / Ltd.]Pharmaceutical Warehouse DivisionIndustrial Area [Street][Town] [State] [Zip Code] [Country].

Finished product release testing and annual stability testing is performed by[Generic Company Name Inc./Ltd.] Analytical Research / QC Laboratories inaccord with the Division of Generic Drugs Policy and Procedure Guideat:

[Generic Company Name Inc. / Ltd.]Analytical Research / QC LaboratoriesIndustrial Area [Street][Town] [State] [Zip Code] [Country].

(Additional information on these sites is provided herein.)

4





STATEMENT OF GMP[Generic Company Name Inc. / Ltd.]

[Generic Company Name Inc. / Ltd.] certifies that the methods used in, and thefacilities and controls used for, the manufacture, processing, packaging and storageof drugs at our [Generic Company Name Inc./Ltd.] manufacturing plant conform toCurrent Good Manufacturing Practice in accord with 21 CFR Parts 210 and 211.

Central File Numbers (CFN) for all facilities used in the manufacture, processing,labeling and packaging and quality control are CFN [00-0000-00]

and/or

[Third Party Company Name Inc. / Ltd.] certifies that the methods used in, and thefacilities and controls used for, the manufacture, processing, packaging and storageof drugs at our [Third Party Company Name Inc. / Ltd.] plant conform to CurrentGood Manufacturing Practice in accord with 21 CFR Parts 210 and 211.

Central File Numbers (CFN) for all facilities used in the manufacture, processing,labeling and packaging and quality control are CFN [00-0000-00]


Plant General ManagerPharmaceutical Manufacturing Division[Generic Company Name Inc. / Ltd.]


QA ManagerPharmaceutical Manufacturing Division[Generic Company Name Inc. / Ltd.]

(Signed GMP statement required for all processing, warehousing and testing sites.)

4



SECTION X SECTION 10

Outside firms and Contract Facilities


10.1 Title Page and statement

10.2 Name and Site Address of all Contract Laboratories

10.3 Registration No. of each Contract Laboratory

10.4 List of Test(s) or functions to be Performed by Contract Laboratory

10.5 Certification letter of GMP/GLP Compliance of Contract Laboratory

10.6 Statement on the cGMP Status and Certification of Compliance w.r.t

- a contract manufacturing site- a contract labeler or packaging site.

10.7 Statement on the PAC-ALTS (Post-approval Changes - Analytical testing Laboratory Sites)

FDA's Published January 1999 ANDA Guideline requirements:-Section X.

Outside Firms, Including Contract Testing Laboratories1. Full address2. Functions3. CGMP certification/GLP

4





Contract Facilities[Generic Company Name Inc./Ltd.] does not intend the use of any outsidemanufacturing contract facilities at the prevailing time. If a contract outside facility isdesired in the future, the appropriate documentation will be submitted to this ANDA.

(and / or)

Contract Testing Laboratories

[Generic Company Name Inc./Ltd.] does not intend the use of any contract testinglaboratories facilities at the prevailing time. If a contract laboratory or outsidelaboratory is required in the future, the appropriate CBE documentation according toPAC-ALTS (Post-approval Changes - Analytical testing Laboratory Sites, April 1998)will be submitted to this ANDA.


QA ManagerPharmaceutical Quality Assurance Unit[Generic Company Name Inc./Ltd.]


Production ManagerPharmaceutical Manufacturing Division[Generic Company Name Inc./Ltd.]

4





(or where used)

Contract Testing Laboratories

The following contract testing laboratory was used during the development of [DrugProduct] [00] mg & [00] mg: [Contract Laboratory Name Inc./Ltd.] [Address]

The above laboratory developed and validated the analytical method for testing[Organic Volatile Impurities.] This method was transferred to [Generic CompanyName Inc. Ltd.] and the active raw material for the pivotal batches was testedaccording to this method.

Future commercial production batches will be tested also according to this method in[Generic Company Name Inc. Ltd.].

Enclosed [Contract Laboratory Name Inc./Ltd.] annual registration of drugestablishment for the year 200Y.


QA ManagerPharmaceutical Manufacturing Division[Generic Company Name Inc./Ltd.]



4





ADDRESSES OF FACILITIES

Manufacturing, processing, bulk packaging, bulk labeling, handling and storage ofthe bulk [Generic name] Drug [000.0]mg [USP]. will take place at thepharmaceutical manufacturing facility identified below:

[Third Parties Company Name Inc. / Ltd.]Pharmaceutical Manufacturing DivisionIndustrial Area [Street][Town] [State] [Zip Code] [Country]

(and / or)

Unit packaging, Labeling and handling of all packed [Generic name] Drug [USP][000.0] mg. will take place at the manufacturing and packaging facility identifiedbelow:

[Third Parties Company Name Inc. / Ltd.]Pharmaceutical Packaging DivisionIndustrial Area [Street][Town] [State] [Zip Code] [Country]

(and / or)

The packaged and labeled product will be distributed through the [Address]warehouse located at:

[Third Parties Company Name Inc. / Ltd.]Pharmaceutical Warehouse DivisionIndustrial Area [Street][Town] [State] [Zip Code] [Country]

Finished product release testing and annual stability testing is performed by[Generic Company Name Inc./Ltd.] Analytical Research / QC Laboratories inaccord with the Division of Generic Drugs Policy and current Procedure Guides

[Third Parties Company Name Inc. / Ltd.]Analytical Research / QC LaboratoriesIndustrial Area [Street][Town] [State] [Zip Code] [Country]





STATEMENT OF GMP OF[Third Parties Company Name Inc. / Ltd.]

[Third Parties Company Name Inc. / Ltd.] certifies that the methods used in,and the facilities and controls used for, the manufacture, processing, packaging andstorage of drugs at our [Third Parties Company Name Inc. / Ltd.] plant conform toCurrent Good Manufacturing Practice in accord with 21 CFR Parts 210 and 211.


General ManagerPharmaceutical Division[Third Parties Company Name Inc. / Ltd.]


QA ManagerPharmaceutical Division[Third Parties Company Name Inc. / Ltd.]

Note: Current cGMP or if applicable CGLP certification statement(s) are required forEACH of the third party firms (outside firms) listed in this section



Generic Drug Enforcement Act - 1992Third Party Letterhead

STATEMENTWhere Company has NO previous convictions

AND does not use a debarred person in connection with the ANDA

Certification Made Pursuantto the

Generic Drug Enforcement Act of 1992.

n behalf of [3rd Party Company Name Inc. / Ltd.], we hereby certify, pursuantto Section 2(k) Generic Drug Enforcement Act of 1992, 21 USC 335a (k), that

the the undersigned firm has not used, is not using and will not in the future use inany capacity the services of any person who has been debarred pursuant to Section2 (a) and or Section 2 (b) Generic Drug Enforcement Act of 1992, 21 USC 335a (a)and/or (b), in connection with this application.

We further certify that there have been no conviction of applicant for any of thetypes of crimes set forth in Section 2(a) and Section 2(b) of the Generic DrugEnforcement Act of 1992, 21 USC 335a (a) and/or (b), within the five years prior tothe date of this certification, nor has any person affiliated with our contracting firm,who is responsible in whole or in part, for the development or the submission of thisapplication been convicted of any crime of the type listed in Section 2(a) and Section2(b) of the Generic Drug Enforcement Act of 1992, 21 USC 335a (a) and/or (b),within the five years prior to the date of this certification.


Regulatory Affairs Director[3rd Party Company Name Inc. / Ltd.]

[Signature of Responsible Person]__________________________ ______________________[Name of Responsible Person] Date

Director Quality Assurance UnitPharmaceutical Manufacturing Division[3rd Party Company Name Inc. / Ltd.]

O



Generic Drug Enforcement Act - 1992Third Party Letterhead

STATEMENTWhere Company has a previous conviction

but does not use a debarred person in connection with the ANDA



n behalf of [3rd Party Company Name Inc. / Ltd.], we hereby certify, pursuantto Section 2(k) Generic Drug Enforcement Act of 1992, 21 USC 335a (k), that

the undersigned firm has not used, is not using and will not in the future use in anycapacity the services of any person who has been debarred pursuant to Section 2(a) and or Section 2 (b) Generic Drug Enforcement Act of 1992, 21 USC 335a (a)and/or (b), in connection with this application.

Wet further certify that during the previous five years our firm has sustained thefollowing conviction for the types of offenses as set forth in Section 2(a) and Section2(b) of the Generic Drug Enforcement Act of 1992, 21 USC 335a (a) and/or (b),Date of Conviction MM/DD/YYNature of Conviction Conviction on two counts of fraudulent documentation

pertaining to analytical reports

To the best of [3rd Party Company Name Inc. / Ltd.], knowledge no personaffiliated with the applicant, who is responsible in whole or in part, for thedevelopment or the submission of this application has been convicted of any offenseof the type listed in Section 2(a) and Section 2(b) of the Generic Drug EnforcementAct of 1992, 21 USC 335a (a) and/or (b), within the five years prior to the date of thiscertification.


Regulatory Affairs Director[3rd Party Company Name Inc. / Ltd.]

4End of Section 10.

O





STATEMENT OF PAC-ATLS[Generic Company Name Inc. Ltd.]

[Generic Company Name Inc. Ltd.] certifies that when submitting a change inan analytical testing laboratory site the applicant will confirm in a written statementwhy a PAC-ALTS CBE supplement is appropriate. If the proposed change in theanalytical testing laboratory site does not fall within the scope of PAC-ALTS, thechange will be filed in a prior approval (PA) supplement.


QA ManagerPharmaceutical Manufacturing Division[Generic Company Name Inc./Ltd.]




24 V24 Volume DDrug DDevelopment SSeries Sect:11. 1 Topical SEMISOLID

SECTION XI SECTION 11

Proposed Manufacturing Instructions

TABLE OF CONTENTS(Current ANDA Guideline Requirements for this Section.)


◊ Description of Manufacturing Process

◊ Manufacturing Procedure Flow Chart

◊ Blank Master Production Batch Records(largest intended commercial production lots.)

◊ Blank Packaging Records(largest intended commercial production lots.)

◊ Formula comparison(compares pivotal batch parameters with intended commercial production)

◊ Equipment Comparison(compares pivotal batch parameters with intended commercial production)

◊ Description of Intended Commercial Packaging Operation

◊ Reprocessing Statement(if reprocessing step is undertaken full data, process validation rework specificationsand stability must be shown in Section 21)

FDA's ANDA Guideline Requirements:-(as Published January 1999)

Section XI. Manufacturing and Processing Instructions

1. Description of the manufacturing process (including microbiological verification in Section XIV, as appropriate)

2. Blank batch records(for largest intended commercial production runs with equipment specified)

3. Reprocessing statement.

4





Section contents:

• Outlines of process and controls

• Description of Manufacturing Process

• Manufacturing Procedure Flow Chart

• Blank Master Production Batch Records for intended production lots

• Blank Packaging Records for intended production lots

• Formula comparison between pivotal and intended commercial lots

• Equipment Comparison pivotal and intended commercial lots

• Description of Packaging Operation

• Reprocessing Statement(s)

4




Proposed Manufacturing InstructionsOUTLINE OF STANDARD OPERATING PROCEDURES FOR :

MANUFACTURING AND PROCESSING

1. Production Office - Prepares a production order file for each productionbatch according to the production schedule.

2. Production Office - Assigns batch numbers, according to the existing codeprocedure, and enters these numbers in the batch numbers log.

3. Production Office - A photocopy of the master formula record andmanufacturing instructions is prepared with the specific manufacturing batchnumber.

4. Production Office - Prepares all forms needed in the manufacturingprocess which are placed in the product order file.

The file is then transferred to the Weighing Center/Dispensing Area. 5. Dispensing Area - Weighs all raw material components according to the

master formula record. For each weighing, the raw material receivinglogbook number is entered on the master formula record. All materialsbelonging to one manufacturing batch of the product is placed on a separatepallet and covered with a pallet cover or clear shrink-wrap.

As per production schedule the pre-weighed raw material on pallets aretransferred to productions, by production personnel, under the responsibilityof the department head.

6. Production Depts. - During manufacturing, the product test results arerecorded on the control forms which are attached to the master formula andmanufacturing instructions batch record.

7. Production Office - forwards a “Standard Packaging Sheet” with thecomputerized order to the packaging department.

8. Packaging Department - forwards the “Standard Packaging Sheet” and thecomputer order to the packaging materials warehouse.

9. Packaging Department - Authorizes packaging startup, in-processcompliance, on the “Packaging Work Sheet”.

10. After packaging, the packaged goods are transferred to thewarehouse/holding area under a quarantine status, pending QC release.

11. The product is tested by the QC analytical laboratory. 12. Production records and test results are analyzed by QA Department and on

release the product is moved to the warehouse ready for shipment. 13. The batch records are archived by the Quality Assurance Department. 14. Shipping Department - maintains a complete and traceability record of the

dispatches of each product batch number and its final destination.





OUTLINE OFSTANDARD OPERATING PROCEDURES

FOR:

IN-PROCESS CONTROLS

1. At all stages of manufacturing, processing, time limitations and packagingappropriate control procedures are employed in conformity with current goodmanufacturing practice.

2. Appropriate in-process controls include material testing by quality control andquality assurance personnel. These test cover:

⇒ Physical specifications of the bulk material (Uniformity of Content) ⇒ Fill Weights

3. In-process material testing is performed by Qualified Personnel.

4. The Quality Assurance Department reviews the batch test results and evaluatesthe acceptance or rejection of each batch lot.

4





IN-PROCESS CONTROLSDURING SEMISOLID FILLING

In-process testing is conducted independently by both production andquality control trained personnel. The tests specified in the underlyingtables are performed in accord with the in-process product specifications.When, a test is not required, according to the written specifications, it willnot be performed.

Production personnel test the physical specifications of random samplesaccording to the individual product specifications: A minimum sampling frequency istabulated for each eight hour (shift) period.

Production In-processTesting Schedule:

TEST

PERFORMED

Sample

Size

Frequency

per shift (1) (min)

Acceptance

Criteria (2)

Bulk Description 1 At start. Within written specifications.

Fill Weight (Active) 10 At 30 min.intervals.

NMT 2 Containers from of the 20 testedmay deviate from product spec. Nodeviation permitted from Double Limits(3)

specification.

Cap Torque 6 At 30 min.intervals.

No deviation from product specifications ispermitted.

KEY:

1The testing frequency is performed twice when the overall filling time is less than four hours.2Deviations from specifications and acceptance criteria, arising during the in-processcontrols, shall determine the corrective action to be performed on the filling machinery during the filling stage.





uality Control personnel test the physical specifications of random samplesaccording to the individual product specifications sheets: A minimum sampling

frequency is tabulated for each eight hour (shift) period.

Quality ControlIn-process Testing Schedule:

TEST

PERFORMED

Sample

Size

Frequency

per shift (1) (min.)

Acceptance

Criteria (2)

Material Description 1 (1) Once

at start

No deviation from product specificationis allowed.

Individual Fill

Weight

20 (1) 60 min NMT 2 Containers from of the 20tested may deviate from product spec.No deviation permitted from DoubleLimits(3) specification.

CAP TORQUE 6 (1) 60 min No deviation from product specificationis allowed

KEY:

1Samples are taken, independently by QC personnel for batch release purposes, at leastonce per hour throughout the FILL run, producing a total representative sample quantity of 20- 40 Containers . This representative sample lot is for QC batch release purposes .2Deviations from specifications and acceptance criteria, arising during the in-process controls,shall determine the corrective action to be performed on the filling machinery during thefilling stage.3Double Limits for the Individual Fill Weight test are defined as the double value from the minimum or maximum limit in relation to the nominal Fill value (i.e. target weight value).

Q





BATCH RECORDS FORPOST-APPROVAL

PRODUCTION BATCHES

nclosed are the production batch records (master, packaging and labeling) forPost-Approval production batch.

Translation Policy - for Non English Speaking Areas:Certain manufacturing and process and control documents may be written in[English and the National Foreign language] with some information in English only.

Where information is provided in [English and a Foreign language], an authorizedEnglish translation is provided preceding the document in [English and the Foreignlanguage].

Where only English is used on a page, no translation is provided.

4

E




Proposed Manufacturing InstructionsMANUFACTURING INSTRUCTIONS FOR COMMERCIAL PRODUCTION

Product name: [Generic name] SEMISOLID USP [000.0] mg per g.Batch Number: 000Department: ______________ Batch Size: 0000 Kg/unitsPrecautions: �� Sub-lot No: þ1 ý 2 ý 3Caution: �� Manufacture Date: Month DD, YYCat./Formula No: # F0000 SEMISOLID þþBased on PQ: Batch # PQ-000 ý PIVOTAL BATCH

ý Validation Lot þþ Commercial LotChange Control for this document: Original - No Change þ : Change ýChanges made: - none

KEY:KEY:Precautions: ��Wear Mask and Gloves

��Wear disposable overalls

��Use air stream face visor with AIR filter

��Use Mask, Gloves and Safety glasses

Caution: ��Avoid exposure to light / Protect form light

��Store in well closed containers

��Potential danger to pregnant women

��Pregnant women prohibited in this area

��Do not heat above 00øøC� Room humidity below 30%

Note:

(A modern real life manufacturing process for a SEMISOLID is providedas an example of how to prepare the manufacturing instructions. Thisspecific set of manufacturing instructions was chosen as it represents themost complex example).





MANUFACTURING INSTRUCTIONCOMMERCIAL PRODUCTION

[Generic name] SEMISOLID [USP] [000.0] mg/g Lot: 000Miconazole Cream USP [20.0] mg/gram

Batch No: Weighing Date :

Page 1 of 2 pagesMgPer

gram

%Excess Raw Material Names # per [150] kg

Signweigh.Dept.

Kg g mg L mL A BPART I - OIL PHASE

180.00 Pegoxol 7 Stearate[Tefose 63™]

27 000

25.20 Heavy Mineral OIL NF 3 7802.00 Benzoic Acid USP 3000.05 Butylated Hydroxyanizole 7 500

207.252 Theoretical End Weight. 31 087 500

PART II20.00 [Miconazole USP Micronized 3 00030.00 Peglico 5 Oleate

[LABRAFIL M 1944™] 4 500

1.50 Edetate Disodium USP 2259.60 Heavy Mineral OIL (1st Rinsing) 1 440

10.00 Heavy Mineral OIL (2nd Rinsing) 1 500

Theoretical End Weight. 10 665

PART III - AQUEOUS PHASE721.650 Purified Water USP 108 247 500


PART: IV MIXING STAGE1000.0 Combined Phases - [1+2] + 3 150 000

1000.0 Theoretical End Weight. 150 000

Edition Number:01

Effective Date: APPROVEDEd. Status:

NewDD/MM/YY _____________ __________ _______________ _________/________

Department R &D RA QC / QA





MANUFACTURING INSTRUCTIONCOMMERCIAL PRODUCTION




gram


Signweigh.Dept.



54 000




[LABRAFIL M 1944™] 9 000




PART III - AQUEOUS PHASE721.650 Purified Water USP 216 495




Edition Number:01


NewDD/MM/YY _____________ __________ _______________ _________/________






MANUFACTURING INSTRUCTION COMMERCIALPRODUCTION

[Generic name] SEMISOLID [USP] [000.0] mg/g Lot: 000

Batch No: Weighing Date:

Page 1 of 4 pages

MANUFACTURING INSTRUCTIONSMachine Sign

A + BDate

Step 1. IDENTIFY the equipment and verify the cleanliness priorto use.

