Handbook of Pharma Generic Develop._part II (2000)

ORAL TABLETS DOSAGE FORM Drug Development

I m m e d i a t e R e l e a s e

HANDBOOK OF PHARMACEUTICAL

GENERIC DEVELOPMENT

OR A L

Tablets

VOLUME I - Part TWODrug Development - So l id Ora l Dosage Forms

GENERIC DEVELOPMENT

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

HHandbook of PPharmaceutical GGeneric DDevelopment 24 volume Drug Development 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 eReview Process: Generic & Innovative Drug Development Division

Research Center - Locum International Research

Handbook of Pharmaceutical Generic DevelopmentPart I (Development) & Part II (Development ANDA or EU Dossier)

Vol. 1 - Tablets Oral


Vol. 2 - Capsules


Vol. 3 - Semisolids


Vol. 4 - Liquids


Vol. 5 - SG Capsules

Handbook of Pharmaceutical Generic DevelopmentPart I (Development Pharmaceutical Stability) & Part II (Analytical PAI)

Vol. 6 - e-SOPs / SOPs


Vol. 7 - Suspensions


Vol. 8 - Eye & Nose


Vol. 9 - Aerosols MDI


Vol. 10 - Tablets CR/MR


Vol. 11 - Capsules ER


Vol. 12 - Tablets Oral DR

Handbook of Pharmaceutical Generic DevelopmentPart I (Method Validation) & Part II (Analytical Methods 1994-2003)

Vol. 13 - Analytical50 Generic SI 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 - SuspensionsHandbook of Pharmaceutical Drug Development (1-5)(Master Formula & Manufacturing Instructions Parts 1 - 5)

Vol. 17 - MF and MMI

Handbook of Pharmaceutical Drug Development (6-10)(Master Formula & Manufacturing Instructions Parts 6 - 10)

Vol. 18 - MF and MMI

Handbook of Pharmaceutical Drug Development (1-5)(Part I, Part II & Part III.(Development, Manufacturing &Engineering)

Vol. 19 - ValidationProtocols/PAI-Checklists


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

Available either as Hard Bound, Soft Bound or Soft Spiral Cover (for Updating).For Drug Specific Handbooks refer to the 120+ Drug Development Series

READY-TO-GO™ DRUG DEVELOPMENT SERIEShttp://www.locumusa.com/2go & http://www.iagim.org


ANDA Development

P a r t T w o T w o TABLETSOO r a l

p p p

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

H a n d b o o k o f

PharmaceuticalGeneric

Development

Copyright © 1995-00 - 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.


SERIAL NUMBER - DO NO REMOVE! - REGISTERED WITH

LOCUM INTERNATIONAL PUBLISHERS REGISTRATION SERVICESWARNING: THIS ISSUE A IS MULTIPLE PAGE UV ENCODED EDITION.

HPGD 24 Vol. SERIES - ORAL TABLETS - Part IIFirst 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.

ISSN 0793 8632ISSN 0793 8640 - Electronic Version (Diskette, CD ROM and e-mail attachment version)Handbook Development 24 volume seriesGeneral Generic Development ISSN Series number 0793 7407General Generic Development ISSN Series number 0793 7792 - Electronic Issue (Disketteand e-mail attachment version are identical in size and content to the printed hard or softcover version.)

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 $1 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 . com

PRINTED IN USAPRINTED IN ISRAEL

Current Printing (last digit) : 10 9 8 7 6 5 4 3 2 PRINTED IN REPUBLIC OF SOUTH AFRICA


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 .

24 Volume SeriesHandbook of Generic development

Third International Edition.

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


I N T R O D U C T I O NHandbook of Generic Development - Oral Tablet Dosage Form

This handbook is the third international edition of the ongoing 24 volume seriesunder the cumulative title of Handbook of Generic Drug Development. It is a hands-on, technical presentation that portrays the current drug requirement stepsnecessary at the time of going to print, of the Abbreviated New Drug Application fororal tablet dosage form, namely tablets and caplets. It is written in conjunction withPart Two of the Handbook which models as a representative ANDA and as anexample of the drug development process required for solid oral dosage forms TheHandbook is available in electronic format (CD ROM) and e-format (on-line). TheHandbook is up-dated to current regulatory requirements once or twice annually.Complete updates are available without charge to Association Members of the DrugDevelopment Association - IAGIM.

This handbook provides a proven pathway to solid oral dosage form development.Modern commercial formulations highlight the common tablet/caplet developmentroutes namely the classical wet granulation, spray granulation, dry granulation andfinally slugging and direct compression. Low active dosage (<10mg) and highpotency (>50%) examples are specially chosen to demonstrate the formulation stepsand process stages as a prerequisite to developing stable, elegant and ruggedformulas.

This second edition of the Handbook includes additional data on analytical methodvalidation has been redesigned to meet the January 2000 Guidance for Industry -Organization of an Abbreviated New Drug Application and an Abbreviated AntibioticApplication as well as all FDA guideline and requirements of the Center of DrugEvaluation and Research (CDER) until January 2000. Editor-in-Chief.

Ó�ÎThird International Edition

p20±00p© COPYRIGHT 1995-00

Ï�Ð

ISSN 0793 8632A n o n - g o i n g s e r i e s

A 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 nGeneral Drug Development Series ISSN 0973 7601

Electronic Drug Development Series ISSN 0973 761X

HANDBOOK OF GENERIC DRUG DEVELOPMENT [email protected] 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 [Generic name] qTablets/qCapsules qIR/qMR/qCR/qER [000/000]mg.(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 an in-vivo Bioequivalence study. The Studycompares qTablets / þþCapsules þþIR / qMR / qCR / qER [000/000]mgmanufactured by [Generic Manufacturing Co. Inc./ Ltd.] to the reference listed drugunder [food / fasting] 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 Fasting Study⌦Results of Food Study

⌦Results of Multiple Dose Study Dissolution Data Waiver Request



SECTION I SECTION 1


TABLE OF CONTENTSSECTION 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, (from February 1999).

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

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

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

.2 Basis for ANDA Submission

SECTION 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.

SECTION 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).

SECTIONS V - LABELING5.1 Section Page (with TAG) and brief descriptor of the section.

.2 Proposed Generic labeling (for capsules include formula for empty capsule shell)

.3 Four (4) copies of DRAFT labeling- (obtain latest insert from FDA FOI).OR Twelve (12) copies of FINAL PRINTED labeling

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.)



SECTION I SECTION 1

Application/ Table of ContentsTABLE OF CONTENTS

SECTIONS VI - BIOAVAILABILITY / BIOEQUIVALENCE STUDY

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

.1 Financial Certification / Disclosure Statement - (Form 3454 or 3455)

.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 Dissolution Protocol using 12 dosage units each - (all strengths)

.8 Comparative Dissolution Protocol (CDP study results, statistics, tables andgraphs)

.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 INVIVO Biostudy PROTOCOL and Study Reports conducted on pivotal batch

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 CONTROLActive ingredients


.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



SECTION I SECTION 1


TABLE OF CONTENTS

SECTIONS VIII - RAW MATERIAL CONTROLActive & Inactive ingredients (cont.)

ACTIVE SUBSTANCE .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)

.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 ACTIVE IR Identification Spectra of Reference Standard (Pharmacopoeial).Physical Specifications from ACTIVE Manufacturer:- Bulk Density- Particle Size (note: water insoluble material)

.12 ACTIVE Physical and Analytical Test Methods.

.13 Routine Testing Protocol and Frequency of tests for ACTIVE Material

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

NON-ACTIVE EXCIPIENTS .15 Monographs of each NON-ACTIVE from Generic QC lab

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

.17 - Composition of Approved Pigments and Dyes

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

.19 CoA from Approved Manufacturer (Suppliers Release Certificate)

.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).

.25 Composition of tablet/caplet Printing Inks (CFR, Food grade)

.26 Capsule Cap and Body Specifications from Generic QC lab



SECTION I SECTION 1


TABLE OF CONTENTS

SECTIONS VIII - RAW MATERIAL CONTROLEmpty Hard Gelatin Capsules

8.25 Title Page and brief narrative statement of what this section contains:-

.26 Letter of Access referring DMF # of Capsule Manufacturer

.27 Empty Capsule Specifications (Cap and Body) from vendor

.28 CoA of Empty Capsule from Approved Capsule Manufacturer

.29 CoA of Empty Capsule from Generic/Development QC lab

.30 Composition of Empty Capsules

- Composition of Capsule Approved Pigments and Dyes

- Composition of Capsule Printing Inks (CFR, Food grade)

.31 Raw Materials Laboratory Capsule Test Protocol (Incoming tests performed).

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 manufacturingsite

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



SECTION I SECTION 1


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

11.1 Title Page (with TAG) and brief narrative statement of what this section contains. .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 for dried milled material- Blank forms - In-process specifications sheet for final blend.- Blank forms - In-process test result sheet of the blended mix- Blank forms - In-process specifications for filled capsules- Blank forms - In-process test results sheet of filled capsules- Blank forms - In-process Specifications for ink jet printed CAPSULES- Blank forms - In-process test results of ink jet printed CAPSULES- 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

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.



SECTION I SECTION 1


SECTIONS XIIPivotal Manufacturing and Processing Instructions

12.1 Title Page (with TAG) and brief narrative statement of what this section contains..2 Outline of In-process SOPs.

.3 In Process Controls and sampling plan summary.

.4 Executed Manufacturing Procedure Flow Chart.

.5 Pivotal Batch Record 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).Granulates may be wet/dry granulated, slugged & milled prior to blending, add thedocumentation for the slug and milling procedures, including production yields.

.12 - Executed forms - In-process specifications for dried milled material.

.13 - Executed forms - In-process specifications for blended mix.

.14 - Executed forms - In-process test results sheet of the blended mix

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

.16 - Executed forms - In-process specifications.