PART ONE - OIL PHASEStep 2. LOAD into kettle No [ ] fitted with [Mixer # [ ]-Type & No)the ingredients in the following order:Pegoxol 7 Stearate [Tefose 63™]Heavy Mineral OIL NFBenzoic Acid USPButylated Hydroxyanizoleand mix for [20] minutes at mixer setting speed II

Step 3. HEAT while mixing to NMT [45]º C (Target: [42]º C).Time of adding [ ] min.Total Mixing Time [ ] min.

PART TWO Active OILY PHASE

Step 4. LOAD into a [Small Mixer-Type & No) the ingredients inthe following order:Miconazole USP - MicronizedPeglico 5 Oleate - [LABRAFIL M 1944™]Edetate Disodium USPMix for [20] minutes at mixer speed [II] until mix is fully micronizedmaterial is suspended and homogeneous.Step 5. HEAT while mixing to NMT [45]º C (Target: [42]º C).Target Temperature [ ]º CSTART of mixing [ ]END of mixing [ ]Total Mixing Time [ ] min

Edition Number:01

Effective Date: APPROVEDEd. Status

NewDD/MM/YY _____________ __________ _______________ _______/________





Proposed Manufacturing InstructionsMANUFACTURING INSTRUCTION COMMERCIAL

PRODUCTIONPage 2 of 4 pages

MANUFACTURING INSTRUCTIONS Machine SignA + B

Date

PART THREE AQUEOUS PHASE

Step 6. Heating the Water Phase(i) WEIGH or MEASURE 000.0 Kg [PURIFIED WATER USP] into astainless steel mixing kettle fitted with a high speed variable mixer. (#0)(ii) Operate the mixer while HEATING to NMT [95]º C (Target: [95]º C).(iii) Hold the heated Water at the target temperature for NLT60 minutes

Target Temperature [ ]º C).Time of Heating [ ]Total Process Time [ ] min

Step 7. Cooling the Water PhaseCOVER and Cool Step 6 [PURIFIED WATER USP] to a targettemperature while slowly stirring - Target Temperature 280C [±20C]

Target Temperature NMT [ ]º CStart of Cooling Time [ ]End of Cooling Time [ ]Total of Cooling Time [ ] min

PART FOUR - ADDITION OF OILY PHASE

Step 8. Add the Active Oily Phase STEP 4 to the Bulk Oil Phase STEP2 and mix at speed [III] until homogeneous. RINSE active material twicewith heavy mineral oil. Drain container fully after each RINSE procedure.

Start of Mixing [ ]End of Mixing [ ]Total of Mixing Time [ ] minStep 9. Check that the oil phase after the mixing period is ahomogeneously dispersed oily suspension - if necessary mix for anadditional 20 minutesStart of Mixing [ ]End of Mixing [ ]Additional Mixing Time [ ] min

Edition Number:01


NewDD/MM/YY _____________ __________ _______________ _________/________








Date

ADDITION OF AQUEOUS PHASEStep 10. RECORD the Aqueous and Oil Phase temperatures.Temperature of AQUEOUS Phase NMT [30]º C (Target: 280C [±20C])Temperature of OIL Phase NMT [30]º C (Target: 280C [±20C])

Step 11. ADD the aqueous phase to STEP 8 while continuously mixingat mixer speed III.Start of Mixing [ ]End of Mixing [ ]Total Mixing Time [ ] min

Step 12. ATTACH the mixing kettle temperature graphs (Type & No) tothe manufacturing instructions. Add the batch number to the temperaturegraph and Immediately date and sign it..

COOLING OF COMBINED PHASESStep 13. COOL Step 11 to a target temperature while slowly stirring[Set I].Target Temperature 250C [±20C] Record Temperature ______0CStep 14. PASS the SEMISOLID through an HOMOGENIZER (Type &No) fitted with a [0.0 mm] screen into an ultra clean holding bin.Step 15. CHECK pH [25]º C of a sample of the homogenizedSEMISOLID).Record pH Result: _________ [Units]DETERMINE the viscosity using (Type & No) Brookfield Viscometer; Spindle No [3] RPM [5] Temperature [25]º CRecord First result: __________ [Cp]Cp Limits: [4000 to 6000]

Step 16. If necessary, continue to Homogenize the bulk material (re-circulate) under the same conditions as STEP 14, until the viscosity isclose to the midpoint of the given range limits and check viscosity again.Record Second result: __________ [Cp]Step 17. PUMP the semisolid into (Type & No) [000] liter container.Pumping Stop Time: _________

Step 18. WEIGH the bulk material ______Kg.

Step 19. Immediately ADD the batch number to the scale print-out, andattach to the manufacturing instructions, date and sign the print-out.

Edition Number:01


NewDD/MM/YY _____________ __________ _______________ _________/________








Date

YIELD CALCULATIONStep 20. Theoretical Weight [00.0] Kg. Yield ___________ %(Yield Limits: NLT 95% of Theoretical Weight.) No of Bins ______

Step 21. COLLECT 10 samples, each equivalent to the approximateweight of 10 g in labeled sample containers. Collect samples from upper,middle and lower part of the container. Send the samples to the QClaboratory for Content Uniformity Testing.

Step 22. WEIGH the final material

Actual weight: [00.0] Kg.

Theoretical Weight [00.0] Kg. Yield __________ %

No. of containers _____ .

(Yield Limits: NLT 98% of total actual weight

PART FIVE - FILLING PROCEDUREStep 23. IDENTIFY and verify the cleanliness of the filling equipment inuse.FILL the material according to the written specifications into air blowntubes WITHIN 24 hours after manufacture.CAUTION: (Do not leave standing over weekends/holidays.)

Check filling weight every 15 minutes.Check end-crimp every 30 minutes.Check Lot No and Expiration Date over stamping at start and end of run.Check Lot No and Expiration Date after reset or replacing type.

Air Blowing machine: (Type & No).Filling machine: (Type & No).Machine Speed _______ Tubes per minute.Limit of output NLT _______ units; NMT _______ units.

Step 24. COUNT the total units produced:

Actual production count: [00.0] Units.

Weight of Samples taken: [00.0] Units.

Vacuum and rejects number: [00.0] Units.

Total Units [00.0] Units

Theoretical Weight [00.0] Kg.

Yield _________ %

(Yield Limits: NMT 3% unexplained loss compared to the final bulkweight from STEP 20.Edition Number:

01Effective Date APPROVED

Ed. Status:New

DD/MM/YY _____________ __________ _______________ _________/________ Department R &D RA QC / QA



Nitrogen blanketOIL PHASE

MIXER(S/S Mixing vessel)

Oily Solvent Lipophobic EmulgentEmulsifier

(Ross mixer)



PRODUCTIONFLOW CHART

Chart One

Water Phase Heating

Water Water Phase Cooling

Purified Water USPWater Soluble

Excipients

MIXER

Purified Water USPLipophyllic Emulgent

Nitrogen blanketSolvent NFAntioxidant NFActive USP

Viscosity Agent(Specify Type)

at controlled temp - T 0C

880-920C

Inlet temp.up to 62°C

(target 60°C)

DE-AERATOR Homogeneous

Semisolid

HOLDING TANKUnder Nitrogen

Fill tubes accordingto specifications

1st RINSE

Target Temp.500-520C

600-620C

2nd RINSE

Cool to 280C

Ultra-clean FILLING

YIELDSOverall Production Yields

IPQC TestingpH

ViscosityContent Uniformity

Microbial limits

3rd RINSE(microgram Actives )





MANUFACTURING INSTRUCTION COMMERCIALPRODUCTION

ATTACHMENTS:THE FOLLOWING ATTACHMENTS ARE PLACED HERE:

Process

Attachment # 1 Weight Print-Outs of the raw material / solvents. Attachment # 2 Temperature Print-Outs of manufacturing process stage .

In-process

Attachment # 3 pH Print-Outs of Bulk.

Attachment # 4 Viscosity Print-Out of Bulk material.

Final BulkMixing Process.Attachment # 5 Mixing time Print-Out(s) of the Final Bulk. Attachment # 6 Weight Print-Out of the Final Bulk.

Weight ControlFilling Process.Attachment # 7 In-process weight Print-Outs of the filled material

NOTE:Where automatic print-outs are not available, Statistical Data Work Sheets are filledout, during the filling process. Suitable Semisolid Filling machines are highlightedbelow.

Filling process: [ALL-FILL \ KING]





IN-PROCESS CONTROL SPECIFICATIONBULK MATERIAL

SUMMARY

Product: [Generic name] SEMISOLID [USP] [000.0] mg / g Lot No: 000

Quantity 000000 MNF Date: Month DD, 1998 / 9

YieldsBulk Yield Limit: NLT 98.0%

Total Final Yield Limit: NLT 98.0% (based on actual quantitiesprocessed).

Overall Production Yield NLT 95.0%

1Target Fill Weight ____________ g.Limits 5.0%

NLT 00.000g - NMT 00.000g

Target Cap Torque (jars) ____________ Kg

Cap Torque Check (jars) ____________ Kg

¹ Recorded on Statistical Data Work Sheets.





IN-PROCESS CONTROLSPECIFICATIONS

SUMMARY

PRODUCT: [GENERIC NAME] SEMISOLID [000.0] mg.

Labeled Amount: EACH gram contains [000.0] mg [Active Material]

In-process Specifications

Description Opaque uniform homogeneous Semisolidwith a [type] color and [type] odor.

Active Fill Weight (±5.0%) Target 000 Limit: 000 - 000 mL

pH (±1.0 / 0.5 unit) Target 0.0 Limit: 0.0 - 0.0

Viscosity Target 0000 Limit: 0000 - 0000 cp.Brookfield, Spindle #[ 0] After [ 0] rpm

In-Process Semisolid Content Uniformity Limit: 94.0 - 106.0% of labeled amount

RSD ≤ 6.0% (as per attached specifications)

Particle Size (microns) Median 000µ Limit: 000 - 000 µ

YieldsActual Bulk Weight Limit: NLT 98.0% (based on actual quantities

processed)

Calculated Filling Yield Limit: NLT 100.0% (based on bulk weight/target fill weight).

Actual Filling Yield NMT 2.0% unexplained loss from theprevious final blend step

Overall Filling Yield NLT 95.0%

Note: Exact Decimal points have been set for each specification¹ Recorded on Statistical Data Work Sheets.





IN-PROCESS CONTROL SPECIFICATION

SUMMARY

Product: [Generic name] SEMISOLID [USP] [000.0] mg / g Lot No: 000


Lowest Mean Highest

Weight Controls

¹Target Fill weight 000.0 (g) 000.0 000.0 000.0

¹Weight of 10 Containers #1 (g) 000.0 000.0 000.0








In-Process Yields¹Yield after filling vs. bulk material 00.0 %¹Yield after filling to theoretical 00.0 %Semisolid Yield NMT 2.0% unexplained loss

from the previous step

¹ Recorded on Statistical Data Semisolid Filling Work Sheets.




Proposed Manufacturing InstructionsRELEASE SPECIFICATION FOR SEMISOLID [USP]

SUMMARY

Product: [Generic name] Semisolid [000.0] mg / g

Labeled Amount: Each gram contains [000.0] mg [Active Material]

Description [Opaque] uniform homogeneous Semisolidwith a [type] color and [type] odor.

Identification A: The Infra Red Absorption Spectrum conformsto the Reference Standard

Identification B: The Chromatogram of the sample solutionexhibits a peak with the same retention timeas the standard solution.

Fill Volume (±5.0%) Target 000 Limit: 000 - 000 mL

pH (±0.5 / 1.0 unit) Target 0.0 Limit: 0.0 - 0.0Viscosity Target 0000 Limit: 0000 - 0000 cp.Brookfield, Spindle #[ 0] After [ 0] rpm

Uniformity of Dosage Units: Conforms to the current USPContent Uniformity

Total Microbial Count NMT 100 CFU / gTotal Aerobic Count NMT 100 CFU / g

Objectionable Organisms Absent: S aureus; E coli; P aerugenosa;Salmonella species; Indicator orgs

Impurities /Degradation Products determination- Each Individual: NMT 0.5% of the labeled amount- Any other Individual: NMT 0.5% of the labeled amount- Total: NMT 2.0% of the labeled amount

Assay (Preservative) Limit: 50.0 - 105.0% of labeled amount(Where Appropriate) [00.0] - [000.0] mg / g

Assay (Active) Limit: 90.0 - 110.0% of labeled amount[00.0] - [000.0] mg / g





RELEASE SPECIFICATION FOR SEMISOLID [USP]

OUTLINE ofIN-HOUSE ANALYTICAL SOP

Content UniformityThe requirements for content Uniformity are met if the amount of the active ingredient ineach of the 10 samples, as determined from the Content Uniformity Analytical Method, lieswithin the range of 90.0 - 110.0% of the labeled amount and the Relative StandardDeviation is less than or equal to 6.0%.

If 1 sample is outside the range of 90.0 - 110.0% of labeled amount and no sample isoutside the range of 80.0 - 120.0% of labeled amount, or if the Relative Standard Deviationis greater than 6.0%, or if both conditions prevail, test 20 additional samples.

The requirements are met if not more than 1 sample of the 30 is outside the range of 90.0 -110.0% of labeled amount and no sample is outside the range of 80.0 - 120.0% of labeledamount, the Relative Standard Deviation of the 30 samples does not exceed 7.8%.

Preservative EfficacyPreservative Efficacy Testing (USP) is omitted as a routine QC test when fully qualified withjustification during the formulation development, process qualification AND pivotal batch lottesting.

Preservative Efficacy Test USP are evaluated on stability testing at time of manufacture, 12;24; and 36 months for PQ, Pivotal and validation batches only.

Preservative Efficacy / Preservative AssayPreservative Efficacy Testing (USP) and Assay is omitted as a routine QC test when fullyqualified with justification during the formulation development, process qualification ANDpivotal batch lot testing.

Preservative Efficacy / Preservative Assay are evaluated on stability testing at time ofmanufacture, 12; 24; and 36 months for PQ, Pivotal and validation batches only.

Regulatory Requirements - Preservative AssayIn cases of regulatory requests or insistence Preservative Assays are performed on every5th production batch or at least once per year where only one batch is made.





COMPARISON OF EXECUTED (PIVOTAL) AND PRODUCTION FORMULAE

Product: [Generic name] q [Semisolid] [000.0] mg per g. Lot: S-000

INGREDIENTAmount per

[0] mL

(mg)

Executed

Batch

0000

(Kg)

Production

Batch

0000

(Kg)

Miconazole USP

Micronized

Pegoxol 7 Stearate [Tefose

63™]


Benzoic Acid USP


Peglico 5 Oleate


Purified Water USP

00.00

00.00

00.00

00.00

00.00

00.00

00.00

00.00

00.00

00.00

00.00

00.00

00.00

00.00

00.00

00.00

00.00

00.00

00.00

00.00

00.00

00.00

00.00

00.00

00.00

00.00

00.00

00.00

00.00

00.00

Total 000.000 000.000 000.000

Adjust where applicable (i.e. if moisture content of active is greater than 0.5-1.0%):





COMPARISON OF EQUIPMENT AND MANUFACTURING CONDITIONS

BETWEEN EXECUTED AND PRODUCTION BATCHES


Equipment andManufacturing Conditions

ExecutedBatch

000 Kg

ProductionBatch

000 Kg

PROCESSING KETTLE Production Production

MIXER I

MIXER II

Production

Production

Production

Production

KING AIR MACHINE JD / BB Production Production

ZANASSI FILLING MACHINELA-60

Production Production

ALL FILL FILLING MACHINESMR / 14

Production Production

KING CAPPER C80 Production Production

YAMATO CHECK WEIGHER Production Production

Equipment Variation NONE NONE

Manufacturing Area Production Production

Staff Production Production

SOP Production Production




Proposed Manufacturing InstructionsPACKAGING OPERATION DESCRIPTION


Stage One.PACKAGING COMPONENTS:

1. Bulk Product 2. HDPE / Aluminum / Glass Containers 3. Package Outsert (Product Leaflets) 4. Container Label 5. Master Cartons 6. Carton Shipping Labels

Stage TwoPACKAGING PROCEDURE:

HDPE Containers & Bulk Feed

Tube/Jar Cleaning Process(Air and Vacuum)

Count & Fill

Capping(Tube/Jar)

Jar Closure Torque Test

Container Labeland Outsert Attachment

Packed in Master ShippingCartons




Proposed Manufacturing InstructionsPACKAGING OPERATION - EQUIPMENT LISTING:


Machine Operation Manufacturer

Supplier

Type Serial # Output

CONTAINERSper min2

1 Schenck HDPE Bottle

or Amber

Glass

Feeding

Schenck Process

GMBH Darmstadt

1000-S

AccuRate

No:

543123

50 Low

100 High

2 King Air Cleaning C.E. King Ltd, UK

SuperKleen

MK-

2994

50 Low

100 High

3 Cream

Filling

ALLFILL

KINGFILLER(1)

L-333

L-334

Count

4 Capper Capping KING CAPPER CAP 80 2232-

2234

50 Low

100 High

5 Torque Torque H.G.Kalish Inc.,Canada

2234-

9987

50 Low

100 High

6. Groninger Outserter Groninger & Co

KarlsHeim,

Germany

DFVK

3000

5664 50 Low

100 High

7. Prestek Labelling &

Printing

Prestek Ltd

Science Park

Nottingham UK

SmartDate

Intelligent

Thermal

Transfer Printer

53342 50 Low

100 High

(1) Average figures for containers per minute output for Slow and High Speed.

(2)All indicated machine outputs are adjusted to the Filling rate.

50 10050* 100*





BATCH RECORDS FOR EXECUTED BATCH

TYPE OF SEMISOLIDLot No

Enclosed are the batch records of the executed batch (master, packaging andlabeling).

Note:Translation Policy - (Foreign Manufacturing Plants):All documents provided are authenticated photocopies of the executed batchdocument.

The documents are written in (local language) with parts of the data and informationpresented in English.

Where information is provided in the (local language), a verified English translationis provided together with the original document in the local language. Where, onlyEnglish is used in a document, the original copy document is provided.

Executed batch of [Generic Name] SEMISOLID was manufactured on productionequipment under actual production conditions.

ACTIVE MATERIALThe active material is manufactured by [BPC] Pharmaceutical and ChemicalManufacturing Company - [Address].





REPROCESSING STATEMENT(Delete statement where appropriate)

The COMPANY is unable to anticipate what manufacturing qualifying factors, if any,may lead to the need for reprocessing at this time. If reprocessing of a batch isrequired once the product has been marketed, the reprocessing procedure as wellas the relevant supporting data will be submitted, (according to the SUPACguideline, where appropriate), for supplementary review and approval of the Officeof Generic Drugs prior to implementation.

[Signature of Responsible Person]------------------------------------------------ ---------------------------------------[Name of Responsible Person] DatePlant ManagerPharmaceutical Manufacturing Division[Generic Company Name Inc. / Ltd.]

[Signature of Responsible Person]------------------------------------------------ ----------------------------------------[Name of Responsible Person] DateDirector Quality Assurance UnitPharmaceutical Manufacturing Division[Generic Company Name Inc. / Ltd.]