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

.18 - Executed forms - In-process specifications for filled capsules- Executed forms - In-process test results sheet of filled capsules- Executed forms - In-process Specifications for printed CAPSULES- Executed forms - In-process test results of printed CAPSULES- FILL weight Verification study and results

.19

Individual and overall production yieldsExecuted forms for production yields and weighing print-outs attachments- Stage I - (End of Drying).- Stage II - (End of Blending)- Stage III - (End of filling)- Stage IV - (End of online printing)

.20 Finished Product Release Specifications

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

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

.23 Production Packaging Work Sheets - (translations)

.24 Production Packaging Control Forms - (translations)

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

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



SECTION I SECTION 1


TABLE OF CONTENTS

SECTION XIIIPackaging and labeling Procedures


.2 Summary / Outline of Packaging and Labeling Procedures

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

CONTAINERS, GLASS OR THERMOPLASTIC - (REQUIREMENTS FOR EACHCONTAINER.)

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

.5 i. LoA from manufacturer referencing their container Type III DMF #.

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

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

.8 - drawings/diagrams and dimensions

.9 - test protocol and Certificates meeting USP and 21 CFR requirements

- DSC thermal analysis (for thermoplastic containers only)

- Manufacturer’s Container CoA

.10 Testing Specifications / Protocol ; Acceptance Criteria and TEST RESULTS (CoA)of Applicant Lab.

.11 CoAs of Containers from Applicant Lab.

.12 Batch Compliance Results



SECTION I SECTION 1


TABLE OF CONTENTSMETAL CAPS AND THERMOPLASTIC CLOSURES

(PER EACH CLOSURE.)

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

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

.15 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


.17 Batch Compliance Results.

INNER CLOSURE LINER:

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

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

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


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

.23 Batch Compliance Statement.

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

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

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

.26 Foam seal Specifications or Certificate of Conformance from manufacturers


.28 CoA or test results of Foam seal from Applicant Lab.




SECTION I SECTION 1


TABLE OF CONTENTSCotton Coil

13.30 Item description and use USP requirements.

.31 LoA from manufacturer to applicant referencing their DMF # of cotton coil.

.32 Cotton Coil Specifications or Certificate of Conformance frommanufacturers.


.34 CoA or test results of cotton coil from Applicant Lab.


Silica Gel Drying Agent

LoA referencing DMF # of drying agent manufacturer (if relevant)

.36 Specifications or Certificate of Conformance from manufacturers


.38 CoA or test results of drying agent from Applicant Lab.

.39 CoA of drying agent from manufacturer’s QC Lab.


Section XIV - Controls for the Finished Dosage Form14.1 Title Page (with TAG) and brief summary 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 Methods15.1 Title Page (with TAG) and brief narrative statement of what this section contains.-

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.

Drug Substance / 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.

- dissolution test procedure.

.7 Finished Product Analytical Validation methodology

- stability Indicating Assay.

- impurity limits or specific Impurity Quantitation.

- dissolution.



RESERVED SECTIONNOT FOR CURRENT USE

SECTION I SECTION 1


TABLE OF CONTENTS

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

Application/Table of ContentsTABLE OF CONTENTS

Section XXII - ADDITIONAL INFORMATION22.1 Title Page (with TAG) and brief narrative statement of what this section contains.

22.2 General Informationa. Copy of cover letter (or page reference)b. Label/package insert copy (or page reference)c. Summary of manufacturing process including components andcompositionstatement (or page reference)d. Copies of pages from completed batch production record containingholding times, filtration integrity testing, and sterilization records (or pagereference).

22.3 If the microbiology section is presented in a separate volume, provide copies of theindicated information in other micro sections of the application - NOT page references

STERILIZATION ASSURANCE INFORMATION AND DATA.Note: This section can be provided as a separate volume for ease of review. Use theGuideline 'Submission of Documentation for Sterilization Process Validation in Applicationsfor Human and Veterinary Drug Products'

Where a section is not applicable It is included in the Table of Contents with the statement:

' THIS SECTION IS NOT APPLICABLE TO THE SUBMITTED APPLICATION '

COMPOSITION OF ALL ANDA SUBMISSION COPIESANDA

SECTIONARCHIVAL

COPY[Full]

REDCOPY[CMC]

ORANGECOPY

[Biostudy]

FIELDCOPY[Full]

I þ þ þ þ

II þ þ þ þ

III þ þ þ þ

IV þ þ þ þ

V þ þ þ þ

VI (Bio) þ - þ þ

VII þ þ þ þ

VIII - XX(Chemistry)

þ þ - þ

XXII (Micro) þ þ - þ

CMS - Chemistry manufacturing and Controls containing No Biostudy.Review Copies - Red and Orange Copies.Archive and review Copies - send by courier or special parcel service



SECTION I SECTION 1


FDA FORM 3439or

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 ).

GLOSSARY

Abbreviated Application: An application described under 21 CFR 314.94,including all amendments and supplements to the application.

Archival Copy: A complete copy of the abbreviated application intended to serveas the official reference source for the Agency. It is retained by the Agency andserves as the sole file copy of the approved application.

Electronic Format: The voluntary submission of parts of an ANDA in electronicmedia for use to facilitate the review process and in conjunction with the requisitehard copy of the application.

Field Copy: A duplicate of the archival copy to be submitted for use by FDAinvestigators.

Review Copy: A duplicate of the archival copy for use by Agency reviewers. It isdestroyed after approval of the application.

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 21/22)

× Do not number volumes - FDA will number the volumes. Ø

4End of Section 1.



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] qTablet /qCapsule manufactured by [RLD Company Name Inc. / Ltd.].

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.] Generic qTablet/ qCapsule is the same as that of the RLD brand name

We refer the reviewer to [Applicant Company Name Inc. / Ltd.] annotated labelingand the current approved labeling of the RLD as shown in Section IV-05 of thisANDA (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 qTablet / qCapsule 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 [Generic qTablet /qCapsule Name] was successfully conducted in terms of current approvalparameters by Clinical Research Laboratories [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] Imodium 1/Imodium 2 Generic qTablet / qCapsule manufactured by [RLDCompany 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] Imodium1/Imodium2 qTablet / qCapsule manufactured by [RLD InnovatorCompany 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 (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:


ORIGINAL ABBREVIATED NEW DRUG APPLICATION[Generic name] Oral Tablets/Capsules

Dear Sir,

We submit herewith the ANDA SUITABILITY PETITION APPROVAL LETTERfor the drug product [Generic name qTablet / qCapsule [000 / 000] mg.


[ANDA SUITABILITY PETITION APPROVAL LETTERAttached in Section XXII]

4End 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.

I





' 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] Product [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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HANDBOOK OF GENERIC DRUG DEVELOPMENT ANDA DEVELOPMENT

24 V24 Volume DDrug DDevelopment SSeries Sect: 4.1 DEVELOPMENT OralOral Tablets

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) / Innovator

Tabulate 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. tablets[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 that the side-by-side labeling comparisonshould appear in Section IV-5. Applicants may place the comparison in both sectionIV-5 and V until the FDA are conversant with the new guideline

4




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

[RLD] TABLETS / [Generic name] TABLETS[RLD Company Name]. [Generic Co. Name].

Conditions of Use

The conditions of useprescribed or recommendedor suggested for [RLD]TABLETS [USP] may befound in the package insert(see section V).

The conditions of use prescribed,recommended or suggested for[Generic name] TABLETS [USP]are the same for [RLD]TABLETS [USP] and may befound in the package insert (seeSection V).

Active Ingredient [Active Material] is the same [Active Material] is the same

Non-activeIngredient

There are no safety issuesconcerning the proposedformulation as the inactiveingredients are essentiallysimilar to the referencelisted drug

Inactive ingredients in bothproduct are similar and do notrequire to be identical in terms ofQ&Q policy (Nov 17 1994)

Dosage Form TABLETS [USP](I R dosage Form)

TABLETS [USP](I R dosage Form)

Administration Oral Oral

StrengthsNumber ofStrengths

000.0 mg000.0 mg000.0 mg000.0 mg

000.0 mg000.0 mg000.0 mg000.0 mg

BioequivalentData

Bioequivalent Bioequivalent

Labeling Essentially Similar Essentially Similar

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.

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] TABLETS [USP] [000.0] mg.

Prescription Drug Rx - þThis 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.

orif not a prescription drug

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



4




Generic and RLD ComparisonLabelingPROPOSED 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.




Generic and RLD ComparisonLabelingLabeling similarity and differences between Generic and Brand RLD insert

GENERIC INSERTLABELING

RLD INSERTLABELING

Description DescriptionDifferences are:- Differences are:-Trade Name Trade NameColor, shape and embossing/printing Color, shape and embossing/printing

Similarities are:- Similarities are:-Dosage Form Dosage FormStrength StrengthDispensing information Dispensing informationAll text is identical except for [one] useindication namely [indication]

All text is identical except for [one]patented use indication namely[indication]

Clinical to AdministrativeSection


Differences are:- Differences are:-Specific use patent indication excluded Specific use patent indication under

exclusivity rights

Similarities are:- Similarities are:-Dosage Form Dosage FormStrength Strength

How Supplied How Supplied

Differences are:- Differences are:-Trade Name Trade NameAddresses (Applicant & Distributing) AddressesNDC # NDC #

Similarities are:- Similarities are:-Dosage Form Dosage FormStrength StrengthQuantities Quantities




Generic and RLD ComparisonLabeling

ATTACHMENTS


24 Volume Drug Development Series Sect: 5.1 DEVELOPMENT Oral Dosage Form

SECTION V SECTION 5

Labeling


Section Page (with Color Section TAG) and brief descriptor of the section.Included in this section is a copy of the currently approved labeling for theReference Listed Drug [RLB Name] and the draft labeling for the [Applicant Company Name Inc. / Ltd.] Drug Product.

The annotated side-by-side labeling comparison with the labeling of the GenericDrug and Reference Listed Drug [RLB Name] that also appears in Section IV-5

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

2. Proposed Generic Insert / Outsert

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

4. Innovators container panel labeling for each strength and pack size

5. Side-by-side comparison of package leaflet (insert or Outsert.) Statementof labeling similarity and differences between Generic and Brand RLD.

6. Side-by-side comparison of label for each strength and pack size. Statementof labeling similarity and differences between Generic and Brand RLD.

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

4



SECTION V SECTION 5

LabelingPROPOSED GENERIC CONTAINER PANEL LABELING000 Tablets [USP]

Main Panel NDC [0-00-000-00][Generic Name] Tablets [USP]000 mg_________________________Each Tablet contains:[Active Material] 000 mg

Caution: Federal law prohibits dispensing without prescription

000 TABLETS [USP]


Side Panel Usual Adult dosage : One tablet twice a day.See package for full prescribing information

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.

Dispense contents in tight light resistant containers as definedin the USP with a child resistant closure (as required)KEEP THIS AND ALL MEDICATIONS OUT OF REACH OFCHILDREN

01/98.

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

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



SECTION V SECTION 5

Labeling

PROPOSED GENERIC CONTAINER PANEL LABELING0000 Tablets

Main Panel NDC [0-00-000-00][Generic Name] Tablets [USP]000 mg_________________________Each Tablet contains:[Active Material] 000 mg


000 TABLETS [USP]


Side Panel Usual Adult dosage : One tablet twice a day.See package for full prescribing information

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.

Dispense contents in tight light resistant containers as definedin the USP with a child resistant closure (as required)KEEP THIS AND ALL MEDICATIONS OUT OF REACH OFCHILDREN

01/98.

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

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



Lot #&

Exp.Date

SECTION V SECTION 5

Labeling

PROPOSED GENERIC LABELING FOR PRESENTATIONS IN:BLISTER PACKAGING (FOIL / PVC)

QUANTITY: [00] Tablets

Name000 mg

Name000 mg

Name000 mg

Name000 mg

Name000 mg

Name000 mg

Name000 mg

Name000 mg

Name000 mg

Name000 mg

PVC / PVDC / Aluminum Foil Printing:1. Generic name and dosage strength (per cell).2. MNF Lot #.3. Expiration date.

Note:Tablet / caplet thickness upper limits critical to fit blister mold.



SECTION V SECTION 5

LabelingPROPOSED GENERIC PACKAGE INSERT LABELING


An annotated side-by-side comparison of package leaflet (insert or Outsert.) andcontainer label of the generic drug product and the Brand RLD. Labeling similaritiesand differences between Generic and Brand RLD are highlighted both below and onthe side-by-side comparison itself

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 package insertsfor Generics - on the Internet - See FDA Website. Note the approved labeling MAYNOT the market place label. Recheck section V data just prior to submission in case ofany approved labeling changes.



SECTION V SECTION 5

LabelingPROPOSED GENERIC CONTAINER LABEL LABELING


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

LabelingPROPOSED GENERIC CONTAINER ADHESIVE LABELING

000 TABLETS [USP]

(Show ALL fill sizes)

NDC [0-00-000-00]

[GENERIC Name] Tablets [USP]000 mg

Each Tablet contains:[Active Material] 000 mg


000 TABLETS [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. Dispense contents in tight light resistantcontainers as defined in the USP with a child resistant closure (as required). KEEP THIS AND ALLMEDICATIONS OUT OF REACH OF CHILDREN

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

NOTE:Examine innovator's labeling carefully and reproduce meeting all regulatoryrequirements. Obtain the latest printing of the innovator's product labeling.



SECTION V SECTION 5

Labeling Certification StatementINNOVATIVE CONTAINER ADHESIVE LABELING

000 TABLETS [USP]

(Show ALL fill sizes)

NDC [0-00-000-00]

[INNOVATIVE Name] Tablets [USP]000 mg

Each Tablet contains:[Active Material] 000 mg


000 Tablets [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. Dispense contents in tight light resistantcontainers as defined in the USP with a child resistant closure (as required). KEEP THIS AND ALLMEDICATIONS OUT OF REACH OF CHILDREN

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

NOTE:Examine innovators labeling carefully and reproduce meeting all regulatoryrequirements



SECTION V SECTION 5

Labeling Certification Statement

[Generic name] TABLETS[USP] [000.0] mg.

Certification.Drug's proposed labeling same as 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] TABLETS [USP] NDA # 00-000.





SECTION V SECTION 5

LabelingLabeling similarity and differences between Generic and Brand RLD insert

GENERIC INSERTLABELING

RLD INSERTLABELING

Description DescriptionDifferences are:- Differences are:-Trade Name Trade NameColor, shape and embossing/printing Color, shape and embossing/printing

Similarities are:- Similarities are:-Dosage Form Dosage FormStrength StrengthDispensing information Dispensing informationAll text is identical except for [one] useindication namely [indication]

All text is identical except for [one]patented use indication namely[indication]



Differences are:- Differences are:-Specific use patent indication excluded Specific use patent indication under

exclusivity rights

Similarities are:- Similarities are:-Dosage Form Dosage FormStrength Strength

How Supplied How Supplied

Differences are:- Differences are:-Trade Name Trade NameAddresses (Applicant & Distributing) AddressesNDC # NDC #

Similarities are:- Similarities are:-Dosage Form Dosage FormStrength StrengthQuantities Quantities


24 Volume Drug Development Series Sect: 6.1 DEVELOPMENT Oral Tablets

SECTION VI SECTION 6

Bioavailability / Bioequivalence


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

6.2 Formula Composition of Generic product

6.3 Percent Composition of Formula

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

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

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

6.7 Comparative Dissolution Protocol using 12 dosage units each - (allstrengths).

6.8 Comparative Dissolution Profile

• CDP study results

• Statistics

• Tables

• CDP Graphs

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

6.10 Outline of packaging container closures - proposed marketing packs.

6.11 Tablet trail of all packed units.

6.12 Biostudy protocol

Biostudy Study Reports (conducted on pivotal batch).

*(Biostudy = Bioavailability / Bioequivalence Study)

4





Section 6.1 contains the Biostudy reports of the in vivo Bioequivalence studyconducted. The lot numbers of test product and reference product compared in thisstudy are:

Generic Product

• [Generic name] Tablets [USP] [000.0] mg. Lot: [IA-000-00]was manufactured at[Generic Company Name Inc./Ltd.] [Address] facility, utilizing the production areaand incorporating standard production staff, procedures and equipment. The Batchsize was: [0000 000] Tablets [USP].

Reference Product

• [RLD Company Name Inc./Ltd.], [RLD] Tablets [USP] [000.0] mg lot: Lot:AA000 Expiry Date: Month 199? / 200?

This Section contains: • Statement of composition of the generic product [Generic name] Tablets [USP]

[000.0] mg. • Percent composition of the generic product [Generic name] Tablets [USP]

[000.0] mg. • Qualitative comparative Ingredient List Reference Listed Product and Generic. • Certificates of Analysis for both products used in the Bioequivalence namely:

♦ ♦ [Generic name] Tablets [USP] [000.0] mg. Lot: [000-00]CoA No: [0000]

♦ [RLD] Tablets [USP] [000.0] mg. Lot: [AA000]♦ CoA No: [0000]

Comparative Dissolution Profile of the following:Reference Product♦ [RLD] Tablets [USP] [000.0] mg. Lot: [AA000]

CoA No: [0000] Generic Product

♦ ♦ [Generic name] Tablets [USP] [000.0] mg. Lot: [000-00]CoA No: [0000]

Packaging and Disbursement Summary for [Generic Company Name Inc./Ltd.]pivotal Lot: [000-00]





6.2 FORMULA COMPOSITIONComposition of the drug, stating the name and amount of each ingredient, whetheractive or not, contained in a stated quantity of the drug, in the form in which it is to bedistributed.

[Generic name] Tablets [USP] [000.0] mg.(equivalent to [000.0] mg [Active Material]

Ingredients Amount per Unit

per 20 mg Tablet (in milligrams)

[Active Material] 23.601 Active

Povidone USP 9.00 Non-active

Colloidal Silicon Dioxide NF 2.10 Non-active

Starch NF 5.302 Non-active

Starch NF (Re-dried) 27.00 Non-active

Anhydrous Lactose NF 230.00 Non-active

Magnesium Stearate NF 3.00 Non-active

Total 300.00

Calculation for Active Material Weight on a Dry Basis.

Weight Adjustment Calculation:

1 Note: [00.0] mg for [Active Salt] is equivalent to 00 mg of [Active] base.Quantity of [Active Salt] to be weighed = [Lot Size] x [00.0] x 100

100 -LODWhere LOD = Loss on Drying of for [Active Salt] =

2 The actual quantity of [Excipient] NF used in the formula will depend on the WEIGHT for [Active Salt] used.





6.3 PERCENT COMPOSITION OF THE PRODUCT


Ingredients

per 00 mg Tablet

Each Tablet

Contains - (%)

[Active Material] 7.871

Povidone USP 3.00

Colloidal Silicon Dioxide NF 0.70

Starch NF 1.762

Starch NF (Re-dried) 9.00

Anhydrous Lactose NF 76.67

Magnesium Stearate NF 1.00

Total 100.00

Calculation for Active Material Weight on a Dry Basis.


1 Note: [00.0] mg for [Active Salt] is equivalent to 00 mg of [Active] base.Quantity of [Active Salt] to be weighed = [Lot Size] x [00.0] x 100

100 -LODWhere LOD = Loss on Drying of for [Active Salt] =

2 The actual quantity of [Excipient] NF used in the formula will depend on the WEIGHT for [Active Salt] used.





QUALITATIVE COMPARATIVE INGREDIENTS LIST

[Generic name] Tablets [USP] [00.0] mg.

[Active Material]

[Generic Company Name Inc. / Ltd.]

[RLD] Tablets [USP] [00.0] mg.

[Active Material]

[RLD Company Name Inc. / Ltd.]*

[Active Material] [Active Material]

Povidone USP Povidone

Colloidal Silicon Dioxide NF Colloidal Silicon Dioxide

Starch NF Starch

Starch NF (Re-dried) Lactose

Anhydrous Lactose NF Magnesium Stearate

Magnesium Stearate NF Another ingredient

* Reference Source - PDR 1998/200Y





CERTIFICATES OF ANALYSIS REPRESENTING THE DRUG PRODUCTS USED IN BIOEQUIVALENCY STUDY

♦ ♦ [Generic name] Tablets [USP] [000.0] mg. Lot: [IA-000-00]

CoA No: [00-00]

♦ [RLD] Tablets [USP] [000.0] mg. Lot: AA000

CoA No: [00-00]

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 fromthe Analytical Research Laboratories at [Generic Company Name Inc. / Ltd. &Address].