[Signature of Responsible Person]------------------------------------------------ -----------------------------------[Name of Responsible Person] DateDirector Pharmaceutical Research & DevelopmentPharmaceutical Division






REPROCESSING STATEMENT(Delete statement where appropriate)

The following manufacturing stages have been reworked during the full size processQualification batch (essentially similar to the pivotal batch shown) and the finishedproduct specifications were evaluated.

At time of manufacture (Time zero):No detectable change was recorded for the following test studies

pHViscosityContent UniformityAt 3 months stability station (40o C / 75% RH):The above parameters showed no detectable changes. The full re-work study ispresented in the “Product Development Report” and a Summary outline is given inSection XXI.

Conclusion:It is concluded that an additional 20 minute mixing (last stage) may be repeatedonce as shown, without affecting or impacting on the products physical parametersas shown in the in-process, release or stability (check) specifications.

[Signature of Responsible Person]------------------------------------------------ --------------------------------------[Name of Responsible Person] DatePlant ManagerPharmaceutical Manufacturing Division[Generic Company Name Inc. / Ltd.]

[Signature of Responsible Person]------------------------------------------------ -------------------------------------[Name of Responsible Person] DateDirector Quality Assurance UnitPharmaceutical Manufacturing Division[Generic Company Name Inc. / Ltd.]



SECTION XII SECTION 12

Pivotal Manufacturing and Controls

TABLE OF CONTENTS.(as stated in FDA Feb. 1999 Guidance for Industry).

12.1 Copy of the executed Pivotal batch manufacturing record with- equipment used- batch reconciliation

12.2 Copy of the executed Pivotal batch packaging record with- equipment used- label reconciliation

IN-PROCESS CONTROLS

12.3.1 Sampling plans and testing procedures

12.3.2 Specifications and data

FDA's ANDA Guideline Requirements:-(as Published January 1999)

Section XII..In-Process Information

1. Copy of executed batch record with equipment specified(including packaging records, and batch reconciliation)

2. In-process controls

Delete specific data or delete whole sections which are not applicable to this Section 12 of the ANDA The use of bold and squarebrackets e.g. [00] where actual names or figures are inserted.

4






• Outlines of Standard Operating Procedure for In-Process Controls

• In-Process Control tabulation chart (Summary)

• Executed Manufacturing Procedure Flow Chart

• Executed Batch documents

• Batch Records Packaging Records and labeling reconciliation

• Summary of FILL WEIGHT Verification

• Summary of CONTENT UNIFORMITY Verification

• Packaging and Disbursement Summary

4






FOR:

IN-PROCESS CONTROLS

1. At all stages of processing, appropriate control procedures are employed inconformity with current good manufacturing practice.

2. Appropriate in-process controls include material testing by quality control andquality assurance personnel. These test are:

⇒ Content uniformity of final blend. ⇒ Physical specifications of the SEMISOLID bulk. ⇒ Fill weight verification.

3. In-process material testing is performed by Qualified Personnel.

4. The Quality Assurance Department reviews the batch test results and evaluatesthe acceptance or rejection of each batch lot.

4





IN-PROCESS CONTROLSDURING SEMISOLID FILLING

In-process testing is conducted independently by both production andquality control trained personnel. The tests specified in the underlyingtables are performed in accord with the in-process product specifications.When, a test is not required, according to the written specifications, it willnot be performed.

Production personnel test the physical specifications of random samplesaccording to the individual product specifications: A minimum sampling frequency istabulated for each eight hour (shift) period.

Production In-processTesting Schedule:

Test

PERFORMED

Sample

Size

Frequency

per shift (1) (min)

Acceptance

Criteria (2)

Bulk Description 1 At start. Within specifications.

Fill Weight (Active) 10 At 30 min.intervals.

NMT 2 Containers from of the 20 testedmay deviate from product spec. Nodeviation permitted from Double Limits(3)

specification.

Cap Torque (Jars) 6 At 30 min.intervals.

No deviation from product specifications ispermitted.

KEY:

1The testing frequency is performed twice when the overall filling time is less than four hours.2Deviations from specifications and acceptance criteria, arising during the in-process

controls, shall determine the corrective action to be performed on the filling machinery during the filling stage.





uality Control personnel test the physical specifications of samples taken atrandom according to the individual product specifications sheets: A minimum

sampling frequency is tabulated for each eight hour (shift) period.

Quality ControlIn-process Testing Schedule:

TEST

PERFORMED

Sample

Size

Frequency

per shift (1) (min.)

ACCEPTANCE

CRITERIA (2)

Material Description 1 (1) Onceat start

No deviation from product specificationis allowed.

Individual Fill

Weight

20 (1) 60 min NMT 2 Containers from of the 20tested may deviate from product spec.No deviation permitted from DoubleLimits(3) specification.

CAP TORQUE(Jars)

6 (1) 60 min No deviation from product specificationis allowed

KEY:

1Samples are taken, independently by QC personnel for batch release purposes, atleast once per hour throughout the FILL run, producing a total representative samplequantity of 20 - 40 Containers. This representative sampling is for the QC Unit batchrelease purposes2Deviations from specifications and acceptance criteria, that arise during the in-process controls, determine the corrective action undertaken on the filling machineryduring the line filling stage.3Double Limits for the Individual Fill Weight tests are defined as the double valuefrom the minimum or maximum limit in relation to the nominal fill value (i.e. target fillweight value).

Q






FOR:SAMPLING PLAN OF PIVOTAL LOTS

FOR STABILITY AND BIOAVAILABILITY STUDIES.

tandard Operating Procedures are in place at the commercial manufacturingfacility, that define the overall packaging procedures for the pivotal lot(s) andthe representative sampling of the various pack sizes for the purpose ofquality control, stability testing and bioavailability studies. These procedures

are summarized below.

The entire pivotal lot (i.e. 100%) is packaged in the commercial productionpackaging department, using routine production equipment, and operated by thestandard production personnel.

The smallest and largest pack size of each pack type is packaged, not less than 15-20% of the pivotal batch is packed into each pack type.

The number of each type of pack size sampled is calculated in order obtainapproximately equal numbers of each presentation size.

A sampling plan for each type of package, is determined on the basis of the totalnumber of packages and the number of packages required for control, stability andtopical bioavailability studies.

The sampling plan is representative of the entire pivotal batch.

4

S





EXECUTED PIVOTAL BATCH MANUFACTURING INSTRUCTIONS

Product name: [Generic name] SEMISOLID [USP] [000.0] mg.Batch Number: 000Department: ______________ Batch Size: 150 KgPrecautions: �� Sub-lot No: þþ1 ý 2 ý 3Caution: �� Manufacture Date: Month DD, YYCat./Formula No: # F0000 SEMISOLID þBased on PQ: Batch # PQ000 þþ PIVOTAL BATCH

ý Validation Lot ý Commercial Lot

Change Control for this document: Original - No Change þ : Change ýChange made: - none

KEY:KEY:Precautions: ��Wear Mask and Gloves

��Wear disposable overalls

��Use air stream face visor with AIR filter

��Use Mask, Gloves and Safety glasses

Caution: ��Avoid exposure to light / Protect form light

��Store in well closed containers

��Potential danger to pregnant women

��Pregnant women prohibited in this area

��Do not heat above 00øøC� Room humidity below 30%





EXECUTED PIVOTAL BATCH MASTER FORMULA




gram


Signweigh.Dept.



27 000




[LABRAFIL M 1944™] 4 500




PART III - AQUEOUS PHASE721.650 Purified Water USP 108 247 500




Edition Number:01


NewDD/MM/YY _____________ __________ _______________ _________/________






EXECUTED PIVOTAL BATCH MASTER FORMULA

[Generic name] SEMISOLID [USP] [000.0] mg/g Lot: 000

Batch No: Weighing Date:

Page 1 of 4 pages

MANUFACTURING INSTRUCTIONSMachine Sign

A + BDate

Step 1. IDENTIFY the equipment and verify the cleanliness priorto use.

PART ONE - OIL PHASEStep 2. LOAD into kettle No [ ] fitted with [Mixer # [ ]-Type & No)the ingredients in the following order:Pegoxol 7 Stearate [Tefose 63™]Heavy Mineral OIL NFBenzoic Acid USPButylated Hydroxyanizoleand mix for [20] minutes at mixer setting speed II

Step 3. HEAT while mixing to NMT [45]º C (Target: [42]º C).Time of adding [ ] min.Total Mixing Time [ ] min.

PART TWO Active OILY PHASE

Step 4. LOAD into a [Small Mixer-Type & No) the ingredients inthe following order:Miconazole USP - MicronizedPeglico 5 Oleate - [LABRAFIL M 1944™]Edetate Disodium USPMix for [20] minutes at mixer speed [II] until mix is fully micronizedmaterial is suspended and homogeneous.Step 5. HEAT while mixing to NMT [45]º C (Target: [42]º C).Target Temperature [ ]º CSTART of mixing [ ]END of mixing [ ]Total Mixing Time [ ] min

Edition Number:01


NewDD/MM/YY _____________ __________ _______________ _______/________





Pivotal Manufacturing and ControlsEXECUTED PIVOTAL BATCH MANUFACTURING INSTRUCTIONS

Page 2 of 4 pages


Date

PART THREE AQUEOUS PHASE

Step 6. Heating the Water Phase(i) WEIGH or MEASURE 000.0 Kg [PURIFIED WATER USP] into astainless steel mixing kettle fitted with a high speed variable mixer. (#0)(ii) Operate the mixer while HEATING to NMT [95]º C (Target: [95]º C).(iii) Hold the heated Water at the target temperature for NLT60 minutes

Target Temperature [ ]º C).Time of Heating [ ]Total Process Time [ ] min

Step 7. Cooling the Water PhaseCOVER and Cool Step 6 [PURIFIED WATER USP] to a targettemperature while slowly stirring - Target Temperature 280C [±20C]

Target Temperature NMT [ ]º CStart of Cooling Time [ ]End of Cooling Time [ ]Total of Cooling Time [ ] min

PART FOUR - ADDITION OF OILY PHASE

Step 8. Add the Active Oily Phase STEP 4 to the Bulk Oil Phase STEP2 and mix at speed [III] until homogeneous. RINSE active material twicewith heavy mineral oil. Drain container fully after each RINSE procedure.

Start of Mixing [ ]End of Mixing [ ]Total of Mixing Time [ ] minStep 9. Check that the oil phase after the mixing period is ahomogeneously dispersed oily suspension - if necessary mix for anadditional 20 minutesStart of Mixing [ ]End of Mixing [ ]Additional Mixing Time [ ] min

Edition Number:01


NewDD/MM/YY _____________ __________ _______________ _________/________






Page 3 of 4 pages


Date

ADDITION OF AQUEOUS PHASEStep 10. RECORD the Aqueous and Oil Phase temperatures.Temperature of AQUEOUS Phase NMT [30]º C (Target: 280C [±20C])Temperature of OIL Phase NMT [30]º C (Target: 280C [±20C])

Step 11. ADD the aqueous phase to STEP 8 while continuously mixingat mixer speed III.Start of Mixing [ ]End of Mixing [ ]Total Mixing Time [ ] min

Step 12. ATTACH the mixing kettle temperature graphs (Type & No) tothe manufacturing instructions. Add the batch number to the temperaturegraph and Immediately date and sign it..

COOLING OF COMBINED PHASESStep 13. COOL Step 11 to a target temperature while slowly stirring[Set I].Target Temperature 250C [±20C] Record Temperature ______0CStep 14. PASS the SEMISOLID through an HOMOGENIZER (Type &No) fitted with a [0.0 mm] screen into an ultra clean holding bin.Step 15. CHECK pH [25]º C of a sample of the homogenizedSEMISOLID).Record pH Result: _________ [Units]DETERMINE the viscosity using (Type & No) Brookfield Viscometer; Spindle No [3] RPM [5] Temperature [25]º CRecord First result: __________ [Cp]Cp Limits: [4000 to 6000]

Step 16. If necessary, continue to Homogenize the bulk material (re-circulate) under the same conditions as STEP 14, until the viscosity isclose to the midpoint of the given range limits and check viscosity again.Record Second result: __________ [Cp]Step 17. PUMP the semisolid into (Type & No) [000] liter container.Pumping Stop Time: _________

Step 18. WEIGH the bulk material ______Kg.

Step 19. Immediately ADD the batch number to the scale print-out, andattach to the manufacturing instructions, date and sign the print-out.

Edition Number:01


NewDD/MM/YY _____________ __________ _______________ _________/________






Page 4 of 4 pages


Date

YIELD CALCULATIONStep 20. Theoretical Weight [00.0] Kg. Yield ___________ %(Yield Limits: NLT 95% of Theoretical Weight.) No of Bins ______

Step 21. COLLECT 10 samples, each equivalent to the approximateweight of 10 g in labeled sample containers. Collect samples from upper,middle and lower part of the container. Send the samples to the QClaboratory for Content Uniformity Testing.

Step 22. WEIGH the final material

Actual weight: [00.0] Kg.

Theoretical Weight [00.0] Kg. Yield __________ %

No. of containers _____ .

(Yield Limits: NLT 98% of total actual weight

PART FIVE - FILLING PROCEDUREStep 23. IDENTIFY and verify the cleanliness of the filling equipment inuse.FILL the material according to the written specifications into air blowntubes WITHIN 24 hours after manufacture.CAUTION: (Do not leave standing over weekends/holidays.)

Check filling weight every 15 minutes.Check end-crimp every 30 minutes.Check Lot No and Expiration Date over stamping at start and end of run.Check Lot No and Expiration Date after reset or replacing type.

Air Blowing machine: (Type & No).Filling machine: (Type & No).Machine Speed _______ Tubes per minute.Limit of output NLT _______ units; NMT _______ units.

Step 24. COUNT the total units produced:

Actual production count: [00.0] Units.

Weight of Samples taken: [00.0] Units.

Vacuum and rejects number: [00.0] Units.

Total Units [00.0] Units

Theoretical Weight [00.0] Kg.

Yield _________ %

(Yield Limits: NMT 3% unexplained loss compared to the final bulkweight from STEP 20.Edition Number:

01Effective Date APPROVED

Ed. Status:New

DD/MM/YY _____________ __________ _______________ _________/________ Department R &D RA QC / QA



Nitrogen blanketOIL PHASE

MIXER(S/S Mixing vessel)

Oily Solvent Lipophobic EmulgentEmulsifier

(Ross mixer)



FLOW CHARTChart One

Water Phase Heating

Water Water Phase Cooling

Purified Water USPWater Soluble

Excipients

MIXER

Purified Water USPLipophyllic Emulgent

Nitrogen blanketSolvent NFAntioxidant NFActive USP

Viscosity Agent(Specify Type)

at controlled temp - T 0C

880-920C

Inlet temp.up to 62°C

(target 60°C)

DE-AERATOR Homogeneous

Semisolid

HOLDING TANKUnder Nitrogen

Fill tubes accordingto specifications

1st RINSE

Target Temp.500-520C

600-620C

2nd RINSE

Cool to 280C

Ultra-clean FILLING

IPQC TestingpH

ViscosityContent Uniformity

Microbial limits

3rd RINSE(microgram Actives )





EXECUTED PIVOTAL BATCHMANUFACTURING INSTRUCTIONS

THE FOLLOWING ATTACHMENTS ARE PLACED HERE:

Process

Attachment # 1 Weight Print-Outs of the raw material / solvents. Attachment # 2 Temperature Print-Outs of manufacturing process stages .

In-process

Attachment # 3 pH Print-Outs of Bulk.

Attachment # 4 Viscosity Print-Out of Bulk material.

Final BulkMixing Process.Attachment # 5 Mixing time Print-Out(s) of the Final Bulk. Attachment # 6 Weight Print-Out of the Final Bulk.

Weight ControlFilling Process.Attachment # 7 In-process weight Print-Outs of the filled material

NOTE:Where automatic print-outs are not available, Statistical Data Work Sheets are filledout, during the filling process. Suitable Semisolid Filling machines are highlightedbelow.

Filling process: [ALL-FILL \ KING]





IN-PROCESS CONTROL SPECIFICATION BULK MATERIAL

SUMMARY

PIVOTAL BATCH

Product: [Generic name] SEMISOLID [USP] [000.0] mg/g Lot No: 000


YieldsManufacturing Yield Limit: NLT 98.0%

Total Final Bulk Yield Limit: NLT 98.0% (based on actual quantitiesprocessed).

Overall Production Yield NLT 95.0%

1Target Fill Weight ____________ g2Limits 5.0%

NLT 00.000g - NMT 00.000g

Target Cap Torque ____________ Kg

Cap Torque Check ____________ Kg

Cap Torque Limits Min____ Kg Max ____ Kg

¹ Recorded on Statistical Data Work Sheets.





IN-PROCESS CONTROLSPECIFICATIONS

SUMMARY

PRODUCT: [GENERIC NAME] SEMISOLID [000.0] mg /g.

Labeled Amount: EACH gram contains [000.0] mg [Active Material]

In-process Specifications


pH (±1.0 / 0.5 unit) Target 0.0 Limit: 0.0 - 0.0SG Target 0.000 Limit: 0.000 - 0.000 g/mLViscosity Target 0000 Limit: 0000 - 0000 cp.Brookfield, Spindle #[ 0] After [ 0] rpm

In-ProcessSemisolid Content Uniformity Limit: 94.0 - 106.0% of labeled amount(as per attached specifications) RSD ≤ 6.0%

Fill Weight (±5.0%) Target 000 Limit: 000 - 000 mL

Individual Fill Weight (±7.5%) Target 000.0 Limit: 000.0 - 000.0 g

YieldsActual Bulk Weight Limit: NLT 98.0% (based on actual quantities

processed)

Calculated Filling Yield Limit: NLT 100.0% (based on bulk weight /target fill weight).

Actual Filling Yield NMT 2.0% unexplained loss from theprevious final blend step

Overall Filling Yield NLT 95.0%

Note: Exact Decimal points have been set for each specification¹ Recorded on Statistical Data Work Sheets.





IN-PROCESS CONTROL SPECIFICATION

SUMMARY

PIVOTAL BATCH

Product: [Generic name] SEMISOLID [USP] [000.0] mg/g. Lot No: 000


Lowest Mean Highest

Weight Controls

¹Target Fill weight 000.0 (g) 000.0 000.0 000.0









In-Process Yields¹Yield after filling vs. bulk material 00.0 %¹Yield after filling to theoretical 00.0 %Permissible Loss NMT 2.0% unexplained loss

from the previous step

¹ Recorded on Statistical Data Semisolid Filling Work Sheets.




Pivotal Manufacturing and ControlsRELEASE SPECIFICATION FOR SEMISOLID [USP]

SUMMARY

Product: [Generic name] Semisolid [000.0] mg / 5 mL

Labeled Amount: Each [00.0] g contains [000.0] mg [Active Material]


Identification A: The Infra Red Absorption Spectrum conformsto the Reference Standard

Identification B: The Chromatogram of the sample solutionexhibits a peak with the same retention timeas the standard solution.