Attached:

Certificate of Analysis Number 0006 Date: Month DD 1998

Certificate of Analysis Number 0007 Date: Month DD 1998





COMPARATIVE DISSOLUTION PROFILE FOR DRUG PRODUCT LOTSUSED IN BIOEQUIVALENCE STUDIES:

[Generic name] Tablets [USP] [000.0] mg. Lot: [IA-000-00]

CoA No: 0000

[RLD] Tablets [USP] [000.0] mg. Lot: AA000

CoA No: 0000

Dissolution conditions used for Comparative Dissolution Profiles (IR):

Volume :: 000 mLMedia :: 0.0 N [Media Type / Buffer]Surfactant (where used) :: [0.0%] [Surface Active Agent]pH :: [0.0 Ñ 0.05] pHTemperature :: 37 Degrees C Ñ 0.5ÐApparatus : : No. 1 USP (basket) / (Paddle),Speed: :: 000 rpm (calibrated)Tolerance (IR) :: NLT 00% (Q) in 000 minutes

Attached:

Dissolution Profile Number 00006 Lot: [IA-000-00] Date: Month DD 200Y

Dissolution Profile Number 00007 Lot: AA000 Date: Month DD 200Y




Bioavailability / BioequivalenceRLD Product Batch No:______ Exp.___

Generic Drug Batch No:______ Exp.___

COMPARATIVE DISSOLUTION PROFILE12 Dosage Units

Method

SI-00-00

Percentage Assay of the labeled amount dissolved in:-

Edition #

00-00

20 min 30 min 45 min 80 min

Dosage

Unit No.

RLD

[name]

Generic

[name]

RLD

[name]

Generic

[name]

RLD

[name]

Generic

[name]

RLD

[name]

Generic

[name]Unit 1 00.0 00.0 00.0 00.0 00.0 00.0 00.0 00.0

Unit 2 00.0 00.0 00.0 00.0 00.0 00.0 00.0 00.0

Unit 3 00.0 00.0 00.0 00.0 00.0 00.0 00.0 00.0

Unit 4 00.0 00.0 00.0 00.0 00.0 00.0 00.0 00.0

Unit 5 00.0 00.0 00.0 00.0 00.0 00.0 00.0 00.0

Unit 6 00.0 00.0 00.0 00.0 00.0 00.0 00.0 00.0

Unit 7 00.0 00.0 00.0 00.0 00.0 00.0 00.0 00.0

Unit 8 00.0 00.0 00.0 00.0 00.0 00.0 00.0 00.0

Unit 9 00.0 00.0 00.0 00.0 00.0 00.0 00.0 00.0

Unit 10 00.0 00.0 00.0 00.0 00.0 00.0 00.0 00.0

Unit 11 00.0 00.0 00.0 00.0 00.0 00.0 00.0 00.0

Unit 12 00.0 00.0 00.0 00.0 00.0 00.0 00.0 00.0

X¡ (Mean)

RSD¡22.91.4

22.71.5

45.81.5

48.01.3

65.01.7

68.01.6

102.01.5

100.71.5

¡Model values supplies.






Tolerance: NLT 00 % (Q) in 00 mins.12 Tablets [USP]

[Generic name] Tablets [USP] [000.0] mg. Lot: [000-00]

Figure No. 1. Comparative Dissolution Profile

Generic Tablets vs RLD 00mg

0

20

40

60

80

100

120

0 20 40 80

TIME (min)

% DISSOLVED

S-12345 RLD AA0000

0 20 40 800 20 40 80

Limits: NMT 5% variation between Generic and RLD data points.






Tolerance: NLT 00 % (Q) in 00 mins.12 Tablets [USP]

Stress Study - 3 months Stability at 40° C / 75% RHFigure No. 2. Comparative Dissolution Profile

Generic Tablets vs RLD 00mg - Stressed

0

20

40

60

80

100

120

0 30 60 120

TIME (min)

% DISSOLVED S-12345

RLD-AA000

IMPORTANT NOTE:Evaluate Comparative Dissolution Profiles (CDP) with 3 to 4 different dated RLD batchLots obtained at 1-3 month intervals apart, from time of manufacture.

Stressed Profiles: CDP using 3 to 4 different dated RLD batch Lots placed on stabilityat 40° C / 75% RH for 3 - 6 months. (Evaluate Assay and Impurity profiles).It is significant to evaluate the variability in the RLD product at normal, post stressedand at different RLD manufacturing dates (RLD products made at different times).

Success of a costly Bioequivalence study may hinge or depend on the detail of theRLD's data (i.e. Multiple lots at different manufacturing date, normal, and agedstudies). The intra-batch and inter-batch variability of the RLD should be evaluatedwith care.




Bioavailability / BioequivalenceCERTIFICATE OF ANALYSIS

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

Standard ChromatogramBarr spec.15 26/9/97 10:03Assay Innovator Tablets 20mgSampleD-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 553456 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 26/9/97 10:43Assay Generic Tablets 20mgSampleD-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 553456 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] Tablets 20 mg - Bioequivalence Study Submitted in this ANDA.

[Generic Product] Tablets 10 mg - Waiver hereby being requested.

WAIVER REQUEST[Generic Firm] hereby request a waiver of evidence of in-vivo bioavailability for[Generic Product] Tablets 10 mg,An in-vivo bioavailability study was conducted on [Generic Product] Tablets 20 mg anda full report of the biostudy is included in section VI of this ANDA.

The [Generic Product] Tablets 20 which is the subject of this application, has the samegeometric proportional formulation as the [Generic Product] Tablets 10 mg. Themilligrams per tablet and comparative percent compositions of the two strengths areshown for purposes of similarity.

The [Generic Product] Tablets 20 mg, (this application), has a dissolution profile whichis essentially identical to that of the [Generic Product] Tablets 10 mg.

Comparative dissolution profiles are included herewith. We also include a dissolutionprofile of three batches of the innovator product (TRADE) (Active material).The variation in the innovators product profile is demonstrated statistically.

Dissolution testing was performed on 12 individual Tablets from each lot, using USPapparatus and method. Samples were taken at [20], [30], [45] and [80] min andassayed for (Active material) and expressed as a percentage of the labeled amount.

Dissolution testing was performed under the following conditions: Method No. 00-00 Edition No. 00-00 Volume :: 000 mL

Media :: 0.0 N [Media Type / Buffer]Surfactant :: [0.0%] [Surface Active Agent]pH :: [0.0 Ñ 0.05] pHTemperature :: 37 Degrees C Ñ 0.5ÐApparatus : : No. 1 USP (basket) / (Paddle),Speed: :: 000 rpm (calibrated)Tolerance (IR) :: NLT 00% (Q) in 000 minutes




Bioavailability / BioequivalenceData submitted in support of request for waiver of in-vivo

bioavailability studies.

Profile 1. [Generic] 20mg Batch No. Exp. 00/99Profile 2. [Generic] 10mg Batch No. Exp. 00/99

COMPARATIVE DISSOLUTION PROFILE12 Dosage Units

Method

SI-00-00

Percentage Assay of the labeled amount dissolved in:-

Edition #

00-00

20 min 30 min 45 min 80 min

Dosage

Unit No.

20g

Generic

10g

Waiver

20g

Generic

10g

Waiver

20g

Generic

10g

Waiver

20g

Generic

10g

WaiverUnit 1 00.0 00.0 00.0 00.0 00.0 00.0 00.0 00.0

Unit 2 00.0 00.0 00.0 00.0 00.0 00.0 00.0 00.0

Unit 3 00.0 00.0 00.0 00.0 00.0 00.0 00.0 00.0

Unit 4 00.0 00.0 00.0 00.0 00.0 00.0 00.0 00.0

Unit 5 00.0 00.0 00.0 00.0 00.0 00.0 00.0 00.0

Unit 6 00.0 00.0 00.0 00.0 00.0 00.0 00.0 00.0

Unit 7 00.0 00.0 00.0 00.0 00.0 00.0 00.0 00.0

Unit 8 00.0 00.0 00.0 00.0 00.0 00.0 00.0 00.0

Unit 9 00.0 00.0 00.0 00.0 00.0 00.0 00.0 00.0

Unit 10 00.0 00.0 00.0 00.0 00.0 00.0 00.0 00.0

Unit 11 00.0 00.0 00.0 00.0 00.0 00.0 00.0 00.0

Unit 12 00.0 00.0 00.0 00.0 00.0 00.0 00.0 00.0

X¡ (Mean)

RSD¡22.91.4

23.51.5

45.21.5

46.01.3

66.01.7

67.01.6

101.01.5

100.71.5

¡Model values supplies.





FORMULA COMPOSITION OF BIOSTUDY and PROPOSED WAIVER STRENGTH

[Generic name] Tablets [USP] [20.0] and [10.0] mg.(equivalent to [00.0] mg [Active Material]

Ingredients Amount per Strength

per Tablet (in milligrams)

[Active Material BP / Ph. Eur] 20.00 10.00 (Biostudy) (Waiver)

[Active Material] 23.60 11.80Povidone USP 9.00 4.50Colloidal Silicon Dioxide NF 2.10 1.05Starch NFPurified Water

5.30 2.652

qs2 qs2

Starch NF (Re-dried) 27.00 13.50Anhydrous Lactose NF 230.00 115.00Magnesium Stearate NF 3.00 1.50

Total 300.00 150.00

2 Processing solvent only.

SUMMARY

The following summary supports the request for the for waiver of in-vivobioavailability studies

FORMULATION & MANUFACTURE: Same Active material from same Approved SupplierIdentical granulate manufactured with identical manufacturing equipment Geometric proportion of non-active ingredients

ANALYTICAL & STABILITY12 point Dissolution Profile of both strengths do not vary by more than 5%Stability Profile and impurity profile essentially similar to study formulation.

4





Biostudy Section ofPackaging and Disbursement

Summary for Pivotal Lot: [IA-000-00]

30cc H.D.P.E. Container with Child Resistant Cap Closure [33 mm]

H.D.P.E = High Density polyethylene

30cc H.D.P.E. Container with Metal Cap Closure [33 mm]

Refer to Section 12 for complete Packaging and Disbursement summary of

Pivotal Lot: [IA-000-00]

4

500 units x 30 tablets = 15,000 tablets

Packaging date: Month DD, 200Y

Nov.28, 1996

5 units x 30 tabsQC Testing

Month DD, 200Y

40 units x 30 tabsBiostudy (European Market)

Month DD, 200Y

400 units x 30 tabsBalance stored in

Pivotal Warehouse

55 units x 30 tabsRelease & Stability Testing

Month DD, 200Y



Nov.28, 1996

9 units x 100 tabs

QC Testing & Reserve units

Month DD, 200Y

25 units x 100 tabs

Release & Stability Testing

Month DD, 200Y

40 units x 100 tabs

Biostudy & Retained Samples

Month DD, 200Y

60 units x 100 tabs

Balance stored in

Pivotal Warehouse





FINAL BIOEQUIVALENCE REPORT

(Summary Report Here)

FULL BIOEQUIVALENCE PRESENTED IN SEPARATE BINDINGS AS

STAND ALONE VOLUME(S) USING FDA BIO JACKET COVERS (RED).



Bioavailability/ Bioequivalence

24 VOLUME DRUG DEVELOPMENT SERIES Sect: 6.15 Oral Dosage Forms

FINAL REPORT

TITLEBIOEQUIVALENCE Evaluation

of two Oral [Active Material] Preparationsin [00] Healthy Volunteers.

Attached (page Ref.: 00-00) are the actual results including graphs, curves, tabulated results ofdata, individual subject data and summaries and analysis for the invivo bioequivalence for[Applicant Company Name Inc. / Ltd.] the bioequivalence study also contains a description ofthe analytical and statistical methods used in the study. Also Attached (page Ref.: 00-00 -Section 4) is the protocol for the invivo bioequivalence performed by [CRO Testing Lab NameInc. / Ltd.] for [Applicant Company Name Inc. / Ltd.]. the study was conducted with theinformed consent regulations in 21 CFR 50 and in compliance with the institutional reviewboard regulations in 21 CFR 56 (page Ref.: 00-00 - Section 4).

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

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

ANALYTICAL CENTER[CRO Testing Lab Name Inc. / Ltd.]

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

PRINCIPAL INVESTIGATOR [Name of Principal Investigator]Principal Investigator Qualifications

CLINICAL STUDY DATESStart DateCompletion date

Month DD, 2001Month DD, 2001Month DD, 2001

DATE OF COMPLETIONOF FINAL REPORT

Month DD, 2001

Report Code No [S00/00/00]





TABLE OF CONTENTS

VOLUME ONE1. Section :: Project Summary2. Section :: Rationale for [Food] / [Fasting] study.3. Section :: Summary of Statistical Analysis4. Section :: Study protocol, Protocol amendments, Informed Consent, IRB

Approval, and Clinical Report.5. Section :: Summary of Bioavailability Data.6. Section :: Individual Linear and Semi-log graphs7. Section :: Statistical report on [Active Material] and [Active Metabolite M1]

in Plasma8. Section :: Analytical Report for [Active Material]9. Section :: Analytical Report for [Active Metabolite M1]10. Section :: Results of [Active Material] in Plasma11. Section :: Statistical Data of Standards and Quality Control Samples for

[Active Material] in Plasma12. Section :: Chromatograms of [Active Material] in Plasma

VOLUME TWO1. Appendix :: Validation of [Active Material] in Plasma2. Appendix :: Validation Report for [Active Material] in Plasma3. Appendix :: Validation of [Active Metabolite M1] in Plasma4. Appendix :: Validation Report for [Active Metabolite M 1I] in Plasma5. Appendix :: Chromatograms of [Active Material] in Plasma6. Appendix :: Chromatograms of [Active Metabolite M 1] in Plasma7. Appendix :: Data for [Active Metabolite M 1] 8. Appendix :: Statistical Data of Standards and Quality Control Samples

for [Active Metabolite M 1] in Plasma9. Appendix :: Short description of Testing Facilities

Testing Facilities in USTesting Facilities in EuropeBIOMETRICAL Center in US

VOLUME THREE1. Appendix :: Case Records Forms.





STATEMENT OF STUDY FACILITY

This 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, 2000

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

[Name of Principal Investigator] DatePrincipal Investigator





STATEMENT OF TESTING FACILITY

The undersigned hereby conforms that our testing facility in [Address] operates incompliance with all regulatory requirements of the US Food and Drug Administration.

[CRO Testing Facilities in US] [Address] guarantees that at the time of the analysis ofbiological samples performed in the Study No [0000] the [Testing Facilities in US] hadno current outstanding deficiencies as cited by the FDA or other government agencyand that the facility fully met the performance requirements for current Good LaboratoryPractice (cGLP) of the US Food and Drug Administration and US Code 21 FederalRegister.

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

CEO / President





STATEMENT OF BIOMETRICAL FACILITY

his 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, 200Y

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

T





PROJECT SUMMARY

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

This project was designed as a randomized, single dose two way crossovercomparative study of the Bioequivalence and pharmacokinetics of the test preparation:

Dosage Form [00] mg (Generic Company)

versus the

Dosage Form [00] mg (Merck)

The Study was performed in health male volunteers who received a [10] mg single doseof [Active Material] under [Food] / [Fasting] conditions.

Determination of [Active Material] and [Active Metabolite M 1] were performedaccording to SOP 00 on the samples collected following administration of the drugs.[Active Material] concentration in plasma was determined by a validated [GC-MS] /[HPLC] method.

[Active Metabolite M 1] concentration in plasma 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] and [Active Metabolite M 1]In addition, for [Active Metabolite M 1] the principle metabolite responsible for themajority of the pharmacological affects of oral doses of [Active Material], therequirements for Bioequivalence are met.

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

T





TITLE:

BIOEQUIVALENCE EVALUATIONof two Oral [Active Material] Preparations

in [00] Healthy Volunteers

Volume OneSTUDY DATA

Project Summary

Section :: Summary of Statistical Analysis

Section :: Rationale for [Food] / [Fasting] study

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

Section :: Summary of Bioavailability Data

Section :: Individual Linear and Semi-log graphs

Section :: Statistical report on [Active Material] and [Active Metabolite M1] inPlasma

Section :: Analytical Report for [Active Material]

Section :: Analytical Report for [Active Metabolite M1]

Section :: Results of [Active Material] in Plasma

Section :: Statistical Data of Standards and Quality Control Samples for ActiveMaterial] in Plasma

Section :: Chromatograms of [Active Material] in Plasma

Section ::





TITLE:


in [00] Healthy VolunteersVolume Two

APPENDIXES

ACTIVE MATERIAL

Appendix:: Validation of [Active Material] in Plasma

Appendix:: Validation Report for [Active Material] in Plasma

Appendix:: Data for [Active Material]

Appendix:: Chromatograms of [Active Material] in Plasma

ACTIVE METABOLITE - WHERE PRESENT

Appendix:: Validation of [Active Metabolite M1] in Plasma

Appendix:: Validation Report for [Active Metabolite M 1I] in Plasma

Appendix:: Chromatograms of [Active Metabolite M 1] in Plasma

Appendix:: Data for [Active Metabolite M 1]

Appendix:: Statistical Data of Standards and Quality Control Samples for[Active Metabolite M 1] in Plasma

FACILITIES

Appendix:: Short description of Testing Facilities

Appendix:: Testing Facilities in US [Address]

Testing Facilities in Europe [Address]

BIOMETRICAL Center in US [Address]





TITLE


in [00] Healthy Volunteers

Volume ThreeCase Records Forms

Appendix :: Case Records Forms.





Attachments:

Disclosures & CertificationAttached (page Ref.: 00-00) are the signed and completed copies of Certification FinancialInterest & Arrangements of Clinical Investigators Form FDA 3454 (3/99) and DisclosureFinancial Interest & Arrangements of Clinical Investigators. Form FDA 3455 (3/99) asappropriate to the bioequivalence study sponsored by [Applicant Company Name Inc. / Ltd.]and consistent with 21CR Part 54.

1. Certification Financial Interest & Arrangements ofClinical Investigators

Form FDA 3454 (3/99)

2. Disclosure Financial Interest & Arrangements ofClinical Investigators.

Form FDA 3455 (3/99)



SECTION VII SECTION 7

Components and Composition


7.1 Title Page and brief summary statement of what this section contains7.2 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

4





LIST OF COMPONENTS

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


[Active Material] (Active Suppliers Name)

Povidone USP

Colloidal Silicon Dioxide NF

Starch NF

Starch NF (Re-dried)

Anhydrous Lactose NF

Magnesium Stearate NF

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.


Formula

Ingredients

Amount in mg

per [00] mg Tablet

[Active Material] (Active Suppliers Name) 23.601

Povidone USP 9.00


Starch NF 5.30




Total 300.00

Calculation for Active Material Weight on a Dry Basis


1 Note: [00.0] mg for [Active Salt] is equivalent to 00 mg of [Active] base.Quantity of [Active Salt] to be weighed = Batch Size x[00.0] x 100

100 - LoDWhere LoD = Loss on Drying of for [Active Salt] =

2 The actual quantity of Starch NF used in the formula will depend on the WEIGHT of [Active Salt] used.

4





PERCENT COMPOSITION OF THE PRODUCT


Formula

Ingredients

Each 00 mg Tablet

contains (Percentage)

[Active Material] (Active Suppliers Name) 7.871

Povidone USP 3.00


Starch NF 1.76




TOTAL 100.00

Calculation for Active Material Weight on a Dry Basis


1 Note: 00.0 mg for [Active Salt] is equivalent to 00 mg of [Active] base.Quantity of [Active Salt] to be weighed = Batch Size x 00.0 x 100

100 - LoDWhere LoD = Loss on Drying of for [Active Salt] =

2 The actual quantity of Starch NF used in the formula will depend on the WEIGHT of[Active Salt] used.

4



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)

8.9 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).

9.0 Inactive Ingredients9.1 Testing Specifications (ID and characterization)9.2 Suppliers Certificate of Analysis (Specifications and Test Results)

413 of 13






• 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 Certificates of Analysis

• Inactive Ingredient Testing Monographs/Test Procedures

• Routine Testing Protocols

4





OUTLINE OF STANDARD OPERATING PROCEDURES FOR HANDLING 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-housemonograph is required. The in-house monograph forms part of the requirements.