Fill Weight (±5.0%) Target 000 Limit: 000 - 000 mL

pH (±o.5/1.0 unit) Target 0.0 Limit: 0.0 - 0.0SG Target 0.000 Limit: 0.000 - 0.000 g/mLViscosity Target 0000 Limit: 0000 - 0000 cp.Brookfield, Spindle #[ 0] After [ 0] rpm

Uniformity of Dosage Units: Conforms to the current USPContent Uniformity

Total Microbial Count NMT 100 CFU / mLTotal Aerobic Count NMT 100 CFU / mLObjectionable Organisms Absent: S aureus; E coli; P aerugenosa;

Salmonella species; Indicator orgs

Impurities /Degradation Products determination- Each Individual: NMT 0.5% of the labeled amount- Any other Individual: NMT 0.5% of the labeled amount- Total: NMT 2.0% of the labeled amount

Assay (Preservative) Limit: 50.0 - 110.0% of labeled amount[00.0] - [00.0] mg / g

Assay (Active) Limit: 90.0 - 110.0% of labeled amount[00.0] - [00.0] mg / g




Pivotal Manufacturing and ControlsRELEASE SPECIFICATION FOR SEMISOLID [USP]

OUTLINE ofIN-HOUSE ANALYTICAL SOP

Content UniformityThe requirements for content Uniformity are met if the amount of the active ingredient ineach of the 10 samples, as determined from the Content Uniformity Analytical Method, lieswithin the range of 90.0 - 110.0% of the labeled amount and the Relative StandardDeviation is less than or equal to 6.0%.

If 1 sample is outside the range of 90.0 - 110.0% of labeled amount and no sample isoutside the range of 80.0 - 120.0% of labeled amount, or if the Relative Standard Deviationis greater than 6.0%, or if both conditions prevail, test 20 additional samples.

The requirements are met if not more than 1 sample of the 30 is outside the range of 90.0 -110.0% of labeled amount and no sample is outside the range of 80.0 - 120.0% of labeledamount, the Relative Standard Deviation of the 30 samples does not exceed 7.8%.

Preservative EfficacyPreservative Efficacy Testing (USP) is omitted as a routine QC test when fully qualified withjustification during the formulation development, process qualification AND pivotal batch lottesting.

Preservative Efficacy Test USP are evaluated on stability testing at time of manufacture, 12;24; and 36 months for PQ, Pivotal and validation batches only.

Preservative Efficacy / Preservative AssayPreservative Efficacy Testing (USP) and Assay is omitted as a routine QC test when fullyqualified with justification during the formulation development, process qualification ANDpivotal batch lot testing.

Preservative Efficacy / Preservative Assay are evaluated on stability testing at time ofmanufacture, 12; 24; and 36 months for PQ, Pivotal and validation batches only.

Regulatory Requirements - Preservative AssayIn cases of regulatory requests or insistence Preservative Assays are performed on every5th production batch or at least once per year where only one batch is made.




Pivotal Manufacturing and ControlsPACKAGING OPERATION DESCRIPTION

Product: [Generic name] SEMISOLID [USP] [000] mg /g - Batch No: 000

Stage One.PACKAGING COMPONENTS:

1. Bulk Product 2. HDPE / Glass Containers 3. Package Outsert (Product Leaflets) 4. Container Label 5. Master Cartons 6. Carton Shipping Labels

Stage TwoPACKAGING PROCEDURE:

HDPE Containers & Bulk Feed

Tube/Jar Cleaning Process(Air and Vacuum)

Count & Fill

Capping(Screw Cap - Jars)

Closure Torque Test

Container Labeland Outsert Attachment

Packed in Master ShippingCartons




Pivotal Manufacturing and ControlsPACKAGING OPERATION - EQUIPMENT LISTING:


Machine Operation Manufacturer

Supplier

Type Serial # Output

CONTAINERSper min2

1 Schenck HDPE Bottle

or Amber

Glass

Feeding

Schenck Process

GMBH Darmstadt

1000-S

AccuRate

No:

543123

50 Low

100 High

2 King Air Cleaning C.E. King Ltd, UK

SuperKleen

MK-2994 50 Low

100 High

3 Cream

FillingALLFILL FILLER(1)

L-333

L-334

Count

4 Capper Capping KING CAPPER CAP 80 2232-

2234

50 Low

100 High

5 Torque

checker

Torque

(Jars)

H.G.Kalish Inc.,Canada

2234-

9987

50 Low

100 High

6. Groninger Outserter Groninger & Co

KarlsHeim,

Germany

DFVK

3000

5664 50 Low

100 High

7. Prestek Labelling &

Printing

Prestek Ltd

Science Park

Nottingham UK

SmartDate

Intelligent

Thermal

Transfer Printer

53342 50 Low

100 High

(1) Average figures for containers per minute output for Slow and High Speed.

(2)All indicated machine outputs are adjusted to the Fill rate.

50 10050* 100*





BATCH RECORDS FOR EXECUTED BATCH

SEMISOLIDLot No

Enclosed are the batch records of the executed batch (master, packaging andlabeling).

Note:Translation Policy - (Foreign Manufacturing Plants):All documents provided are authenticated photocopies of the executed batchdocument.

The documents are written in (local language) with parts of the data and informationpresented in English.

Where information is provided in the (local language), a verified English translationis provided together with the original document in the local language. Where, onlyEnglish is used in a document, the original copy document is provided.

Executed SEMISOLID batch was manufactured on production equipment underactual production conditions.

ACTIVE MATERIALThe active material is manufactured by [BPC] Pharmaceutical and ChemicalManufacturing Company - [Address].

Label Reconciliation:A 100% Label Reconciliation is conducted for each packaging run. All damaged /rejected labels are stuck to a label card and counted & defaced at the end of the run.

Reconciliation Summary:Total number of labels _________ issued [a] Signed by (Warehouse)

Total number of labels _________ On product [b] Signed by (Line Checker)Total number of labels _________ On Samples [c] Signed by (QA Staff)Total number of labels _________ Damaged [d] Signed by (Line Checker)Total number of labels _________ Not used [e] Signed by (QA Staff)

% Label Reconciliation ________ (Calculation a - [b+c+d+e] ) < 5/1000 (NMT 0.5%)

Note: Where the issue of labels are calculated by weight, the issue count errorpermitted is NMT 0.5 %.





FILL WEIGHTRANGE VERIFICATION


The following specification were given for the executed (pivotal) batch:

WEIGHT RANGE

TARGET FILL 0000.0 mg

RANGE NLT 0000.0 - NMT 0000.0 mg

During the manufacture of the executed (pivotal) batch, FILL WEIGHT rangeverification testing was performed.

The result demonstrate that FILLING of _____________SEMISOLID on productionequipment at production speeds was within the proposed weight range (minimum000, maximum 000).

The uniformity of content was evaluated on at least three samples taken at eachspeed. Each tube sampled and tested for U of C from the top, middle and crimppositions.

The weight range results demonstrate that the range limits have been suitablyvalidated for routine commercial production batch manufacture.

NOTE:

Fill Weight Range verification is performed on each strength for multi-strengthpresentations e.g.Table 1 - 000 mg / gTable 2 - 000 mg / g etc.

4





FILL WEIGHTRANGE VERIFICATION


Table 1SAMPLE LOW SPEED HIGH SPEED TARGET SPEED

NO. Fill Weight(g)

Uniformityof Content

(check 3:20)

Fill Weight(g)


(check 3:20)

Fill Weight(g)


(check 3:20)

Machine Type Machine No: Lot No Date

1 00.000 - 00.000 - 00.000 -

2 00.000 - 00.000 - 00.000 -

3 00.000 00.000 00.000 - 00.000 00.000

4 00.000 - 00.000 - 00.000 -

5 00.000 - 00.000 - 00.000 -

6 00.000 - 00.000 - 00.000 -

7 00.000 - 00.000 00.000 00.000

8 00.000 - 00.000 - 00.000 -

9 00.000 - 00.000 - 00.000 -

10 00.000 - 00.000 - 00.000 00.000

11 00.000 - 00.000 00.000 00.000 -

12 00.000 00.000 00.000 - 00.000 -

13 00.000 - 00.000 - 00.000 -

14 00.000 - 00.000 - 00.000 -

14 00.000 - 00.000 00.000 00.000 -

16 00.000 - 00.000 - 00.000 -

17 00.000 - 00.000 - 00.000 -

18 00.000 00.000 00.000 - 00.000 -

19 00.000 - 00.000 - 00.000 -

20 00.000 - 00.000 - 00.000 00.000

AVG.RSD %

USLLSL





PACKAGING TRAILPACKAGING AND DISBURSEMENTS

Product: [Generic name] SEMISOLID [000]mg /g - Batch No: 000

The disposition and distribution of the [000] mg strength are shown as actualnumerical example.

The packaging trail should show the packed units used in the pivotal lot for:-

• Quality Control Testing (Physical, Chemical & Microbial)

• Stability testing

• QA Reserve Samples for Annual Evaluation

• Topical Bioequivalency testing

• Topical Bioequivalency Retention Samples.

Bulk Material:

[150] Kg packed in :

[Two] bulk containers x 75 Kg


[75 Kg] bulk containers

Release Bio & Stability Testing

Month DD, 1999

(US)

[75 Kg] bulk containers

Release Bio & Stability Testing

Month DD, 1999

(EU)





Product: [Generic name] SEMISOLID [000]mg /g - Batch No: 000

000g HDPE Container (Jar) with Screw cap [00 mm]

000g HDPE CONTAINER (Jar) withScrew cap [00 mm]

300 units x 100 g


Nov.28, 1996

5 unit


Month DD, 1999

15 units


Month DD, 1999

280 units

Balance stored in

Pivotal Warehouse

198 units x 500 g


5 unit


Month DD, 1999

25 units


Month DD, 1999

168 units

Balance stored in

Pivotal Warehouse





PACKAGING AND DISBURSEMENT

Product: [Generic name] SEMISOLID [USP] [000]mg /g - Batch No: 000



200 units x 60 g


Nov.28, 1996

5 units x 60 gQC Testing

Month DD, 1999

60 units 60 gBiostudy (European Market)

Month DD, 1999

80 units 60 gBalance stored in

Pivotal Warehouse

55 units x 60 gRelease & Stability Testing

Month DD, 1999

300 units x 30 g


Nov.28, 1996

10 units x 30 g


Month DD, 1999

25 units x 30 g


Month DD, 1999

65 units x 30 g

Biostudy & Retained Samples

Month DD, 1999

200 units x 30 g

Balance stored in

Pivotal Warehouse

BIOSTUDY

BIOSTUDY

Topical BiostudyDisbursements

(See Semisolid Trail)Section 6



NOTES



SECTION XIII SECTION 13

Packaging and Labeling Procedures


This Section contains information on the container-closure systems, including typeIII DMF authorization letters from the component manufacturers, as well as theapplicant's component specifications and component test data.

The container closure system for the drug product are described in detail in thespecifications and drawings included in this section.

13.1 Outlines for Packaging and Labeling Procedures

13.2 Blank Packaging Forms and Packaging reconciliation .

NOTE:

STANDARD OPERATION PROCEDURES - OUTLINES.

Actual Standard Operation Procedures should not generally be included in anANDA submission. For various reasons new editions or amendments to SOPs arecontinually being development or new SOP procedure are introduced from time totime.

The period between submission and pre-approval inspection or first commercialproduction lots may well have resulted in a new SOP in use.

FDA's Published January 1999 ANDA Guideline Requirements:(actual excerpt as published in agency guideline)

Section XIII. Packaging Materials Controls1. Summary of packaging system2. Components specification and test data (Type III DMF references)3. Packaging configuration and sizes4. Container/closure testing (include ingress testing in Section XXII, as appropriate for

sterile processes only)5. Vendor qualification specifications6. Applicants acceptance criteria7. Retest schedule

44

The limit for unexplained loss of 20 per1000 i.e. 2% of the amount received is acommon upper limit industry standard.Unexplained material losses of 0.5 - 1%are generally target levels.

A relatively standardized ANDA sectionthat emphasizes the intended commercialproduction packaging procedures andreconciliation controls in force.




Packaging and Labeling Procedures

OUTLINE OF STANDARD OPERATING PROCEDURES FOR:PACKAGING AND LABELING PROCEDURES

Applicants Acceptance CriteriaThe Acceptance criteria for new packaging components are detailed in the firmsappropriate SOPs required according to cGMP (21 CFR 211). Actual acceptanceactivities are cross-checked by the firms QA department prior to manufacturer.A narrative outline of the QA system is given.

1. The packaging work station is inspected prior to the start of work, for workstation and equipment cleanliness. The packaging station must be free of allprevious leftover work materials and the packaging line must be completelyclear.

2. The product and packaging materials are identified according to the StandardPackaging Sheets printed with the required packaging specifications.

3. In-Process Control of the packaging procedure is carried out at the start ofpackaging procedure, and then at approximately every hour during thepackaging process. When packaging machines are temporary stopped, thework station is re-inspected and full In-Process Control checks are carried outprior to restarting the cleared line.

4. At the end of packaging procedure, a material balance and a packagingreconciliation is performed on the packed product and the unused printedpackaging materials that contain any overprinting (Lot number ; Expiry Date).(Example of the material balance & packaging reconciliation sheet attached).

5. Any quantity absent during packaging reconciliation is resolved as anunexplained loss. The limit for the unexplained loss may not exceed 2% of theamount received.

6. A Packaging Department supervisor / representative and a QA representativechecks and approves that the entire packaging procedure was performedaccording to required specifications, and signs the Packaging Work Sheet.

NOTE:

BLANK PACKAGING FORMSExamples of Blank Packaging Forms are not given in this example. The criticalchecks to proper packaging control forms are;• Identify and quantify - all incoming printed packaging material (including primary

and secondary packaging materials)• Identify and quantify - all incoming containers, closures and containers inserts

(including applicators, special nozzles etc.)

• Perform a material balance check on all Packed Goods and a PackagingReconciliation on all printed materials and containers.

333




Packaging and Labeling ProceduresPackaging Material Balance and Reconciliation

Product & Strength: _______________________ Batch No:

Packaging Size ________________

1. PACKAGING SUMMARY

Date Package MaterialDescription

TotalPackagesReceived

TotalUnits

Packaged

TotalUnits

Rejected

TotalUnits

Sampled

Non packagedQuarantine

Units

Initial

2. PACKAGING Reconciliation

2.1 TOTAL Units

packed

Department Material Balance:

2.2 TOTAL Packs

rejected

100 x [Total no. of units] = _______%

Theoretical no. of units

2.3 TOTAL Packs

sampled

Compare to last production stage

(≤2%)

Signature _______ Date ________

2.4 TOTAL PACKS

3. TOTAL BATCH RECONCILIATION (OF OVERALL PACKAGING PROCESS)

3.1 Material Rejected______________________ units

3.2 Samples Taken______________________ units

[2.1 + 3.1 + 3.2] _x _100 = % (Limits: 95.0% - 103.0%)Theoretical no. of units

Signature: _______________________ Date: _______________Quality Assurance Unit




GlassThermoplastic Containers

Solid oral dosage forms.

Vendor qualification SpecificationsAppropriate documentation from the packaging component manufacturer ashighlighted below is obtained for each component according to in-house SOPs,including but not limited to, DMF reference authorization letters, cGMP compliancecertifications, manufacturers specifications and test results.Furthermore samples of all materials with corresponding manufacturers Certificate ofAnalysis are evaluated for QC and functionality testing as well as any compatibilitytesting with the intended product.

FROM THE GENERIC FIRM'S QC LAB

1. General description (summary) of Container-closure-liner-seal-cottonsystem used for each dosage strength

2. Description of Packaging Components of pack sizes used for each strength3. Testing Specifications or protocol and test results (CoA) of Generic

packaging Lab.4. CoAs of Containers from the QC Packaging Lab.5. Batch Compliance Statement of applicants acceptance tests

FROM THE CONTAINER MANUFACTURER:-

6 Container Specifications:-name, product code and manufacturer (including)- drawings / diagrams with annotated dimensions- Tests performed on closure to include USP <661> and <671> n Light transmission and n moisture vapor permeation- Certificate of Conformance meeting all USP XXIII- Complies to 21 CFR requirements / Food Additives Regulations

- Certificate of Analysis- DSC thermal analysis (for thermoplastic containers only)

7 Brief description of manufacturing process (as appropriate) Letters of Authorization - (LoA)

8 i. LoA from manufacturer referencing their facility DMF #.ii. LoA from manufacturer referencing their container DMF #.Note: Glass requires less tests and documentation

FROM THE RESIN MANUFACTURER:-

9 LoA from resin manufacturer referencing their resin DMF # as used in themanufacture of the container

10 Obtain separate letters for each resin type used in different plasticcontainers

4




Packaging Components Description


Metal Caps orThermoplastic Closures


FROM THE GENERIC FIRM'S QC LAB:-

11 Testing Specifications or protocol and test results (CoA) of Genericpackaging Lab

12 CoA of closures from the QC Packaging Lab13 Batch Compliance Statement of applicants acceptance tests

FROM THE CLOSURE MANUFACTURERS :-

14 Closure Specifications (including)15 - drawings / diagrams with annotated dimensions16 - Tests performed on closure system to include USP <661> and <671>

n moisture vapor permeation17 - Certificate of Conformance meeting all USP XXIII

- Complies to 21 CFR requirements / Food Additives Regulations18 - Certificate of Analysis19 - DSC thermal analysis (for thermoplastic closure only)

Letters of Authorization20 i. LoA from manufacturer referencing their facility DMF #.21 ii. LoA from closure manufacturer referencing DMF # of cap

Statement of GMP compliance of manufacturer

FROM THE RESIN MANUFACTURER:- (Not required for metal closures)

22 i. LoA from (cap) resin manufacturer referring thermoplastic resin DMF #and Statement of GMP compliance of manufacturer

23 Obtain separate letters for each resin type used in thermoplastic closures

Note:Child Resistant Closures (CRCs) may consists of two parts made with differentHDPP/HDPE resins. Both inner (HDPP) and outer part (HDPE) resins need to betreated separately in the documentation requirements.

4






Inner closure liner



24 Testing Specifications or protocol and test results (CoA) of Genericpackaging Lab

25 CoA of liner from the QC Packaging Lab26 Batch Compliance Statement of applicants acceptance tests

FROM THE LINER MANUFACTURER:-

27 Liner Specifications (including);28 - drawings / diagrams with annotated dimensions29 - Tests performed on liner30 - Certificate of Conformance meeting all current USP requirements and

complies to 21 CFR requirements31 - Certificate of Analysis

LETTERS OF AUTHORIZATION:-

32 i. LoA from manufacturer referencing their facility DMF #.33 ii. LoA from liner manufacturer referencing DMF # of liner

STATEMENTS OF COMPLIANCE34 Statement of GMP compliance of liner manufacturer35 Statements of Compliance with Applicable Sections of the Indirect Food

Additive Regulations (21 CFR).

Note:Ø A change from one type of resin to another type - requires prior approval.Ø A change from one type of resin to the same type - prior approval not required.Ø Changing resins requires an equivalency protocol which demonstrates sameness.Ø For solid dosage forms only, The USP section <661> is in fact an existingcompendial interchangeability protocol for equivalent HDPE resins.

4






Foam SealsPressure sensitive, tamper resistant, adhesive seals

(data required for each container seal)Solid oral dosage forms.


36 Testing Specifications or protocol and test results (CoA) of Genericpackaging Lab.

37 CoA of adhesive seal from the QC Packaging Lab.38 Batch Compliance Statement of applicants acceptance tests

FROM THE ADHESIVE SEAL MANUFACTURERS :-

39 Adhesive seal Specifications (including)40 - Drawings / diagrams with annotated dimensions41 - Tests performed on adhesive seal42 - Complies to 21 CFR requirements43 - Certificate of Analysis

LETTERS OF AUTHORIZATION - (LOA)

44 LoA from seal manufacturer referencing their facility DMF #.45 LoA from manufacturer referencing their seal DMF #.

STATEMENTS OF COMPLIANCE46 Statement of GMP compliance of seal manufacturer47 Statements of Compliance with Applicable Sections of the Indirect Food


NOTE:Moisture permeability - USP <661>: Max 10mg/day/Liter.Container closing Torque - USP <671>: Should establish a good seal at targettorque.