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 full monograph. When the reliability of the vendor’s Certificate of Analysis is established and thevendor is approved, the use of an abbreviated monograph is evaluated.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. Further routinetests 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 stipulated inthe 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 cages orin appropriate refrigerated units. 5. The raw materials shall remain in the quarantine area throughout the QC AnalyticalLaboratory 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 by theQC lab computer. Materials having a green Released label will be transferred to thereleased materials storage area. 3





Summary of Batch Numbers of Active and Inactive Raw Materials Usedin the Executed (Pivotal) Batch - Lot: [IA-00-000]

Raw Material Raw Material Batch Numbers

Used for MNF of Lot:

Lot: [IA-00-000]

Representative

Certificate of Analysis(a)

[Active Material]

(Approved Supplier)Lot # [IA-000] CoA # [IA-000]

Purified Water USP Lot # [IA-000] CoA # [IA-000]

Povidone USP Lot # [IA-000] CoA # [IA-000]

Colloidal Silicone Dioxide NF Lot # [IA-000] CoA # [IA-000]

Starch NF BP Lot # [IA-000] CoA # [IA-000]

Starch NF (Re-dried) Lot # [IA-000] CoA # [IA-000]

Lactose Anhydrous NF Lot # [IA-000] CoA # [IA-000]

Magnesium Stearate NF Lot # [IA-000] CoA # [IA-000]

(a) A Certificates of Analysis is provided for each ingredient lot used in the manufacture ofthe Executed Pivotal batch - Lot: [IA-00-000].

In cases where full monograph testing has not been performed on the specified lot used inthe pivotal batch, a representative Certificate of Analysis (that is, within a six month periodfrom date of batch manufacture) is provided to confirm full monograph testing results.

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

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

• Any batch lot of ACTIVE MATERIAL remaining in warehouse stock for a period exceeding12 months shall be fully re-tested to a full monograph prior to manufacture.




Active Material ControlThe 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

Commitment to Compendial Requirement Testing

THE 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] Tablets [USP] [000.0] mg.[Active Material] (Approved Supplier name) 3

DMF STATUSNo US DMF for Active Material has been lodged with the FDA drug master filelisting (at the time of printing this edition)

Attached URL of all current operational Drug Master Files lodged with the FDA

DMF SEARCH

DRUG MASTER FILES

http://www.iagim.org/search




Active Material Control P h y s i c a l S p e c i f i c a t i o n s

of Active Materials

TEST

METHODS

PHYSICAL SPECIFICATIONS

[ACTIVE MATERIAL]

SPECIFICATIONS TESTRESULTS

TEST 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, Physical

and microbiological tests is attached.




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




Active Material Control

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)




Raw Material ControlNon active Ingredients

C E R T I F I C A T E S O F A N A L Y S I S

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 lot of theingredient is provided as a representative CoA.

Hence, in some cases there are more than one set of THE COMPANY’S Certificatesof Analysis for the same raw material ingredient. The first column in the table (below)represents the routine testing procedure CoA and the second column represents thefull 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] Tablets [USP] [000.0] mg.

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

T





Summary of Certificate of Analysis Numbers of Non-active Raw MaterialsUsed 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

Purified Water USP In-house [CA0326-98] [CA388-98]

Povidone USP GAF USA [CA0526-98] [CA237-98]

Colloidal Silicone Dioxide NF DaGussa US [CA0126-98] [CA0637-98]

Starch NF GP Corp. USA [CA0325-98] [CA0224-98]

Starch NF (Re-dried) GP Corp. USA [CA0076-98] [CA0572-98]

Lactose Anhydrous NF GP Corp. USA [CA0024-98] -

MAGNESIUM STEARATE NF -Synpro - vegetable grage™

Ferro Corp [CA0111-98] [CA0111-98]

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

Date Checks

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

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

Note : Approved NON ACTIVE Suppliers are not an FDA OGD requirements at the time of publishing (January1998)




Raw Material Control -Non active Ingredients

Attachments.

CoAs

• Twelve (12) 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: ___ .




Raw Material ControlNon active Ingredients

ROUTINE TESTINGROUTINE TESTING PERFORMED ON EACH BATCH OF INACTIVE INGREDIENTS.

STARCH NF(Trade Name™)DescriptionIdentification TestViscosityMicrobial Limits

STARCH NF (DRIED)(Trade Name™)DescriptionIdentification TestViscosityMicrobial LimitsLactose Anhydrous NF(Trade Name™)DescriptionIdentification Test

Povidone K90 USP (™)DescriptionSolubilityIdentification TestK-Value

Purified Water USPPer week - Microbial TestingPer month - Full USP Monograph

Colloidal Silicon Dioxide NF(Trade Name™)DescriptionIdentification Test

Magnesium Stearate NF(Trade Name™)DescriptionIdentification TestMicrobial Limits

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.)



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 of thebulk [Generic name] Drug [000.0]mg [USP]. will take place at the pharmaceuticalmanufacturing 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 [GenericCompany Name Inc./Ltd.] Analytical Research / QC Laboratories in accord with theDivision 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 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.

We further certify that there have been no conviction of applicant for any of the typesof crimes set forth 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, nor has any person affiliated with our contracting firm, who is responsiblein whole or in part, for the development or the submission of this application beenconvicted of any crime of the type listed in Section 2(a) and Section 2(b) of theGeneric Drug Enforcement Act of 1992, 21 USC 335a (a) and/or (b), within the fiveyears 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.]



HANDBOOK of GENERIC DRUG DEVELOPMENT ANDA Development


SECTION XI SECTION 11

Proposed Manufacturing Instructions



◊ 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

◊ Equipment Comparison

◊ Description of Packaging Operation

◊ Reprocessing Statement

4





OUTLINE OF STANDARD OPERATING PROCEDURES FOR :MANUFACTURING AND PROCESSING

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

2. Production Planning - Assigns batch numbers, according to the existingcode procedure, and enters these numbers in the batch numbers log.

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

4. Production Planning - 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 Planning - 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.




Proposed Manufacturing InstructionsMANUFACTURING INSTRUCTIONS FOR COMMERCIAL PRODUCTION

Identification of Batch Parameters.

Product name: [Generic name] Tablets [USP] [000.0] mg.Batch Number: [000-00]Department: ______________ Batch Size: [000-00] unitsPrecautions: �� Sub-lot No: þ1 þ 2 ý 3Caution: �� Manufacture Date: Month DD, 199YCat./Formula No: # 00000 Cores þ : Coated þ Tablets þBased on Validation: Batch # 00000 ý Validation Lot

þ Commercial LotChange 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%

Special Note:

A BLANK manufacturing process for film-coated tablets is provided asan example of how to prepare the manufacturing instructions.

Each 'information or data field' is part of the essential record in order tomeet current US cGMP and FDA Pre-approval expectations. Section 12includes a DIRECT COMPRESSION (Alendronate) example.




Proposed Manufacturing InstructionsPROPOSED COMMERCIAL BATCH MASTER FORMULA

[Generic name] Tablets [USP] [000.0] mg. Lot: [0000-00]Batch No: Weighing Date:

PerUNITmg

%Excess Raw Material Names

RM.LotNo

per [000 000] unitsSign

weigh.Dept.

Kg g mg L mL A BPART ONE - GRANULATIONSUBLOT ONE

00.0 [Active Ingredient] 00 00000.0 [Intra-granular excipient NF] 00 00000.0 [Intra-granular excipient NF] 00 000

GRANULATING SOLUTION 1- [Purified Water USP] 00 000 - [Purified Water USP] q.s. 00 000

00.0 [Granulating Agent NF] 00 000- [Alcohol USP 95%] 00 000- [Alcohol USP 95%] q.s. 00 000

000.0 Theoretical End Weight. 00 000

PART ONE - GRANULATIONSUBLOT TWO

[Active Ingredient] 00 00000.0 [Intra-granular excipient NF] 00 00000.0 [Intra-granular excipient NF] 00 000

GRANULATING SOLUTION 2- [Purified Water USP] 00 000- [Purified Water USP] q.s. 00 000



PART TWO - BLENDINGSUBLOTS: ONE + TWO

000.0 Combined Granulates - Sublots 1 +200.0 [Extra-granular Disintegrant NF] 00 00000.0 [Extra-granular Glidant NF] 00 00000.0 [Extra-granular Lubricant NF] 00 000


Edition Number:01

Effective Date: APPROVEDEd. Status:

NewDD/MM/200Y _____________ __________ _______________ _________/________

Department R &D RA QC / QA




Proposed Manufacturing InstructionsPROPOSED COMMERCIAL BATCH MASTER FORMULA

[Generic name] Tablets [USP] [000.0 ³] mg. Lot: [0000-00]

Batch No: Weighing Date:Per

UNITmg


RM.LotNo


weigh.Dept.

Kg g mg L mL A B

PART THREE - AQUEOUS FILMCOAT SUSPENSION ¹

- 00 Aqueous Film Coating Suspension - -

- Purified Water USP 00 00000.0 0PADRY OY-S-0000 [color] 00 000

- Theoretical End Weight. 00 000

PART FOUR - FILM COATING,SUBLOT 11

000.0 [Name] Tablets [000] mg CORES 000

00.0²Name] Tablets [000] mg CORESAqueous Film Coating Suspension

000

000.0 Theoretical End Weight. 000

PART FIVE - FILM COATING,SUBLOT 22

000.0 [Name] Tablets [000] mgCORES

000


000


PART SIX - FILM COATING,SUBLOT 33


000


000


Edition Number:01


NewDD/MM/200Y _____________ __________ _______________ _________/________


¹ Aqueous film coat suspension contains 00.% solids

² Solids remaining in film coat. ³ Each strength has a full set of manufacturing instructions.





MANUFACTURING INSTRUCTIONS MachineNo:

Sign

Sign

Date

1 Identify the equipment and verify the cleanliness prior to use.PART ONE

2. Put into the [Diosna 000] (Type & No) the ingredients in the followingorder:

[Active Material][DRY INGREDIENT NF][DRY INGREDIENT NF]and mix for [ 0 ] minutes at mixer speed I / II and Chopper I / II .