4






Nozzles / Applicators

(required for Applicator/Nozzle )Topical Dosage Forms.

FROM THE GENERIC FIRM:

48 Testing Specifications or protocol and test results (CoA) of Genericpackaging Lab.

49 CoA from the QC Packaging Lab50 Batch Compliance Statement of applicants acceptance tests

FROM THE APPLICATOR MANUFACTURERS :-

51 Applicator/Nozzle Specifications (including)52 - Tests performed on Applicator/Nozzle53 - Compliance to USP requirements54 - Complies to 21 CFR requirements55 - Certificate of Analysis (include resin ID)

LETTERS OF AUTHORIZATION - (LOA)

LoA from Applicator/Nozzle manufacturer referencing their facility DMF #.56 LoA from manufacturer referencing their Applicator/Nozzle DMF #.

STATEMENTS OF COMPLIANCE57 Applicator/Nozzle manufacturer's: Statement of GMP Compliance58 Statements of Compliance with Applicable Sections of the Indirect Food






TABLE OF CONTENTS(Overall ANDA Guideline Requirements for this Section)

This Section Contains:◊ Package Characteristics for container-liner-closure systems

◊ Package Description concerning container-liner-closure systems

◊ Documents for container-liner-closure system include the following:

Ü Certificates of Analysis outlining the components used for packages containing;

Ü 00 / 000 cc Flexible Tube (HDPE nozzle)

Ü 00 / 000 cc HDPE (Bulk) Jar (HDPE cap with liner).

Ü Technical Specifications (Diagrams &Drawings) of each component.

Ü Certificates of Analysis of [Generic Company Name Inc./Ltd.] packages.

Ü DMF Referral Letters

◊ Statements of Compliance with applicable sections of the Indirect Food AdditiveRegulations (21 CFR).

◊ USP XXIII Testing Results of the closure system.

4





PACKAGE CHARACTERISTICS

[Generic name] SEMISOLID [USP] [000.0] mg /g. Lot: 000

Pivotal Lot

ITEM TYPE 1 TYPE 2 TYPE 3 TYPE 4

Containermanufacturer

Drug Plastics &Glass Co. Inc.




Container size 00 / 000cc round,HDPE JAR

00 / 000cc round,HDPE JAR

00 / 000cc HDPE/ COLLAPSIBLE TUBE

(coated metal)


(coated metal)Resin Type HDPE

Quantum LR-7340-43

HDPEQuantum LR-7340-

43


43


43

CapManufacturer

U.S. CAN(Penn-WheelingClosure Corp.)




11087 PE White Master

batch

White Ampacet11078 Polyethylene




Cap / NozzleType

HDPELDPE

HDPELDPE

HDPELDPE

HDPELDPE

Cap Size 00 / 00 mm 00 / 00 mm 00 / 00 mm 00 / 00 mm

Closure LinerFoam seal Mfg

Tekni-Plex Inc.Foamseal PS 22


- -

Inner linercomposition

TEKNISEAL RVT+ LF

TEKNISEAL X-14(polyethylene/Kraft

Paper laminate)

- -

CONTAINER Lot #00000CoA #0000

Lot #00000CoA #0000

Lot #00000CoA #0000

Lot #00000CoA #0000


Lot #00000CoA #0000

Lot #00000CoA #0000

Lot #00000CoA #0000

CAP Lot #00000CoA #0000

Lot #00000CoA #0000

Lot #00000CoA #0000

Lot #00000CoA #0000

Nozzle / Applicator Lot #00000CoA #0000

Lot #00000CoA #0000

Lot #00000CoA #0000

Lot #00000CoA #0000

LINER Lot #00000CoA #0000

Lot #00000CoA #0000

- -

SEAL Lot #00000 Lot #00000 CoA #00000 CoA #00000

CoA = Certificate of Analysis/Compliance





PACKAGING COMPONENT DESCRIPTION FORTHERMOPLASTIC CONTAINERS CONTAINING:

All container and closure systems are certified to comply with the indirectfood additive regulations (Parts 170-199) or are otherwise certified safefor use in contact with a drug product - generally accepted as safe(Appear in the 21 CFR GRAS List)

30 and 60 & 1000 Units

HDPE:Description White, Round HDPE Bottle with 29/33/53 mm/400 Neck Finish

CODE & Size Code 000 - Size: 30, 50, 750 cc

Manufacturer Drug Plastics & Glass Company, Inc., DMF # 1933

Resin used QUANTUM DMF # 885

Color Batch AMPACET 11078 PE, DMF # 8354

DMF (MFG) DMF [0000]

DMF (Item) DMF [0000]

LoA Month DD, YYYY

21 CFR Complies with Food Additives Regulations Part 170 -199

Documentation Relevant data copies of the manufacturers current DMF #[0000] (Type II) are attached for ease and simplicity of review.

General Tests &Assays

All relevant tests applicable to the container closure system asper table 14-A are performed by either the vendor orapplicant and supported in the documentation attached.

Stability Testing Where product stability testing is conducted referencing thisspecific item's code then all above specifications shall apply tothe container-closure item.

4





PACKAGING COMPONENT DESCRIPTION FORCLOSURES OF CONTAINERS CONTAINING:

BULK Units

CLOSURES

Description HDPE cap, 38 mm / 400 White, Unlined Polypropylene Cap withPressure Sensitive Inner Seal

CODE & Size Code 000 - 29/33 mm diameter

Fits Container Size 000 & 000 cc

Manufacturer Owens Brockway

Inner Liner None

Foam Seal Foamseal PS 22 - Pressure Sensitive, adhesive

DMF (MFG) DMF [0000]

DMF (Item) DMF DMF # 2229

LoA Month DD, YYYY











Bulk Containers

METAL SCREW CAP

Description 38/53 mm 400 White, Tin Plated Metal Screw Cap with PressureSensitive Inner Seal

CODE & Size Code 000 - Size: [38/53] mm diameter

Fits Container Size 000 & 000 mL

Manufacturer: U.S. CAN [Full address]

DMF (MFG) DMF #4162

DMF (Item) DMF #4162

LoA Month DD, YYYY






4






Bulk Containers

INNER CAP LINERInner Liner Tekniseal X-14(Polyethylene)

CODE & Size Code 000 - Size: [00] mm diameter

Manufacturer Tekni-Plex Inc.

DMF (MFG) DMF # 1378

DMF (Item) DMF # 1378

LoA Month DD, YYYY


CONTAINER FOAM SEALFoam Seal Foam seal PS 22 - Pressure Sensitive, adhesive

Manufacturer US CAN.

Size [00] mm diameter

DMF (Mfg) DMF # 1378

DMF (Item) DMF # 1378

LoA Month DD, YYYY









[Generic name] SEMISOLID [USP] [000.0] mg/g. Lot: 000

Collapsible Tubes

Description : [000] cc lined collapsible LD Tube with HDPE nozzle

Inner Coating : Epoxy Coat [0.0] mm thick

Length : [00] mm

Size : 000 & 000 g

Manufacturer : [Name].

Seal : Heat sealed or breaking inner seal

DMF of MNF : DMF [0000]

Product DMF : DMF [0000]

LoA : Month DD, YY

Extended Nozzle

Description: : [000] White, HDPE Nozzle

Size : [00] mm (length)

Fits Sizes : 000 & 000 mL

Manufacturer: : [Name]

DMF of MNF : DMF [0000]

Product DMF : DMF [0000]




Packaging Components DescriptionU.S. Pharmacopoeia / National Formulary

General Tests and Assays - Table 1

Ref.No

USP<No>

TITLE SUBTITLEGeneral Tests and Assays

1. <1> Injections

2. <87> In vitro Biological Reactivity Tests

3. <88> In vivo Biological Reactivity Tests

4. <161> Transfusion Transfusion and Infusion Assemblies

5. <381> Elastomeric closures for injections

6. nn Biological Test Procedures

7. nn Physiochemical Test Procedures

8. <601> Aerosols

9. <661> Containers

10. nn Light transmission

11. nn Chemical resistance - Glass Containers

12. nn Biological Tests - Plastic and others

13. nn Polymer

14. nn Physiochemical Test - Plastics

15. nn Polyethylene Containers

16. nn Polyethylene Terephthalate / Terephthalate G Bottles

17. nn Single Unit Containers & Unit Dose (Containers forNon-sterile solid & liquids dosage forms )

18. nn Customized Patient Medication Packages

19. <671> Containers Permeation - nn Multiple unit containers for capsulesand tablets

20. nn Permeation - nn Single unit containers and Unit dosefor capsules and tablets

21. <691> Cotton Cotton or Purified Rayon Monograph (withexclusions)

22. <771> Ophthalmic Ointments

23. <1151> Pharmaceutical Dosage Forms



Above - Table 1 contains all USP testing procedures described in the pharmacopoeia that impact onaspects of container closure systems. All components comply with the appropriate tests.



SECTION XIV SECTION 14

Finished Dosage Form Controls


14.1 Section Page and Title

State if drug product is:

q Compendial and test methods¡ used are USP XXIII

q Non-Compendial and test methods¡ are validated in-house methods.

q Non-Compendial and test methods¡ based on published analytical methods² and validated.

14.2 Certificate of Analysis of Pivotal Batch(es), including:-

q HPLC, TLC, GC, UV chromatograms and spectra for all pivotal strengths

q CoA for each strength of SEMISOLID [USP] + HPLC chromatograms

¡ Stability Indicating AssayImpurity Limit TestsUSP Monograph tests

² USPC Inc. Pharmacopeial ForumPublished Reference Works





This section contains:THE DRUG PRODUCT IS NON-COMPENDIAL.

Certificates of Analysis for the finished drug product [Generic name] SEMISOLID [000.0] mg/g (all strengths).

Copies of the test methods and method validations are enclosed in Sections XVI, for “Analytical Methods”.

These methods are used for release and stability purposes, assuring identity,strength, quality and purity of the finished drug product.

Note:Additionally, separately bound copies of all non-compendial methods have beenprovided in accordance with 21 CFR 314.50(e)(2)(i).

or

THE DRUG PRODUCT IS COMPENDIAL.

Certificates of Analysis for the finished drug product [Generic name] SEMISOLID [000.0] mg/g (all strengths).

The drug product is compendial. Copies of the stability indicating test methods andmethod validations are enclosed in Sections XVI, under “Analytical Methods”.

Compendial methods are used for release, assuring identity, strength, quality andpurity of the finished drug product on batch release.

Stability indicating test methods are used for stability, assuring identity, strength, andpurity of the finished drug product during the entire shelf life period of the drug.

Note:Additionally, separately bound copies of all non-compendial methods have beenprovided in accordance with 21 CFR 314.50(e)(2)(i).





SUMMARY OF CERTIFICATE OF ANALYSES AND ANALYTICAL SPECTRA :

Pivotal Batch C of A No.

Executed Lot

Pivotal Lot No: [000-01] [000.0] mg per g C 000-01

G C SPECTRAPivotal Lot No: [000-01] [000.0] mg per g C 000-01

UV SPECTRA


HPLC SPECTRA


TLCPivotal Lot No: [000-01] [000.0] mg per g C 000-01

(Labeled Photocopies of TLC plates provided)

NOTE: Attach summary and spectra for each of the pivotal lots and strengthsmanufactured. Above table represents one pivotal lot of each dosage strength.





SUMMARY OF ANALYTICAL METHODS AND METHOD NUMBERS:

Table details the analytical Control Methods used :

Analytical Method StabilityPURPOSES

QC ReleasePURPOSES

MethodValidation

Active Ingredient Not Applicable QC-021-00 SI -V -021-00

Finished ProductPhysical TESTS

SI-A22-00

Finished Product Assay / Impurities

SI-A23-00QC-025-00

SI -V -A23-00

Finished ProductMicrobial testing

SI-D24-00 SI -V -D24-00

- -

KEY

QC = A Quality Control Method that has been validated and based on the R&D validated method.

SI = A Stability Indicating Method that has been fully validated

A = An Assay Method

V = The full validation procedure and test results of a corresponding stability indicting method (Note: the same method number is used)

00 = The last two zeros (-00) indicated the editions number of the procedure - i.e. edition number three is written as '-03.'

Test methods for release and for stability purposes. The R&D analytical methods areused for product stability purposes.

The QC. testing methods which are based on the R&D methods are used for therelease of the raw material and the drug product.

QC Release and Stability testing use the same validated Analytical Method. ThusQC-025-00 is in fact, a combination of SI-A23-00 & SI-A24-00.


Edition Number:01

Effective Date: APPROVEDEd. Status :

NewDD/MM/YY _____________ __________ _______________ _________/________


24 VOLUME DRUG DEVELOPMENT SERIES: Sect: 15.1 ANDA ANDA Development

SECTION XV SECTION 15

Analytical MethodsTABLE OF CONTENTS(Overall ANDA Guideline Requirements for this Section).

Included in his section are the analytical methods, method validations and testspecifications and data for the drug substance [Generic name] and the drug product[Generic name] tablets [000]mg manufactured by the applicant. The methodologyincludes validated stability indicating analytical assay methods

State if drug substance and drug product is:q - Compendial and test methods used are USP XXIVq - Non-Compendial and test methods in-house and validated.q - US Non-Compendial test methods based on published reference works

and validated (e.g. Ph Eur / BP / Japan Pharm / DAB.)Active material15.1 Active Ingredient Test Method (QC Release method)15.2 Active Ingredient Test Method Validation (Stability Check method)In-process Material15.3 Final Blend Test MethodsFinished Product15.4 Finished Product Test Methods (QC Release method)

- physical tests- Chemical tests- microbiological tests - (where required)

[If compendial - methods are USP monograph]15.5 Finished Product Test Methods (Stability Check method)

- stability Indicating Test Method- impurity limit Test Method- dissolution Test Method

15.6 Finished Product Analytical Validation methodology.- Validation of Stability Indicating Assay- Validation of impurity limits- Validation of dissolution method.


Section XV.Analytical Methods (two additional separately bound copies if the drug substanceand/or drug product are not USP articles)

1. Methods for drug substancea. Method validationb. Test specifications and data (derived from bioequivalent batch lot)

2. Methods for drug producta. Method validationb. Test specifications and data (derived from bioequivalent batch lot)


Edition Number:01


NewDD/MM/YY _____________ __________ _______________ _________/________




Analytical Methods

Non Compendial USP materials.

The active drug substance, [Active Material], and the finished drug product[Generic name] [USP] [000.0]mg., are both non-compendial in the USPharmacopoeia. The active material is of compendial status in the BP and Ph. Eur.ý - US Pharmacopoeiaý - US Pharmacopoeial Forumþ - BP Pharmacopoeiaþ - Ph. Eur. Pharmacopoeiaþ - In-house Stability Indicting methods (based on BP Pharmacopoeia)

Drug Product analytical methods and stability indicating methodology are in-housebased on the current BP ; Ph. Eur. or US Pharmacopoeial Forum and have beenfully validated in-house.ý - US Pharmacopoeiaý - US Pharmacopoeial Forumþ - BP Pharmacopoeiaþ - Ph. Eur. Pharmacopoeiaþ - In-house Stability Indicting methods (based on BP Pharmacopoeia).

This analytical section contains:

• Active Ingredient Test Methods (ref. pages [00] to [00])

• Final Blend Test Methods (ref. pages [00] to [00])

• Finished Product Test Methods (Release) (ref. pages [00] to [00])

• Finished Product Test Methods (Stability) (ref. pages [00] to [00])

⇒ Assay/Impurities

⇒ Degradation Products Determination

⇒ Dissolution Test

⇒ Test of Appearance

• Finished Product Analytical Method Validation (ref. pages [00] to [00])

Note:

Additional separately bound copies are provided in accordance with 21 CFR314.50(e)(2)(i).


Edition Number:01


NewDD/MM/YY _____________ __________ _______________ _________/________




Analytical Methods

SUMMARY OF ANALYTICAL METHODS AND METHOD NUMBERS:

Analytical Method Method No.

Active Material

Stability Indicating Assay SI-1000-01

Impurity Limit tests SI-1000-01

Validation of Stability Indicating Assay SI-1000-01

In-process Material

Content Uniformity (on bulk material) SI-2000-01

Microbial Limit test (on bulk material)

Finished Product Release SI-4000-01

QC Release Assay SI-4000-01


Content Uniformity (on bulk material) SI-4000-01

Microbial Limit test (on bulk material)

Finished Product Stability Methods

Stability Indicating Assay SI-5000-01


Validation of Stability Indicating Assay SI-5000-01

Microbial Limit test SI-5000-01

Preservative Efficacy test SI-5000-01

(All Analytical Methods Placed Here)


Edition Number:01


NewDD/MM/YY _____________ __________ _______________ _________/________




Analytical Methods

(TYPICAL ANALYTICAL METHOD VALIDATION)1. PURPOSEThe purpose of this Standard Analytical Procedure is to demonstrate the procedurerequired to validate in-house HPLC analytical methods and to show that the methodsare stability-indicating. Methods based on the USP but modified for stabilityindicating test purposes require full in-house validation.This procedure ensures that the Product Development Process and ProcessQualification Batch analysis is based on a foundation of Good Laboratory Practiceusing validated test procedures.

2. RESPONSIBILITYThe Head of Analytical Development in coordination with the managers of QC andRegulatory Affairs at the proposed manufacturing site.

3. FREQUENCYFor each non-compendial analytical method intended for ANDA (or OTC ANDA)manufactured products.

For Stability-Indicating Assays and limit testing of impurities that may be based on compendial methods. Each Product strength will follow the full method validationprocedure.

4. PROCEDURE[a]. Method ValidationNon-compendial methods validation will follow the USP direction for parametersneeded for the validation of test methods.Typical parameters for validating assays and other non-compendial analyticalmethods designed for providing quantitative results shall include :

• Accuracy • Recovery • Precision ( System reproducibility, Method reproducibility ) • Specificity • Linearity • Range • Ruggedness (different analysts / days /different equipment models / columns)

[b]. Placebo Analysis.A mixture of non-actives (placebo) shall be prepared and subjected to analysis.No interfering peaks shall be observed in the graph of the placebo chromatogram.


Edition Number:01


NewDD/MM/YY _____________ __________ _______________ _________/________



[c]. The stability of the Standard solution is assessed by re-injection of thestandard solution after 24 x n hours (where n = number of days the Standard will beused).

Standard Preparation for AssayComparison of standard solutions for Assay of Active material, injected after onemonth and freshly prepared demonstrate that the standard solutions are stable anddoes not lose its quality after one month if refrigerated.

Standard Preparation for ImpurityComparison of standard solutions of Guanine, injected after one month and freshlyprepared demonstrate that the standard solutions are stable and does not lose itsquality after 1 month if refrigerated.

Name of standards Storage conditions Difference. relativeto freshly prepared

standard

[Active] 100% 4°C <2%

[Impurity] 100% 4°C <2%

Standard Solutions are stored at controlled temperatures and light conditions as perlabeling.