3. Granulation Solution Preparation(i) Weigh [00] Kg [PURIFIED WATER USP] into a stainless steel vesselfitted with a roller mixer. (#0)(ii) Operate the mixer and add the [INGREDIENT NF] and mix until fullydissolved.(iii) While mixing, add the [ALCOHOL USP 95%].

4 Add the granulating solution in the set time to the [Diosna 000] (Type& No) while mixing at mixer speed II and chopper speed II. Total MixingTime is 45 seconds.

Time of adding Solution - [40] secondsTime of mixing - [ 5] seconds

5. If necessary, add the [ALCOHOL USP 95%]. q.s. and/or mix at thesame conditions as in stage 4.Amount of additional [ALCOHOL USP 95%]: __________ Kg.Additional mixing time ___________Seconds

6. Discharge the wet granulate to the FBD mobile bed (Type & No) whilemixing at mixer speed I.

Dry the wet granulate in the FBD (Type & No) under the followingsettings:Inlet Air Temperature NMT 00ºC (Target: 00ºC)Outlet Air Temperature NMT 00ºC (Target: 00ºC)

Attach the temperature graph of the FBD (Type & No) to themanufacturing instructions. Immediately add the batch number to thetemperature graph and date and sign it.

7. Mill about 1Kg. 'check portion' the dried granulate through aOSCILLATING GRANULATOR (Type & No) fitted with a [0.0 mm]screen.





MANUFACTURING INSTRUCTIONS Machine Sign Date

7b. Check the milled granulate portion for Loss on Drying (LOD).Use (Type & No) IR machine with temperature set at temperature 00ºCRecord First result: __________ [0.0%] LOD Limits: [0.0 to 0.0%]

7c. If necessary, continue to dry the bulk granulate under the sameconditions as stage 6, until the LOD is close to the midpoint of the givenrange limits and check moisture again.Record Second result: __________[ 0.0%]

8. Pass the remainder of the dried granulate through the OSCILLATINGGRANULATOR (Type & No) fitted with a [0.0 mm] screen into a [000]liter container or bin.

9. Weigh the milled granulate. ______Kg. Immediately add the batchnumber to the scale print-out, attach to the manufacturing instructions,date and sign the print-out.

10. Theoretical Weight [00.0] Kg. Yield ___________ %(Yield Limits: NLT 95% of Theoretical Weight.) Bins ___________

PART TWO

11. Transfer the milled granulate from stage 10 of both sub lots to a twinshell blender / Flow bin (Type & No).

12. Add to the twin shell blender / Flow bin (Type & No).[INGREDIENT NF]

13. PASS the following material through a sieve (Type & No) fitted with a[00.0] mm screen[GLIDANT INGREDIENT USP][DISINTEGRATING AGENT USP]

14. Add the sieved materials from stage 13 to the blender / Flow bin(Type & No) from stage 12 and mix/blender for [00] minutes. Speed:[00.0] rpm.Mixing Start Time: _________ Mixing Stop Time: _________

15. Collect 10 samples, each equivalent to the approximate weight ofone tablet (000 mg) in labeled sample containers. Collect samples fromupper, middle and lower part of the container. Send the samples to theQC laboratory for Blend Uniformity Testing.

16. Weigh the final blended materialActual weight: [00.0] Kg.Theoretical Weight [00.0] Kg. Yield ___________ %No. of containers _____ .(Yield Limits: NLT 98% of total actual weight from the (2) / (3) sublots,including the dry ingredients added at stage 12 & 14).






PART THREE

Tabletting - Compression17. Identify and verify the cleanliness of the tabletting equipment in useCompress the final blend according to the written product specificationsTabletting machine: (Type & No).Machine Speed _______ Tablets per hourLimit of rpm NLT _______ rpm ; NMT _______ rpm

18. Weigh the tablets:Actual production weight: [00.0] Kg.Weight of Samples taken: [00.0] Kg.Vacuum and rejects Weight: [00.0] Kg.Total weight [00.0] KgNo of Bulk Containers [ 0 ]Theoretical Weight [00.0] Kg. Yield ________ %(Yield Limits: NMT 2% unexplained loss compared to the final blendweight from stage 16.

19. Seal the double PE plastic bags (clear inner, black outer) with plasticties then close all containers, and attach (bar coded) labels to the BulkContainers for transport to the holding area.

PART FOUR20. Identify and verify the cleanliness of the coating equipment.Weigh [00] Kg PURIFIED WATER USP into a stainless steel vesselfitted with a roller mixer. (#0)21. ADD gradually while mixing the [OPADRY S-0000 - Color] to thePURIFIED WATER USP and mix to a uniform dispersion - about 45minutes Mixing time ________minutes.

22. PASS the AQUEOUS FILM COATING SUSPENSION through a [00]mesh screen into a stainless steel container and close well.

23. SPLIT the AQUEOUS FILM COATING SUSPENSION into twoequal sublots and label with (bar-coded) batch number and Sublotnumber.

24. STIR the AQUEOUS FILM COATING SUSPENSION continuouslyduring the coating process.

Edition Number:01


NewDD/MM/200Y _____________ __________ _______________ _________/________







PART FOURCoating Procedure:25. Identify and verify the cleanliness of the coating equipment in useSublot Size ________ Kg. Equal to ___________ tablets. SUB LOT No 1.PREHEATING OF CORES:Coating machine (Type & No) : Extraction Air Temperature: 00ºC - 00ºCIncoming Air Temperature: 00ºC - 00ºCTotal Warming time: [0] MinutesDrum Speed: _________ rpm (minimum speed)Jogging cycle: One cycle every [0] minutes.Limit of rpm: NLT _[0]_ rpm: NMT _[0]_ rpm.

SPRAYING PARAMETERSPump type: PeristalticSpray rate: 000 - 000 g/minNozzles: [0] - [0.0] mmAngle of Guns to Bed: 90 degreesHeight above Bed: [00] cmIncoming Air Temperature: 00ºC - 00ºC (Target: 00ºC)Extraction Air Temperature: 00ºC - 00ºC (Target: 00ºC)

26. Coat tablet cores at a drum speed of [0] - [0] rpm and a spray rate of[000]-[000] g/min until the target COATED tablet weight of [000] mg isobtained. COATING COMPLETION PROCEDURE27. Reduce drum speed to minimum rpm and perform the following:- Reduce set point of incoming air temperature to 00ºC- on reaching this temperature - close the inlet air- continue drum speed until the Extraction Air Temperature reaches 00ºC- 00ºC

28. TRANSFER coated tablets into containers lined with two PE plasticbags (clear inner, black outer) Seal bags with plastic ties and closecontainers, and attach (bar coded) labels to the Bulk Containers fortransport to the holding area.29. Attach the temperature graphs (Type & No) to the manufacturinginstructions. Immediately add the batch / Sublot number to thetemperature graph(s) and date and sign graph.

30. Weigh of Coated tabletsActual production weight: _______ [00.0] Kg. No of Containers _____

Edition Number:01

Effective Date APPROVEDEd. Status:

NewDD/MM/200Y _____________ __________ _______________ _________/________







PART FIVECoating Procedure:25. Identify and verify the cleanliness of the coating equipment in useSublot Size ________ Kg. Equal to ___________ tablets. SUB LOT No 2.PREHEATING OF CORES:Coating machine (Type & No) : Extraction Air Temperature: 00ºC - 00ºCIncoming Air Temperature: 00ºC - 00ºCTotal Warming time: [0] MinutesDrum Speed: _________ rpm (minimum speed)Jogging cycle: One cycle every [0] minutes.Limit of rpm: NLT _[0]_ rpm: NMT _[0]_ rpm.





Edition Number:01


NewDD/MM/200Y _____________ __________ _______________ _________/________







PART SIX

Coating Procedure:25. Identify and verify the cleanliness of the coating equipment in useSublot Size ________ Kg. Equal to ___________ tablets. SUB LOT No 3.PREHEATING OF CORES:Coating machine (Type & No) : Extraction Air Temperature: 00ºC - 00ºCIncoming Air Temperature: 00ºC - 00ºCTotal Warming time: [0] MinutesDrum Speed: _________ rpm (minimum speed)Jogging cycle: One cycle every [0] minutes.Limit of rpm: NLT _[0]_ rpm: NMT _[0]_ rpm.


26. Coat tablet cores at a drum speed of [0] - [0] rpm and a spray rate of[000]-[000] g/min until the target COATED tablet weight of [000] mg isobtained.COATING COMPLETION PROCEDURE27. Reduce drum speed to minimum rpm and perform the following:- Reduce set point of incoming air temperature to 00ºC- on reaching this temperature - close the inlet air- continue drum speed until the Extraction Air Temperature reaches 00ºC- 00ºC

28. TRANSFER coated tablets into containers lined with two PE plasticbags (clear inner, black outer) Seal bags with plastic ties and closecontainers, and attach (bar coded) labels to the Bulk Containers fortransport to the holding area.

29. Attach the temperature graphs (Type & No) to the manufacturinginstructions. Immediately add the batch / Sublot number to thetemperature graph(s) and date and sign graph. 30. Weigh of Coated tabletsActual production weight: _______ [00.0] Kg. No of Containers _____

Edition Number:01


NewDD/MM/200Y _____________ __________ _______________ _________/________






ATTACHMENTS:THE FOLLOWING ATTACHMENTS ARE PLACED HERE:

DryingAttachment # 1 Temperature Print-Outs of Drying Process - Sub lots I, II, III

Milled granulateAttachment # 2 LOD Print-Outs of the Milled Granulate - Sub lots I, II,IIIAttachment # 3 Weight Print-Outs of the Milled Granulate - Sub lots I, II, III

Final BlendAttachment # 4 Mixing time Print-Out of the Final Blend of Sub lots I, II, IIIAttachment # 5 Weight Print-Out of the Final Blend

Attachment # 6 Weight Print-Out of the total cores

Coated Tablets - weightAttachment # 7 Weight Print-Out of the coated tablets sub lot I.Attachment # 8 Weight Print-Out of the coated tablets sub lot II.Attachment # 9 Weight Print-Out of the coated tablets sub lot III.