[d]. Stability Indicating Procedures.For the Stability Indicating Method, the product sample shall include forceddegradation by stressed analysis. Conditions of concentration and reaction timemay vary depending on the active drug substance and drug product e.g. :

• Oxidation - (H2O2 plus standing time).• Base Hydrolysis - (NaOH x N plus standing time).• Acid Hydrolysis - (HCl conc. plus standing time).• Sun light - (24 hours standing time).• Heat - (x degrees C).

Summary of Stability Indicating Results

Stressed Conditions Temp. Time Raw Material; Tablets

(°°C) (hr) RemainingSubstance.

(%)

Peak Purity,(Figure)

RemainingSubstance

(%)

PeakPurity,

(Figure)

Solution heating 90 12 100.2 pure 98 pure

Solid heating 160 2 101.3 pure 92 pure

Sunlight 765 w/m2 40 14 101.1 pure 84.8 pure

3,3N Sodium Hydroxide 70 10 99.8 pure 100.2 pure

10%Hydrogen Peroxide 37 3 77.5 pure 90.5 pure

5% Hydrochloric Acid Room 20 79.7 pure 78.6 pure


Edition Number:01


NewDD/MM/YY _____________ __________ _______________ _________/________



[e]Specificity and Suitability (Resolution and Tailing Factors).When a satisfactory separations of all the degradation peaks have been achievedthrough the forced degradation reactions, a Resolution Factor (according to theUSP requirements) between the main active peak and the nearest degradant peak iscalculated using the USP formula.A Tailing Factor (according to the USP formula) is calculated for the main activepeak.

[f] System Suitability Test

A mixture of [Active] AS. standard at the concentration about [0.1]mg/mL and of[Impurity] AS. standard at the concentration about [0.01]mg/mL according to MethodSI-1000 was prepared and injected into the HPLC system.

For chromatogram obtained the following values were calculated (according toUSP):

1. Relative Retention Time for [Impurity] peak

RRT = RT [Impurity] = 2.65 = 0.31 RT [Active] 8.45

2. Tailing factor for [Active] peak

T = W

2 =

94.2

= 1.1f0.05

f

The values depict the specificity of the method for resolution between the main peakand impurity peak. (values shown for demonstrations purposes).

Peak PurityThe photo diode-array is used for the evaluation of the stability indicating nature ofthe assay method number SI-1000 for [000]mg and [000]mg tablets using a Waters996™ Unit, controlled by the chromatography manager Millennium 2010™.

Peak purity and match results are reported as:

Purity Angle is a measure of spectral non-homogeneity across a peak - i.e. theweighed average of all Spectral Contrast Angles calculated by comparing all spectrain the integrated peak against the peak apex spectrum.

Purity Threshold is the sum of Noise Angle and Solvent Angle. It is the limit ofdetection of shape differences between two spectra.

Match Angle is a comparison of the spectrum at the peak apex against a libraryspectrum.

Match Threshold is the sum of the Match Noise Angle and Match Solvent Angle.

Noise Angle is a measure of spectral non-homogeneity caused by system noise.


Edition Number:01


NewDD/MM/YY _____________ __________ _______________ _________/________



Peak Purity (Cont.)Solvent Angle is a measure of spectral non-homogeneity caused by solventcomposition.It the purity angle is smaller than the purity threshold and the match angle is smallerthan the match threshold, this indicates that no significant differences betweenspectra are detected. There is no spectroscopic evidence for co-elution and thepeak is considered pure.

[f] Relative Retention Time of Main and Additional peaks.Each stressed analysis shall indicate the percentage by which the Main peak isdecreased as well as the RRT for any other Additional peaks.

If the RRT of an Additional peak corresponds to a known degradant/impurity etc. itshall be stated.The peak purity of the main peak shall be given for each stressed analysis (wherepossible).

[g]. Validation of limit testing for impurity methods shall include : * Specificity * Detection Limit (DL)

* Quantitation Limit (QL)

Detection Limit (DL)The detection limit of an individual analytical procedure is the lowest amount ofanalyte in a sample which can be detested but not necessary quantitated as anexact value.

Quantitation Limit (QL)The Quantitation limit of an individual analytical procedure is the lowestamount of analyte in a sample which can be quantitatively determined withsuitable precision and accuracy. Used in the determination of impurities and ordegradation products.

[h]. Contents of a typical HPLC Analytical Validation Protocol refer Method No. A-0340-01-1299


Edition Number:01


NewDD/MM/YY _____________ __________ _______________ _________/________



Validation of HPLC Analytical MethodMethod No: A-0340-01-1299

[1] Introduction - A brief description is given of the following parameters :

* Method and Edition # used * Batch # of samples tested (test the lowest and the highest label strength)* Type of detector used to analyze stressed samples* Stress testing of Standard solution to determine origin of Additional peaks.

[2] System Reproducibility - PrecisionTen replicate (single) injections of the standard solution at the nominalconcentration described in the method is performed and the RSD calculated. TheResults (sample # and peak areas) are tabulated. The Average Peak Area, SD andRSD are shown in the table. Target values for RSD = 0.5 to 1.0(Keep this standard solution for the stability of Standard Solutions - Point 9)

SYSTEM REPRODUCIBILITY

SAMPLE No. PEAK AREAS

1.2.3.4.5.6.7.8.9.

10.

Average Peak AreaStandard DeviationRelative StandardDeviation

=== 0.5 - 1.0


Edition Number:01


NewDD/MM/YY _____________ __________ _______________ _________/________



[3] Method Reproducibility - Precision

The full analytical method # is carried out and repeated Ten times on the finishedproduct (batch #) and the RSD is calculated. Two HPLC injections are performedper method assay and the peak areas are averaged. The Results (assay %) aretabulated. The Average Assay %, SD and RSD are calculated and shown in thetabulations. Target values for RSD = 1.5 to 3.0.

METHOD REPRODUCIBILITY

SAMPLE NoBatch No:

ASSAY %

123456789

10

Average Assay %Standard DeviationRelative Standard Deviation.

=== 1.5 - 3.0

[4] AccuracyThe Accuracy of an analytical procedure expresses the closeness of agreementbetween the true value and the value found.

Ten replicate (single) injections of the standard solution at the nominal concentrationof x mg/100 mL as described in the Analytical Method / Ed # [00] is made and thepercent deviation from the true values as determined from the linear regression lineis calculated.The Results (Peak areas and % accuracy) are tabulated.

The Mean, SD and C.of.V are shown in the tabulations


Edition Number:01


NewDD/MM/YY _____________ __________ _______________ _________/________



[4] Accuracy (continued).

A C C U R A C Y

INJECTIONNo

PEAKAREA

CALCULATEDCONC.

%ACCURACY

123456789

10

Mean (% Accuracy) =Standard Deviation =% Coef. of Variation =

[5] Recovery (Extraction time)

The extraction efficiency is demonstrated by varying the extraction time of preparedsample solutions as described in the analytical method #. Two HPLC injections areperformed per method assay and the peak areas are averaged. The extraction timesuitable to ensure complete extraction is highlighted.

Not less than three different extraction times are used namely 0.5 T, T and 1.5 T(where T is the extraction time of the method).


Edition Number:01


NewDD/MM/YY _____________ __________ _______________ _________/________



[5] Recovery (Extraction time - tabulations continued).

The Results (Extraction time and Assay %) are tabulated as shown.

RECOVERY - EXTRACTION

TIME IN MINUTESBatch No:

% ASSAY

0.5 TT

1.5 T

[6] Recovery (spiked placebo samples).

Five spiked admixtures of the active substance and the non-active vehicle (placebo)at concentrations of about 50 % to 150 % of the stated concentration required by theassay procedure is prepared and analyzed to show the percentage active recovery.Two HPLC injections are performed per method assay and the peak areas areaveraged.

The Results (Theoretical conc. Actual conc. and % recovery ) are tabulated.The Average Recovery, SD and the % Coefficient of Variation are given.


Edition Number:01


NewDD/MM/YY _____________ __________ _______________ _________/________



[6] Recovery (spiked placebo samples tables - continued).The recovery results are shown graphically (peak area Vs conc. (mg/100 mL).These results also show extraction method and detector linearity.

RECOVERYStandard solution mg/100mL Peak Area =

CONC.

Theoretical(mg/100ml)

PEAK AREA FOUND

CONC.FOUND

(mg/100ml)

PERCENTAGERECOVERY

5075

100125150

Mean (% Recovery) =Standard Deviation =% Coef of Variation =

The Linear Regression value, Slope and Y-Intercept are shown in the GRAPH.The placebo chromatogram (vehicle only) is shown to highlight the absence ofAdditional Peaks

[7] Linearity and range.The linearity on an analytical procedure is its ability (within a given range) to obtaintest results which are directly proportional to the concentration (amount) of theanalyte in the test sample.

Five Standard solutions in a concentration range of (about) 50 % to 150 % of thestated concentration required by the assay procedure are prepared and analyzed bythe stated method.

Two HPLC injections are performed per method assay and the peak areas areaveraged.


Edition Number:01


NewDD/MM/YY _____________ __________ _______________ _________/________



[7] Linearity and range - (continued).The Area count and concentration range is plotted. Linear regression analysis willdemonstrate the acceptability of the method for quantitative analysis over the fullspectrum of the concentration range. Detector linearity is demonstrated.

The Results (Range conc. and peak areas ) are tabulated.

LINEARITY AND RANGE

CONC. Batch No:

PEAK AREAS

50 %75 %

100 %125 %150 %

Linear RegressionY-Intercept

Slope

===

The results are shown graphically (peak area Vs range conc. (mg/100 mL).

GRAPH OF LINEARITY

Conc. mg/100mL

Peak Area

0

20000

40000

60000

80000

100000

120000

0 25 50 75 100 125 150


Edition Number:01


NewDD/MM/YY _____________ __________ _______________ _________/________



[8] RUGGEDNESS & Robustness.Ruggedness measures the lack of external influence on the test results whereasrobustness measures the lack of internal influences on the test results.

The Robustness of an analytical procedure is a measure of its capacity to remainunaffected by small but deliberate variations in method parameters and thusproviding an indication of its reliability normal usage.The method may be evaluated for specificity using two different columns.No differences in specificity, selectivity or column performance should be observed.

RobustnessRobustness determinations are essential when transferring analytical methods fromthe development laboratory to the commercial plant quality control laboratory.There may usually be a difference in columns or HPLC machine models used.Deliberate variations according to the following table were made to the criticalparameters of the method such as column, flow rate and concentration of [organicacid] in the mobile phase. Using the System Suitability solution and LOQ solution asthe Test Solutions the performance of the method was evaluated.

Column 1: Phenomenex Bondclone 10µ, C-18, 300 x 3.9mm (OOH-2117-CD)

Column 2: Waters µ-Bondapak 10µ, C-18, 300 x 3.9mm (27324)

C O N D I T I O N R E S U L T SCondition

No.Column Flow Rate

mL/minBuffer

Conc. (%)RRT Tf RSD

bet. LOQ of[Active]

RSDbet. LOQ of[Impurity]

1 1 2.5 0.1 0.3 1.1 <10 <10

2 1 2.2 0.1 0.3 1.1 <10 <10

3 1 2.8 0.1 0.3 1.1 <10 <10

4 1 2.5 0.15 0.3 1.1 <10 <10

5 2 2.5 0.1 0.3 1.1 <10 <10

Notes on different terms frequently used:

INTERMEDIATE PRECISION

The analytical variation expressed between laboratories on different days; withdifferent equipment; or different analysts is known as - intermediate precision.

REPRODUCIBILITY (INTRA-LAB)

This intra-laboratory precision or the precision between laboratories is known asreproducibility or more specifically - intra-laboratory reproducibility. Both the aboveare ruggedness - and a USP requirement.


Edition Number:01


NewDD/MM/YY _____________ __________ _______________ _________/________



[8] RUGGEDNESS & Robustness - (Tabulations - continued).

The Results (Average assay % for Analyst 1 and 2 ) are tabulated.

RUGGEDNESS

ANALYSTNo 1

%ASSAY

Column I

ANALYSTNo 2

%ASSAY

Column 2123456789

10

Mean (% Accuracy) =Standard Deviation =% Coef of Variation =

Robustness.The evaluation of robustness should be finalized at the end of thedevelopment phase - around the time of the process qualification lotmanufacture. The robustness evaluation should be developed with thecommercial laboratory equipment in mind. It should show the reliability ofan analysis with respect to deliberate variations in the method parameters

A consequence of robustness evaluation is that a series of systemsuitability parameters are established to ensure that the validity of theanalytical procedure is maintained whenever used.

Robustness is defined by both the USP and the ICH Tripartite guidelines as "ameasure of its capacity to remain unaffected by small but deliberate variations inmethod parameters and provides an indication of its reliability during normal use "Robustness is defined both in the USP and ICH, but is not required.


Edition Number:01


NewDD/MM/YY _____________ __________ _______________ _________/________



[9] Stability of Standard solutionsRe-chromatography of ten replicate single injections of the same standard solution(which have been allowed to stand for x hours ) against freshly prepared Standardsshowed no significant differences from the original results.

STABILITY OF STANDARD SOLUTIONS

mg/100mLInitial Analysis

(Date)

mg/100mLRepeat Analysis

2nd (Date)1 injection2 injection3 injection4 injection5 injection6 injection7 injection8 injection9 injection

10 injection

1 injection2 injection3 injection4 injection5 injection6 injection7 injection8 injection9 injection

10 injection

MeanStandard DeviationRelative Standard Dev.

=== NMT 2.0 %

[10] Typical Chromatograms.Representative chromatograms of the following traces are routinely provided:-

♦ System Suitability

♦ Standard Solution

♦ Drug Product

♦ placebo


Edition Number:01


NewDD/MM/YY _____________ __________ _______________ _________/________



Typical ChromatogramsWhen Representative Chromatograms are displayed - all peaks are LABELED withthe peak name and RRT.

Representative chromatogramDrug Product

[11] Conclusion.(Closing Statement)An appropriate conclusion should be given stating clearly that:“The method # IAG00-005 Ed. No [00] is shown to be accurate and precise forcarrying out assay analysis as part of the Assay and Stability Studies for the DrugProduct conforming to the formula as shown in Appendix 1”

[12] References and Appendixes.Acknowledgment to references as well as attachments such as the drug productformula are attached at the end of the validation protocol.

It is important to emphasize that analytical validation applies to a drug formula anda set manufacturing procedure. Extraneous peaks and processing stresses arespecific to a manufacturing procedure, equipment used and the nature of theexcipients.

References:1. "Validation of compendial methods" USP 23 <1225> USPC Rockville Maryland USA 1994.2. USP/NF XXIII USPC Rockville Maryland USA 1994.3. Scale up and Post approval Changes Manufacturing and Controls In vitro Dissolution and In Vivo

Bioequivalence Documentation CEDER 1995 (SUPAC)4. International Conference on Harmonization "Guidelines on validation of Analytical Procedures:

Definitions and Terminology; Federal Register (March 1, 1995.)5. ASTM Standard Guide For Conducting Ruggedness Tests E1169 American Society for testing

Materials Philadelphia 1989.6. G. Kateman and L. Buydens, The Ruggedness Test Quality Control in the Analytical chemistry

John Wiley and Sons NY 2nd Edition 1993, pp118 125.

Label the peakclearly

Name and Retentiontime (8.78 min)


Edition Number:01


NewDD/MM/YY _____________ __________ _______________ _________/________



NOTES



SECTION XVI SECTION 16

Stability of Finished Dosage Form


16.1 Section Page and Title.

16.2 Stability Protocol for Post Approval Production Batches (ANDA commitment)

16.3 Expiration Dating Period Statement

16.4 Package Configuration and sizes (largest and smallest) used in stability studies.

16.5 Stability Protocol used for Pivotal lot

16.6 Stability Reports indicating results of Pivotal lot from 3 months accelerated and controlled room temperature studies

16.7 Stability Data Summary Report (plus 0 and 12 week graphs).


Section XVI - Section 16.

Stability of Finished Dosage Form1. Protocol2. Post-approval commitments3. Expiration dating period4. Stability data submitted5. Stability-indicating test data of samples under various stress

conditions

4





This stability section contains:

♦ Stability protocol for post-approval production batches♦ Proposed expiration date and stability commitment - a signed commitment to

conduct long term stability studies as described in our stability protocol (ref. page[00 - 00])

♦ Summary of Stability summary - that addresses the details of our stabilityprogram for the finished project. This protocol includes container-closure system,storage conditions, methods and specifications , report format , batch size, datesof analysis and room temperature intervals. (ref. page [00 - 00])

♦ Stability reports containing data from 3 month accelerated and 6 monthscontrolled room temperature studies. (ref. page [00 - 00])

♦ Package Characteristic of pivotal batch. (ref. page [00 - 00])OVERVIEWStability testing is performed on the largest and smallest container-closure systemsproposed for marketing; i.e. in each material type, namely plastic (HDPE/HDPP),glass, or push-through blister packs.

When more than one closure for the same container material type (e.g. glass bottle)is used in the proposed marketing containers, the largest and smallest container-closure configuration is tested, - for both accelerated and long term studies.

In cases where plastic bottles of the same size range and shape are manufacturedfrom different thermoplastic resins, they exhibition different storage characteristicsand thus are considered as completely separate container-closure systems.

The expiration dating process starts between 21 to 30 days from the completion ofthe manufacturing of the pivotal batch and release by quality control.

This 21 to 30 day period is in keeping with the 1987 informal guidance documentwhich stipulates that stability testing should initiate at the time of release whichshould not itself exceed 30 days from the date of manufacture.

The example below for the following packaging configuration highlights the numberof stability tests needed. Tests may be reduced using a matrix stability protocol.

1. HDPP (smallest) container with plastic HDPE cap / nozzle2. HDPP (smallest) container with plastic HDPE cap / nozzle3. HDPP (largest) container with plastic HDPE cap / nozzle

When tested on ONE strength with 4 container-closure configuration at acceleratedand long term testing (2) will produce 8 separate stability protocolsCalculation.(4 container/sizes x [1 Strength] x 1 closures x [25–C+40–C] = 8 studies).

4





Proposed Expiration Dateand Stability Commitment

ll stability data support the proposed expiration period of 24 months when theproduct is stored at room temperatures. This conditional dating will be verified by

24 month room temperature studies which will be filed annual as the data becomesavailable, as per our commitment.

Stability commitmentLong term commercial stability studied in accordance with the approved stabilityprotocol shall be carried out by [Generic Company Name Inc./Ltd.] The stabilityresults of these studies shall be submitted in the routine annual ANDA Reports filedon the anniversary date of the submitted product or as specified by the FDA.

Extensions to the expiration date will be made via the annual ANDA Reports asacceptable long term stability data becomes available. The extension will be files inthe annual reports in accordance with 21 CFR 314.70 (d)(5)

Stability data will be submitted in the annual reports in accordance with 21 CFR314.70 (d)(6) or in a prior approval supplement in accordance with 21 CFR 314.70(b)(2), whichever is appropriate at the time of submission.

Rework procedures may be submitted for batches that fail to meet establishedspecifications. Prior to implementation, these procedures will be submitted in asupplement in accord with: 21 CFR 314.70 (b)(2)(x) on a lot by lot basis.[Generic Company Name Inc./Ltd.] commits to remove any batch promptly from themarket place any material falling outside the products check specifications.

BATCH ANALYSIS COMMITMENT

Where future batch analysis of 3 consecutive finished product lots indicate that thespecifications limits of the impurities/degradation products present in futurecommercial production need to be tightened then the stability specifications in thefinished product stability protocols will be amended appropriately.

The stability data of future batches will comply with the new specifications whereappropriate..

[Signature of Responsible Person]------------------------------------------------ -----------------------------------------[Name of Responsible Person] DateRegulatory Affairs Director

4

A




Stability of Finished Dosage FormStability Protocol for Post-approval Production Batches

[Generic name] SEMISOLID [USP] [000.0] mg per g. [Batch No: 00]

FINISHED PRODUCT STABILITY PROTOCOLPackage sizes: Smallest and largest containersStorage Conditions:Controlled Room Temperature: 25-30°C.Test Intervals: 0,3,6,9,12,18,24 and 36 months.Samples: First three marketable production batches and annual batch thereafter.Storage ConditionsAccelerated Temperature: 40°C / 75%RH.Test Intervals: 1, 2, 3 months.Samples: To be submitted as appropriate in supplements to the approvedapplication

Stability Testing.Test parameters will include:

TEST PROCEDURE TEST METHOD& ED. NUMBER

SPECIFICATION

1 Appearance SI-5-000-01 Conforms

2 pH SI-5-000-01 NLT 0.0 NMT 0.0

3 Assay (Preservative)[Only where necessary]

SI-5-000-01 50.0 - 105.0% of labeled amountTo (annually) and End of Study

4 Assay Active material SI-5-000-01 90.0 - 110.0% of labeled amount

IMPURITIES / DEGRADATION PRODUCTS

5 - Each Individual- Any other Individual- Total:

SI-5-000-01SI-5-000-01SI-5-000-01

NMT 0.5% of the labeled amountNMT 0.5% of the labeled amountNMT 2.0% of the labeled amount

6 Microbial Limit Test SI-5-000-01 Meets USP SpecificationsTo (annually) and End of Study

7 Preservative Efficacy SI-5-000-01 Meets USP SpecificationsTo (annually) and End of Study

Report FormatResults will be tabulated in the format of the Stability Report Form:

1) Product Name, and Strength2) Batch Number and Batch size3) Storage Conditions and Intervals 4) Container/Closure Systems - Description5) Inventory Control Number of (4)6) Fill Size and No of units on stability7) Batch Manufacturing Date8) Batch Packaging Date

9) Stability Start Date10) Manufacturing Site11) Manufacturer of Bulk Drug12) Inventory Control Number of (11)13) Manufacturer of Container/Closure14) Formulation15) Data profile16) Methodology and Specifications





SUMMARY OF STABILITY STUDIESStability Data OverviewThe 3 months accelerated (40° ±2°C / 75 RH ±5% ) and 6 months room temperature(25° ±2°C / 60 RH ±5%) stability data in all container-closure systems were examinedfor Lots #[000] and Lots #[000] of [Generic Drug name] [USP] [00.0] mg.Labeled chromatograms for the end 12 week period are included. (ref. page [00 -00])

The data indicate that the formulation is stable, with no observed degradationpeaks, under test conditions. Samples were stored for testing in their proposedmarket container/closure systems.

The stability results indicate that the formulation is stable, with no observeddegradation, under the tested conditions. No significant change in either chemicalor physical attributes was noted in any sample under any of the storage conditions.

This stability data supports the proposed expiry period of the product of 2 years atroom temperature as there was no significant changes in either the physicalchemical, or microbiological specifications in any samples evaluated after theexposed storage test conditions.

The attached tables and graphs are summaries of the results for the parametersused to establish the stability profile of [Generic Drug name] [USP] [00.0] mg. (ref.page [00 - 00])

The attached tables and graphs are summaries of the results for the parametersused to establish the stability profile of [Generic Drug name] [USP] [00.0] mg.Included, are assay chromatogram spectra of the stability tests for zero time (T0) andthe three (3) months accelerated test conditions.[Generic Drug name] [USP] [00.0]mg were stored at accelerated conditions (40°±2°C / 75% RH ± 5%) and at room temperature (25° ±2°C/ 60% RH ±5%) in theproposed market container/closure system.

Where PRODUCTS fail the accelerated testing, Intermediate testing is performedaccording to the following specification.

Intermediate testing 0,1,2,3,6,9 and30±2°C/60±5%RH 12 months

This stability data supports the proposed expiry period of the product of 2 years atroom temperature as there was no significant changes in either the physicalchemical, or microbiological specifications in any samples evaluated after theexposed storage test conditions.

Thus stability data generated support the proposed expiration period of 2 yearswhen the product is stored at the defined room temperatures.

4





SUMMARY OF STABILITY STUDY RESULTS.

HDPE Container Closure liner system 25°C 60%RH 40°C 75%RH

Container Size (cc) Ü Smallest Largest Smallest Largest

000 mL HDPE Tube with (HDPP Cap) þþ þþ þþ þþ

000 mL HDPE Container with (HDPP Cap) þþ þþ þþ þþ

Glass Container Closure liner system

ýý ýý

ýý ýý

ýý ýý

ýý ýý

Bulk Packaging

ýý ýý

Number of Temperature/RH Levels 2

Number of Dosage Strengths 1

Number of Container Closure Sizes 4

Number of Resins present in Containers 1

Number of Closures 1

Number of Resins present in Closures 1

Number of Stability Studies Performed 8

Number of resins used in the HDPE containers = one resin from same supplier.




Stability of Finished Dosage FormSTABILITY REPORT

1 Product name, dosage form and strength. [Generic name] [000.0] mg./g2 Fill size 00 cc SEMISOLID [USP]3 Site of Manufacture NJ MNF SITE4 Batch or lot number 0025 Batch size (type) 000 Kg6 Batch manufacturing Date and Packaging Date Month DD, YY / Month DD YY7 Manufacturer of Active Material (approved supplier) LEK Chemical Co. dd8 Date placed on stability Month DD, YY9 Batch number or receiving number of Active Material LK 232310 Full details of container/closure system (type, material, resin) 80cc HDPE (LR-7340-43)

HDPP white cap (resin LR-7340-43)11 Goods Receiving number of container-liner GRN 96-2-02234 (body)

Goods Receiving number of closure GRN 96-2-02237 (cap) 12 Manufacturer of container/closure Wheeler Cap Co PA USA.13 Objective of the stability program þ Pivotal Batch14 Site where stability test conducted US PA MAN Site15 Number of units to be sent for testing in each time interval 2 x 80cc16 Analytical method number and Edition Number for each stability indicating testS-I 555-03 / S-I 1234 Ed . 0317 Stability specifications indicating names of test required. Tabulated18 Number of packages placed on stability 7019 Testing intervals required 0, 1, 2, 3 months

20 Stability storage conditions 40 degrees C / 75% RH

Stability Parameters

Storage Period

Date ofAnalysis

ContentsAppearance

ASSAY Percentage

Preservative Efficacy Microbial Limits pHTest

SPECIFIC-ATIONS

Months DescriptionCOLOR

90.0 % -110.0%

Preservative Efficacy Microbial LimitsTest

Method # S-I 552 -02 S-I 555 -03

0 6/6/97 conforms 100.8 Meets Specification Conforms Conforms

1 5/7/97 conforms 101.4 - Conforms Conforms

2 7/8/97 conforms 100.3 - Conforms Conforms


21. Product Formula On Stability (Formula No: S000).

1. Miconazole USP Micronized2. Pegoxol 7 Stearate [Tefose 63™]3. Heavy Mineral OIL NF4. Benzoic Acid USP5. Butylated Hydroxyanizole6. Peglico 5 Oleate [LABRAFIL M 1944™]7. Edetate Disodium USP8. Purified Water USP




Stability of Finished Dosage FormSTABILITY REPORT1 Product name, dosage form and strength. [Generic name] [000.0] mg/g. 2 Fill size 00 cc SEMISOLID [USP]3 Site of Manufacture NJ MNF SITE4 Batch or lot number P-54325 Batch size (type) 000 Kg6 Batch manufacturing Date and Packaging Date May 22, 1996 / May 28, 19967 Manufacturer of Active Material (approved supplier) LEK Chemical Co. dd8 Date placed on stability June 15, 19969 Batch number or receiving number of Active Material LK 232310 Full details of container/closure system (type, material, resin) 80cc HDPE (LR-7340-43)

HDPP white cap (resin LR-7340-43)11 Goods Receiving number of container-liner GRN 96-2-02234 (body)

Goods Receiving number of closure GRN 96-2-02237 (cap) 12 Manufacturer of container/closure Wheeler Cap Co PA USA.13 Objective of the stability program þ Pivotal Batch14 Site where stability test conducted US PA MNF Site15 Number of units to be sent for testing in each time interval 2 x 80cc16 Analytical method number and Edition Number for each stability indicating testS-I 555-03 / S-I 1234 Ed . 0317 Stability specifications indicating names of test required. Tabulated18 Number of packages placed on stability 7019 Testing intervals required 0; 3; 6; 12; 18; 24; 36; months

20 Stability storage conditions 25 degrees C / 60% RH

Stability Parameters

Storage Period

Date ofAnalysis

ContentsAppearance

ASSAY Percentage

SPECIFIC-ATIONS

Months DescriptionCOLOR

90.0 % -110.0%

Preservative Efficacy Microbial Limits pHTest

Method # S-I 000-02 S-I 000 -03 S-I 000 -03 S-I 000 -03 S-I 000 -03


3 5/9/97 conforms 99.9 - - Conforms






36 6/3/00

21. Product Formula On Stability (Formula No: S000).

1. Miconazole USP Micronized2. Pegoxol 7 Stearate [Tefose 63™]3. Heavy Mineral OIL NF4. Benzoic Acid USP5. Butylated Hydroxyanizole6. Peglico 5 Oleate [LABRAFIL M 1944™]7. Edetate Disodium USP8. Purified Water USP




Stability of Finished Dosage FormPACKAGE CHARACTERISTICS

[Generic name] SEMISOLID [USP] [000.0] mg per g. [Batch No: 00]

Pivotal Lot Packaging Material Characteristics

ITEM TYPE 1 TYPE 2 TYPE 3 TYPE 4

Containermanufacturer





Container size 00 / 000cc round,HDPE JAR

00 / 000cc round,HDPE JAR


(coated metal)


(coated metal)Resin Type HDPE

Quantum LR-7340-43


43


43


43

CapManufacturer





11087 PE White Master

batch





Cap / NozzleType

HDPELDPE

HDPELDPE

HDPELDPE

HDPELDPE

Cap Size 00 / 00 mm 00 / 00 mm 00 / 00 mm 00 / 00 mm

Closure LinerFoam seal Mfg



- -

Inner linercomposition

TEKNISEAL RVT+ LF

TEKNISEAL X-14(polyethylene/Kraft

Paper laminate)

- -


Lot #00000CoA #0000

Lot #00000CoA #0000

Lot #00000CoA #0000


Lot #00000CoA #0000

Lot #00000CoA #0000

Lot #00000CoA #0000

CAP Lot #00000CoA #0000

Lot #00000CoA #0000

Lot #00000CoA #0000

Lot #00000CoA #0000

Nozzle / Applicator Lot #00000CoA #0000

Lot #00000CoA #0000

Lot #00000CoA #0000

Lot #00000CoA #0000

LINER Lot #00000CoA #0000

Lot #00000CoA #0000

- -

SEAL Lot #00000 Lot #00000 CoA #00000 CoA #00000

CoA = Certificate of Analysis/Compliance



NOTES



SECTION XVII SECTION 17

Reserved


17.1 RESERVED

This section is reserved:

ELECTRONIC FORMATTED ANDAsProposed use is anticipated for electronic formatted ANDAs

4



SECTION XVII SECTION 17

RESERVED

THIS SECTION HAS BEEN RESERVED FOR FUTURE USE.

ELECTRONIC FORMATTED ANDAsProposed use is anticipated for electronic formatted ANDAs

4



SECTION XVIII SECTION 18

Samples of Drug/Article Components



18.2 Statement on Sample Submission Procedures to FDA on request

18.3 Drug substance

18.4 Finished drug product

18.5 Reference Standards with appropriate identification, graphs and spectra


Section XVIII.

Samples (§ 3l4.94(a)(l0)). Sample availability and identification of:1. Drug substance2. Finished dosage form

4



SECTION XVIII SECTION 18

Samples of Drug/Article Components

SAMPLES OF THE

DRUG AND ARTICLESUSED AS COMPONENTS

21 CFR Section 314.50 (e) (1).

[Generic Company Name Inc./Ltd.] shall submit samples of the drugsubstance or the finished drug product or otherwise make such samples FDA,in accordance with their instructions and requirements pertaining to 21 CFRSection: 314.50 (e) (1).

Furthermore the [Generic Company Name Inc./Ltd.] shall submit appropriateREFERENCE STANDARDS with appropriate identification, graphs and spectraas required.

[Signature of Responsible Person]__________________________ ___________________[Name of Responsible Person] Date

Director Quality Assurance UnitPharmaceutical Manufacturing Division[Generic Company Name Inc. Ltd.]

4



SECTION XIX SECTION 19

Environmental Impact Analysis Reports



20.2 Environmental Exclusion Assessment

- Development Site

- Manufacturing Site

20.3 Applicable Environmental Laws (National / State / Local /Foreign)

- Development Site


- Contract Manufacturers

20.4 Site Environmental Certification

- Development Site



20.5 Statement on Environmental Compliance

- Development Site



20.6 Commercial Plant Manager and QA Director Signatures.

FDA's Published January 1999 ANDA Guideline requirements:-

1. Environmental Consideration: Environmental Assessment (EA)or

2. Claim of Categorical Exclusion (§ 3l4.94(a)(9))

4






♦ Requests for Categorical Exclusion

♦ ♦ Environmental Regulations Compliance Certification

♦ ♦ Environmental Regulations Compliance Certification (Foreign Firms)

♦ Site Environmental Certification (USA)

OVERVIEWThis section is used for clarifying the various ENVIRONMENTAL PROTECTIONREQUIREMENTS that apply to the development and the manufacturingenvironment.

Note:-Where the development and/or the manufacturing of the drug product is performedin a foreign country, the applicable National Environmental laws of the country needto be closely observed. Statements of Environmental Compliance with respect to:-

1. Toxic waste2. Waste disposal3. Environmental Compliance Laws

need to be addressed with appropriate signed certification by senior responsiblepersonnel.

The FDA needs to see that there was no infringement of the local countriesEnvironment and Waste Management laws in BOTH the development andmanufacture of the drug product or the drug's Active Ingredient.

4





REQUEST FOR CATEGORICAL EXCLUSION FROM REQUIREMENTS OF AN

ENVIRONMENTAL ASSESSMENT, 21 CFR 25.31(a).

[Generic Company Name Inc./Ltd.] hereby requests a categorical exclusion [inaccord with 21 CFR 25.23(c) and 21 CFR 25.24(c)(1)] from the requirement ofan Environmental Assessment Statement [21 CFR 25.31(a)].

This request is based on two facts:

1. The finished drug product which is the subject of the Abbreviated New DrugApplication will not be administered at higher dosage levels, for longerduration, or for different indications than previously in effect for the listed drugproduct (RLD) as stated more fully in section IV of this application.

2. Data available to the Agency does not establish that, at the expected level ofexposure, the substance may be toxic to organisms in the environment.

On the basis of the forgoing statements [Generic Company NameInc./Ltd.] submits that an Environmental Impact Analysis Statement is notrequired with this application and, therefore requests that it becategorically excluded from the requirements to submit an EnvironmentalImpact Analysis.


___________________________________ _________________[Name of Responsible Person] DateDirector Pharmaceutical Research & DevelopmentPharmaceutical Division[Generic Company Name Inc./Ltd.]





STATEMENT OF ENVIRONMENTALCOMPLIANCE

The undersigned hereby certifies that [Generic Company Name Inc./Ltd.] operatesits [Address] manufacturing facility in compliance with all local and nationalenvironmental laws and with the emission requirements set forth in all permits. Theundersigned further certifies that the approval and subsequent increase inproduction at the facility is not expected to affect compliance with current emissionrequirements or compliance with environmental laws.


Plant ManagerPharmaceutical Manufacturing Division[Generic Company Name Inc. Ltd.]







STATEMENT OF ENVIRONMENTALCOMPLIANCE

FOREIGN SITEDevelopment and manufacturing

The undersigned hereby certifies that [Generic Company Name Inc./Ltd.] operatesa certified waste disposal program its [Address] manufacturing facility which is infull compliance with all Local, State and National environmental laws and with theemission requirements set forth in all required permits.

The undersigned further certifies that the approval and subsequent increase inproduction at the facility is not expected to affect compliance with current emissionrequirements or compliance with environmental laws.




Director Quality Assurance UnitPharmaceutical Manufacturing Division[Generic Company Name Inc. Ltd. ]





Site EnvironmentalCertification

The undersigned hereby certifies that [Generic Company Name Inc. / Ltd.].maintains compliance with all appropriate Federal, Sate and Local environmentallaws and regulations in the distribution of [Generic name] Tablets [USP] [000.0] mg.





333



SECTION XX SECTION 20

Generic Drug Enforcement Act


19.1 Section Page and Title and Color Tag

19.2 Generic Drug Enforcement Act

19.3 U.S. Agent Letter of Authorization


1. Generic Drug Enforcement Act

2. U.S. Agent - Letter of Authorization

4




Generic Drug Enforcement Act - 1992Applicant or Agent Letterhead

STATEMENTWhere Company has NO previous convictions

AND does not use a debarred person in connection with the ANDA



n behalf of [Generic Company Name's Inc. / Ltd.], the applicant, I herebycertify, pursuant to Section 2(k) Generic Drug Enforcement Act of 1992, 21 USC

335a (k), that the applicant has not used, is not using and will not in the future use inany capacity the services of any person who has been debarred pursuant to Section2 (a) and or Section 2 (b) Generic Drug Enforcement Act of 1992, 21 USC 335a (a)and/or (b), in connection with this application.

Applicant further certifies that there have been no conviction of applicant for any ofthe types of crimes set forth in Section 2(a) and Section 2(b) of the Generic DrugEnforcement Act of 1992, 21 USC 335a (a) and/or (b), within the five years prior tothe date of this certification, nor has any person affiliated with the applicant, who isresponsible in whole or in part, for the development or the submission of thisapplication been convicted of any crime of the type listed in Section 2(a) and Section2(b) of the Generic Drug Enforcement Act of 1992, 21 USC 335a (a) and/or (b),within the five years prior to the date of this certification.



[Signature of Responsible Person]__________________________ ______________________[Name of Responsible Person] Date

Director Quality Assurance UnitPharmaceutical Manufacturing Division[Generic Company Name Inc. Ltd. ]

O




Generic Drug Enforcement Act - 1992Applicant or Agent Letterhead

STATEMENTWhere Company has a previous conviction

but does not use a debarred person in connection with the ANDA.



n behalf of [Generic Company Name's Inc. / Ltd.], the applicant, I herebycertify, pursuant to Section 2(k) Generic Drug Enforcement Act of 1992, 21 USC

335a (k), that the applicant has not used, is not using and will not in the future use inany capacity the services of any person who has been debarred pursuant to Section2 (a) and or Section 2 (b) Generic Drug Enforcement Act of 1992, 21 USC 335a (a)and/or (b), in connection with this application.

Applicant further certifies that during the previous five years it has sustained thefollowing conviction for the types of offenses as set forth in Section 2(a) and Section2(b) of the Generic Drug Enforcement Act of 1992, 21 USC 335a (a) and/or (b),

Date of Conviction MM/DD/YYNature of Conviction Conviction on six counts of fraudulent documentation

pertaining to stability reports.

To the best of [Generic Company Name's Inc. / Ltd.] knowledge no personaffiliated with the applicant, who is responsible in whole or in part, for thedevelopment or the submission of this application has been convicted of any offenceof the type listed in Section 2(a) and Section 2(b) of the Generic Drug EnforcementAct of 1992, 21 USC 335a (a) and/or (b), within the five years prior to the date of thiscertification.



O




Letter of Authorization - US Agent

[PRINTED ON US APPOINTED AGENTS LETTERHEAD]

n behalf of [Generic Company Name's Inc. / Ltd.], I, [US APPOINTEDApplicant's Name] hereby certify, that [Applicant Company Name Inc. /

Ltd.] has been duly appointed as representative applicant for the submission of thethis ANDA and that the said applicant shall be the responsible person for all futurecommunications with the relevant agencies in connection with matters pertaining tothis application.


------------------------------------------------ -----------------------------------------[Name of Responsible Person] Date

US APPOINTED APPLICANT[Applicant Company Name Inc. / Ltd.]

[Applicant Company Site Address]

Full Site Address

[Applicant Company Contact Numbers]Contact Person. Responsibility. Tel. Fax.

Director ofRegistrationQuality AssuranceDirector

4

O


HANDBOOK OF GENERIC DRUG DEVELOPMENT Sect: 21. 1 Topical SEMISOLID.

SECTION XXI SECTION 21

Additional Information

OVERVIEWhis section is used for clarifying the various ADDITIONAL DATAREQUIREMENTS that may apply to the development and the manufacturingprocedures of this application.

Note:-Where the manufacturing of the drug product may require a rework procedure thedata validating the process step is summarized in this section. All necessary data ispresented that indicates no significant change in the overall drug specifications bothat product release and during the overall shelf life period claimed for the drug.

Steps that do not require support data are minor process procedures; such as fluidbed drying operations that may require additional drying to reach the required targetmoisture content (LOD %) of the granule or additional bulk mixing or homogenizationin liquids and semisolids. These conditional procedures are highlighted as standardinstructions in the manufacturing method or manufacturing instructions.

This section is also useful to tabulate Drug Master File (DMF) numbers and listLetters of Access (LOA) to various DMFs as referenced in the Application.

LOA letters should be clear copies and display recent dates with correct vendornames and addresses - especially if there has been a name or site change in thevendor's organization.

(Cut and paste where required)

T




Additional Information


21.1 Outline of manufacturing re-work study21.2 Table of DMF Numbers (with LOA dates)

Special Note:DMF numbers are required for active / excipient materials such as.• Active material• Specific Excipients• Capsules (Hard Gelatin)• Film coating color premixes.Colors/dyes (require US Certification.)

DMF numbers are required for container/closure materials.Primary Material in direct contact with the drug product e.g.• Plastic containers• Plastic / Metal caps• Plastic / Metal closures• Plastic liners / laminates• Plastic seals (Foam seals / tamper evident seals)• Plastic application nozzles / integral measuring cups(Glass bottles are exempt from a DMF number)

Product DMF numbers are required for container closure material that is a;Secondary Material in indirect contact or during use of the drug product e.g.• Inner Liners• Closure seals• Epoxy Coated Liners (tubes)• Foam Seals• Cotton Wool (solid dosage forms only.)• Silica gel drying agent in plastic containers (solid dosage forms only.)• Measuring caps as an integral part of closure system.

MNF DMFsManufacturing DMF numbers are required for the manufacturing facility supplyingthe raw material.

LOAsLetters of Access (recent date and two copies is essential) are required for allreferenced DMF numbers.




Additional InformationSUMMARY OF DMF NUMBERS USED IN THIS APPLICATION:

RAW MATERIAL / COMPONENT DMF NO.

ACTIVE MATERIAL(S)

Active material used for Biostudy and Pivotal DMF

Alternative Supplier DMF

Alternative Supplier DMF

NON ACTIVE MATERIALS

Non-compendial Excipient I DMF

Non-compendial Excipient II DMF

Color / Pigment (US Certification) Cert.

Color / Pigment (US Certification) Cert.

Special Ingredients DMF

Special Ingredients DMF

CONTAINER-CLOSURES

HDPE / LDPE Container (rigid / collapsible) DMFHDPE / LDPE Container (rigid / collapsible) DMFHDPE Cap DMFROPP Cap DMFMetal Cap DMFCap liner DMF

Adhesive Tamper evident inner-seal DMFSpecial delivery nozzles or applicators / droppers DMF

THERMOPLASTIC RESINS AND MASTER BATCH DYES

Resin No [001] DMF

Resin No [002] DMF

Resin No [003] DMF

Master Batch White DMF

Master Batch color DMF




Additional InformationSUMMARY OF LOA LETTERS BY DATE AS USED IN THIS APPLICATION:

RAW MATERIAL / COMPONENT LOA DATE.

ACTIVE MATERIAL(S)

Active material used for Biostudy and Pivotal LOAAlternative Supplier LOA

NON ACTIVE MATERIALS

Color / Pigment (US Certification) Cert.Color / Pigment (US Certification) Cert.Special Ingredients LOA

CONTAINER-CLOSURESHDPE / LDPE Container (rigid / collapsible) LOA

HDPE / LDPE Container (rigid / collapsible) LOA

HDPE Cap LOA

ROPP Cap LOA

Metal Cap LOA

Cap liner LOA

Adhesive Tamper evident inner-seal / Foam seals LOA

Special delivery nozzles or applicators / droppers LOA

THERMOPLASTIC RESINS AND MASTER BATCH DYES

Resin No [123456] of THERMOPLASTIC container DMF LOA

Resin No [12345] of Cap DMF LOA

Resin No [1234] of CRC OUTER component1 DMF LOA

Resin No [123] of CRC INNER component1 DMF LOA

Master Batch White LOA

Master Batch color LOA

Resin No [001] LOA

Resin No [002] LOA

Resin No [003] LOA

Master Batch White LOA

Master Batch color LOA

No LOA date greater than two years. Change in Ownership show new DMF Holder.1 Note: Child Resistant Closures consist of both an inner and outer component.



SECTION XXII SECTION 22

Sterilization Assurance


This section applies to sterile processes:

Sterile Manufacturing Processes OnlyCopies of the original batch manufacturing instructions in the language of originq Chinese q Dutch q French q Hebrew q Italian q Polish q Portugueseq Spanish q _________


Section XXII.

Sterilization Assurance Information and Data

Note: This section can be provided as a separate volume for ease of review. If themicrobiology section is in a separate volume, please provide copies of the indicatedinformation that may be in other sections of the application instead of pagereferences.1. General Information

a. Copy of cover letter (or page reference)

b. Label/package insert copy (or page reference)

c. Summary of manufacturing process including components and compositionstatement (or page reference)

d. Copies of pages from completed batch production record containing ¯ holding times, ¯ filtration integrity testing ¯ sterilization records (or page reference)

NOTE:-Follow the portions of guidance for industry on Submission of Documentation forSterilization Process Validation in Applications for Human and Veterinary DrugProducts that apply to the process in the application.

4


24 VOLUME DRUG DEVELOPMENT SERIES ANDA DEVELOPMENT

Do's and Don'ts13 Commandments

when Preparing an Application.

1. þ The less you make the reviewer work the sooner you get the application!

2. þ Make it really easy for agency reviewers to review your work.

3. þ Prepare the applications so that you drag the reviewer through it.

4. þ Don't challenge the FDA reviewer to think deeply.

5. þ Don't make them look for a copy of the Orange Book.

6. þ Don't make them go and find the suitability petition letter.

7. þ Do include every DMF # and GMP certification that you refer to.

8. þ Do prepare a detailed narrative where ever possible to give a quick overview of what they can expect. Write confirmation narrative letters on all protocol discussions.

9. þ Do make your narratives reader friendly - take your time writing them.

10. þ Don't exclude and executive summary just because its not a statutory requirement - they really help to get the message across.

11. þ Do layout and assemble your application so that the reviewer can cruise though it by making it a real joy to read.

12. þ Supply a PDF copy on CD ROM of the full application.

13. þ Do use the KISS principle - ' Keep it Simple Scientist '.



I n t e r n a t i o n a l A s s o c i a t i o n

Drug20××ØØ00ManufacturersHigh Quality Low Cost Drug Development & Manufacturing Excellence World Wide

I n n o v a t i v e & G e n e r i c

HANDBOOK OFDRUG DEVELOPMENT

SeriesPart I - Drug DevelopmentPart I - Drug Development

Part II - US Type Part II - US Type CMCs & EC DOSSIERSCMCs & EC DOSSIERS

USUS

CHEMISTRY MANUFACTURING CONTROLCHEMISTRY MANUFACTURING CONTROL

Know How TechnologyKnow How Technology

&&

EUEU

DOSSIERSDOSSIERS

Know How TechnologyKnow How Technology



I n t e r n a t i o n a l A s s o c i a t i o n

Drug20××ØØ00ManufacturersHigh Quality Cost Effective Drug Development & Manufacturing Excellence World Wide

I n n o v a t i v e & G e n e r i c

HANDBOOK of DRUG DEVELOPMENT+120 Title Specific Series

Part I - Drug DevelopmentPart I - Drug DevelopmentPart II - US Type Part II - US Type CMCs or EC DOSSIERSCMCs or EC DOSSIERS

Generic Development ISSN Series number 0793 7407Generic Development ISSN Series number 0793 7792 - Electronic Issue (Disk/CD ROM)

The follow HBGD HANDBOOKS KNOW-HOW SERIES are available in the mostcommon dosage forms namely solid, semisolid and liquid dosage forms. Thepresentation of the actual data is based on manufactured production batches andthe format of all sections is similar to the data in the standard ANDA.

Drug Development Series Form Strength Volume PartAlendronate Sodium Tablets 5 - 10 mg Volume II 1 & 2Alendronate Sodium Tablets 40 mg Volume II 1 & 2Amitriphyline HCl Tablets 10 mg Volume II 1 & 2Azithromycin Suspension 200 mg Volume II 1 & 2Azithromycin Capsules 250 /600 mg Volume II 1 & 2Azithromycin Tablets 600 mg Volume II 1 & 2Atenolol EU Tablets 50 /100 mg Volume II 1 & 2Atenolol US Tablets 50 /100 mg Volume II 1 & 2Amoxicillin Capsules 250/500mg Volume II 1 & 2Bromhexine Hydrochloride Tablets 8mg Volume II 1 & 2Bromhexine Hydrochloride Syrup 8mg Volume II 1 & 2Bromocriptine Mesylate Tablets 2.5mg Volume II 1 & 2Bupropion Tablets 75.0/100 mg Volume II 1 & 2Buspirone HCl Tablets 5 mg /10 mg Volume II 1 & 2Carbamazepine (EU + US) Tablets 200mg Volume II 1 & 2Carbamazepine (Chewable) Chewable Tab 100 mg Volume II 1 & 2Carbamazepine (Extented Release)≡ Geigy TEGRATOL XR™

Coated Tab 400 mg Volume II 1 & 2

Carbidopa/Levodopa Tablets 10/100 mg Volume II 1 & 2Carbidopa/Levodopa Tablets 25/100 mg Volume II 1 & 2Carbidopa/Levodopa Tablets 25/250mg Volume II 1 & 2Carbidopa/Levodopa ER Tablets 50/200mg Volume II 1 & 2Cefaclor Oral Suspension USP Suspension 125 /187 mg/5mL Volume II 1 & 2Cefaclor Oral Suspension USP Suspension 250/375 mg/5mL Volume II 1 & 2Cefaclor Oral Suspension EU Suspension 250 mg/5mL Volume II 1 & 2Cefaclor Capsules 250/500mg Volume II 1 & 2Cefuroxime Sodium USP Vials 750-1500mg Volume II 1 & 2Clonazepam Tablets USP Tablets USP 0.5/1.0/ 2.0mg Volume II 1 & 2

Latest Lists are viewable on web http://locumusa.com/2go



HANDBOOK of DRUG DEVELOPMENT+120 Series


Clomiphene Citrate Tablets USP 50mg Volume II 1 & 2Clomipramine HCl Capsules 25/50 mg 1 & 2Clomipramine HCl Capsules 75 mg Volume II 1 & 2Diclofenac Potassium Tablets 50 mg Volume II 1 & 2Diclofenac Sodium Tablets 50 / 75 mg Volume II 1 & 2Diclofenac Sodium Tablets 100 mg Volume II 1 & 2Diclofenac Sodium Clear Gel 10 mg/g Volume II 1 & 2Dorzolamide HCL Ophthalmic Solution 2% Volume II 1 & 2Etodolac Capsules 200/300mg Volume II 1 & 2Etodolac ≡ Wyeth Lodine™ Tablets 400 mg Volume II 1 & 2Etodolac ≡ Wyeth Lodine™ Tablets 500 mg Volume II 1 & 2Enalapril Maleate Tablets 40 mg Volume II 1 & 2Etidronate Disodium Tablets 0 mg Volume II 1 & 2Famotidine Tablets 10 mg Volume II 1 & 2Famotidine Tablets 20 mg Volume II 1 & 2Famotidine Tablets 40 mg Volume II 1 & 2Felodipine Tablets 5 mg Volume II 1 & 2Felodipine Tablets 10 mg Volume II 1 & 2Felodipine Extended Release Tablets 2.5 mg Volume II 1 & 2Felodipine Extended Release Tablets 5 mg Volume II 1 & 2Felodipine Extended Release Tablets 10 mg Volume II 1 & 2Flunisolide Hemihydrate solution Nasal solution 1mg/5mL Volume II 1 & 2Flunitazapam Tablets 2 mg Volume II 1 & 2Fluoxetine Capsules 10 / 20 mg Volume II 1 & 2Fusemide Capsules 40 mg Volume II 1 & 2Gabapentin (=Neurontin-Park Davis) Capsules 100/200 mg Volume II 1 & 2Gabapentin (=Neurontin-Park Davis) Capsules 300 /400 mg Volume II 1 & 2Gemfibrosil Tablets 450 mg Volume II 1 & 2Gemfibrosil Extended Release Tablets 600 mg Volume II 1 & 2Glibenclamide Tablets 5 mg Volume II 1 & 2Glipizide Extended Release Tablets 2.5 mg Volume II 1 & 2Ibuprofen Tablets 200-800mg Volume II 1 & 2Isosorbide Mononitrate Tablets 20 mg Volume II 1 & 2Ketorolac Tromethamine Tablets 10 mg Volume II 1 & 2Levodopa/ Benserazide HCl Tablets 200/50 mg Volume II 1 & 2Labetalol HCL Tablets 100 +200mg Volume II 1 & 2Labetalol HCL Tablets 300mg Volume II 1 & 2Loperimide Tablets Volume II 1 & 2Mesalamine (Enteric Coated) Tablets 400mg Volume II 1 & 2Metformin HCl (Coated) Tablets 500 mg Volume II 1 & 2Metformin HCl (Coated) Tablets 850 mg Volume II 1 & 2Miconazole/Hydrocortazone Cream 2% + 1% Volume II 1 & 2Miconazole Nitrate Cream 2% Volume II 1 & 2Nabumatone Tablets 500 mg Volume II 1 & 2Nabumatone Tablets 750mg Volume II 1 & 2

Copyright © 1995-9 by Locum Publishing House Inc. All Rights Reserved. Neither this book nor any part may be reproduced ortransmitted in any form or by any means, electronic or mechanical, including photocopying, microfilming and recording, or by anyinformation storage and retrieval system, without the permission of the publishers




HANDBOOK of DRUG DEVELOPMENT+120 Series


Naproxen (Enteric Coated) Tablets 250mg Volume II 1 & 2Naproxen DR Tablets 375/500mg Volume II 1 & 2Naproxen Sodium Tablets 220 mg Volume II 1 & 2Naproxen Sodium Tablets 275/550 mg Volume II 1 & 2Norfloxacin USP Tablets 400 mg Volume II 1 & 2Ofloxacin Tablets

100/200/400 mg Volume II 1 & 2

Oxolamine Syrup 10 mg/mL Volume II 1 & 2Paracetamol - sugar/dye-free Syrup 125 mg Volume II 1 & 2Paracetamol Chewable Fruit Flavors Tablets 160 mg Volume II 1 & 2Pentoxifylline ER Tablets 400 mg Volume II 1 & 2Penfluridol Capsules 10 mg Volume II 1 & 2Piroxicam Capsules 20 mg Volume II 1 & 2Quinidine Bisulphate Tetrahydrate Tablets 250 mg Volume II 1 & 2Ranitidine HCl Tablets 150 mg Volume II 1 & 2Ranitidine HCl Tablets 300 mg Volume II 1 & 2Simvastatin Tablets 5/10mg 20 / 40 mg Volume II 1 & 2Scopolamine Butylbromide Tablets 10 mg Volume II 1 & 2Selegiline Tablets 5 /10 mg Volume II 1 & 2Sotalol (=Betapace/Berlex) Tablets 80 /120mg Volume II 1 & 2Sotalol (=Betapace/Berlex) Tablets 160 /240mg Volume II 1 & 2Silver Sulphadiazine Cream 1% Volume II 1 & 2Tamoxifen EU Tablets 10 / 20 mg Volume II 1 & 2Tamoxifen EU Tablets 30 / 40mg Volume II 1 & 2Tamoxifen US Tablets 10/20/40mg Volume II 1 & 2Terbutaline Sulfate Syrup 0.3 mg/mL Volume II 1 & 2Terazosin Tablets 1mg / 2mg Volume II 1 & 2Terazosin Tablets 5mg / 10mg Volume II 1 & 2Terfenadine Tablets 60 mg Volume II 1 & 2Tetrahydrozoline HCl USP Eye Drops 2,5mg/5mL Volume II 1 & 2Ticlopidine Tablets 250 mg Volume II 1 & 2Timolol maleate Drops USP Eye Drops 0.25 / 0.5% Volume II 1 & 2Tolmetin Sod. Capsules 400 mg Volume II 1 & 2Tolmetin Sod. Tablets 600 mg Volume II 1 & 2Trazodone Tablets 50/100 mg Volume II 1 & 2Trazodone Tablets 150 mg Volume II 1 & 2Tretinoin Cream USP 0.025% Volume II 1 & 2Sulfamethoxazole Trimethoprim Tablets USP 80/400mg Volume II 1 & 2Sulfamethoxazole Trimethoprim Tablets USP 160/800mg Volume II 1 & 2Sulfamethoxazole Trimethoprim Suspension 80/400mg Volume II 1 & 2Sodium Valproate Syrup 200mg/5mL Volume II 1 & 2Verapamil Hydrochloride Tablets 40 mg Volume II 1 & 2

AN ONGOING SERIES - NEW ADDITIONS ADDED TO SERIES


Second International Edition - 02 (First to Fourth Print). Fourth printing published and distributed in UK, US, EU, Israel, Asia, and Japan in January1998 by Locum International Publishing House (Houston, Israel, South Africa) in Hard Cover; Soft and Spiral Cover; Electronic Diskette; and e-mailattachment versions. All print and electronic versions identical in content and format


136188075 Handbook of Pharmaceutical Generic Development Vol 12 Part 2

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