Coated Tablets - TemperatureAttachment # 10 Temperature profile Print-Out of the coated tablets sub lot I.Attachment # 11 Temperature profile Print-Out of the coated tablets sub lot II.Attachment # 12 Temperature profile Print-Out of the coated tablets sub lot III





IN-PROCESS CONTROL SPECIFICATION

GRANULATION AND TABLETTING SUMMARY

PROPOSED FULL SIZE COMMERCIAL BATCH

Product: [Generic name] Tablets [USP] [000.0] mg. Lot No: [0000]

Quantity [00000][00000] MNF Date: Month DD, 199Y

Dried Granulation Limit: 0.0 - 0.0 %Moisture Content

Milled Granulation Yield Limit: NLT 98.0%

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

In-ProcessFinal Blend Uniformity Limit: 94.0 - 106.0% of labeled amount

RSD ≤ 6.0% (as per attached specifications)

Tabletting Yield NMT 2.0% unexplained loss from theprevious final blend step.

Overall Production Yield NLT 95.0%

¹ Recorded on Statistical Data Work Sheets.





IN-PROCESS CONTROL SPECIFICATION - TABLETCORES

SUMMARY


Product: [Generic name] Tablets [USP] [000.0] mg. - CORESLabeled Amount: Each core contains [Active Material] [000.0] mg.

In-process Specifications for cores.

Punch Diameter 00.00 mmPunch No [00]Die No. [00]

Description [Color] (white to off-white) [shape] (roundbiconvex) core debossed with the number /letters [abc] on one face of the tablet coreand [xyz] on the opposite face.

Scoring [not scored] [scored on one side]

Core Diameter Nominal 00.0 Limit: 00.0 - 00.0 mm

Individual core weight (±7.5%) Nominal 000.0 Limit: 000.0 - 000.0 mg:Average core weight (±5.0%) Nominal 000.0 Limit: 000.0 - 000.0 mg:

Thickness Nominal 00.0 Limit: 00.0 - 00.0 mm

Hardness Target: 00 SCU NLT 0.0 - NMT00 SCU.

Friability NMT 0.0 %





IN-PROCESS CONTROL SPECIFICATION - COATING PROCESSSUMMARY


Product: [Generic name] Tablets [USP] [000.0] mg. Lot No: [0000]

Quantity [00000][00000] MNF Date: Month DD, 199Y

Film Coating Controls Before Coating After Coating¹Theoretical Tablet weight (mg) 000.0 -

¹Target Coated weight (mg) - 000.0

¹Weight of 100 tablets #1 (g) 000.0 000.0¹Weight of 100 tablets #2 (g) 000.0 000.0¹Weight of 100 tablets #3 (g) 000.0 000.0¹Weight of 100 tablets #4 (g) 000.0 000.0¹Weight of 100 tablets #5 (g) 000.0 000.0

¹Average tablet 100 weight (g) 000.0 000.0

¹Average tablet weight (mg) 000.0 000.0

In-Process Yields

¹Yield after coating vs. Pre-coating 00.0%

¹Yield after coating to theoretical 00.0%

Film Coating Yield NMT 2.0% unexplained lossfrom the previous step (tabletting)

¹ Recorded on Statistical Data Tablet Coating Work Sheets.



Differencein dissolution profilefor controlled release

dosage forms


Proposed Manufacturing InstructionsRELEASE SPECIFICATION FOR COATED CR/MR TABLETS [USP]

SUMMARY


Product: [Generic name] Tablets [USP] [000.0] mg.

Labeled Amount: Each tablet contains: [Active Material] [000.0] mg.

Description [Color] (white to off-white) shaped (roundbiconvex) Tablet debossed with the number/letters [abc] on one face of the Tablet and[xyz] on the opposite face

Identification A The Infra Red Absorption Spectrumconforms to the Reference Standard

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

Individual Tablet weight (±7.5%) Nominal 000.0 Limit: 000.0 - 000.0 mgAverage Tablet weight (±5.0%) Nominal 000.0 Limit: 000.0 - 000.0 mg

Uniformity of Dosage Units Conforms to the current USPContent Uniformity

Dissolution Equipment: USP App. No 1 or 2 (Paddle)4 hr. 10 - 30 % Media: 000 mL, 37 C. [00]% of [Sodium8 hr. 35 - 75 % lauryl Sulphate in 0.1N Phosphate Buffer]12 hr. 50 - 90 % pH 0.0 RPM 0024 hr. ò75 %

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 Limit: 90.0 - 110.0% of labeled amount[00.0] - [00.0] mg / Tablet

Note:Residual Solvent if present in the coating solution require a release specification such as; Residual Solvents

- Acetone NMT 500 ppm- Ethanol NMT 1000 ppm- Isopropanol NMT 10 000 ppm




Proposed Manufacturing InstructionsRELEASE SPECIFICATION FOR COATED IR TABLETS [USP]

SUMMARY


Product: [Generic name] Tablets [USP] [000.0] mg.Labeled Amount: Each tablet contains: [Active Material] [000.0] mg.

Description [Color] (white to off-white) shaped (roundbiconvex) Tablet debossed with the number/letters [ABC] on one face of the Tablet and[XYZ] on the opposite face.


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

Individual Tablet weight (±7.5%) Nominal 000.0 Limit: 000.0 - 000.0 mgAverage Tablet weight (±5.0%) Nominal 000.0 Limit: 000.0 - 000.0 mg


Dissolution Equipment: USP App. No 1 or 2 (Paddle)Media: 000 mL, 37 C. [00]% of [Sodiumlauryl Sulphate in 0.1N Phosphate Buffer]pH [0.0] RPM [00]

Tolerance: NLT [00]% (Q) of the labeledis dissolved in [00] minutes.

Impurities /DegradationProducts 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 Limit: 90.0 - 110.0% of labeled amount[00.0] - [00.0] mg / Tablet

IR = IMMEDIATE RELEASE ER = EXTENDED RELEASE

CR = CONTROLLED RELEASE DR = DELAYED RELEASE (ENTERIC COATED)





COMPARISON OF EXECUTED (PIVOTAL) AND PRODUCTION FORMULAE


INGREDIENT

AMOUNT PERTABLETS

(MG)

EXECUTEDBATCH

200,000 TABLETS(KG)

PRODUCTIONBATCH800 000

TABLETS(KG)

Active Ingredient [Source]

Povidone USP

Colloidal Silicon Dioxide

NF

Starch NF

Starch NF (Re-dried)

Anhydrous Lactose NF

Magnesium Stearate NF

Total 140.000 28.000 98.000

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


1 Note: [00.0] mg for [Active Salt] is equivalent to [00.0] mg of [Active] base.

Quantity of [Active Salt] to be weighed = Batch Size x [00.0] x 100 100 - LOD

Where LOD = Loss on Drying of for [Active Salt] =

2 The actual quantity of a non active ingredient such as Starch NF used in the formula will depend on the WEIGHT for [Active Salt] used.





COMPARISON OF EQUIPMENT AND MANUFACTURING CONDITIONS BETWEEN EXECUTED AND PRODUCTION BATCHES

IMMEDIATE RELEASE TABLETS

Equipment andManufacturing

Conditions

ExecutedBatch

200,000 units

ProductionBatch

800,000 unitsPremixing Diosna 25 Diosna 300

Granulating - High Speed

Granulator Diosna 25 Diosna 300

Drying FBD 30 FBD 120

Milling - Oscillating

Granulator

Frewitt Frewitt

Blending Y-cone 50 Y-cone 120

Tabletting Machine FETTA 2000 /

Kilian T-300

FETTA 2000 /

Kilian T-300

Coating Suspension

Mixing Equipment

Stainless Steel

Container

with Roller Mixer

80 mesh Screen

Stainless Steel

Container

with Roller Mixer

80 mesh Screen

Coating Unit AccelaCota™ AC

48/150

AccelaCota™ AC

48/150

Equipment Variation NONE NONE

Manufacturing Area Production Production

Staff Production Production

SOP Production Production



DIRECT COMPRESSIONMODEL

ALENDRONATE TABLETS

5.0 AND 10 mg

DC TABLETS





Identification of Batch Parameters.

Product name: Alendronate Tablets 5.0 and 10 mg.Batch Number: IA97-06Department: ______________ Batch Size: 1000 000 unitsPrecautions: �� Sub-lot No: þþ1 ý 2 ý 3Caution: �� Manufacture Date: 200YCat./Formula No: # MF-104 Cores ý : Coated ý Tablets þBased on PQ: Batch # PQ106 þþ PIVOTAL BATCH

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

KEY to :Precautions: �� Wear Mask and Gloves

�� Wear disposable overalls

�� Use air stream face visor with AIR filter

�� Use Mask, Gloves and Safety glassesMaterial causes extreme irritation to skin and eyesDo not expose to skin or exposed areas.

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

�� Store in well closed containers and minimize or avoidexposure to environmental air

�� Raw material has to be stored at 5°°C - hold active material at 25o C for one hour to reach room temperaturebefore weighing, sampling or processing

�� Potential danger to pregnant women, pregnant women are prohibited in this area

�� Do not heat above [00]øøC

� Maintain Room humidity below 50%





ALENDRONATE TABLETS 5.0 /10mg LOT: IA97-06

Batch No: IA97-06 Weighing Date: 97-06Per100mg


RM.LotNo

per 1 000 000 unitsSign

weigh.Dept.

Kg g mg L mL A B

PART ONE - DRY MIXING

24.50 Lactose Monohydrate NF(Spray dried)

24 500

17.00 Microcrystalline Cellulose NF(Avicel PH-200)

17 000

6.525 Alendronate Na (calculated asequivalent salt)*

6 525

PART TWO - DRY MIXINGDRY BLENDING

24.50 Lactose Monohydrate NF(Spray dried)

24 500

17.00 Microcrystalline Cellulose NF(Avicel PH-200)

17 000

3.475 Povidone USP(PVP K-30)

3 475

5.50 Sodium Starch Glycolate NF(Primojel)

5 500

PART THREEDRY BLENDING

0.75 Silicon Dioxide NF(Aerosil 200)

0 750

0.75 Magnesium Stearate NF 0 750


100 Tablet weight 5 mg200 Tablet weight 10mg

Edition Number:02


SPDS 01DD/MM/200Y _____________ __________ _______________ _________/________


* 13.05 mg of sodium salt is equivalent to free acid





ALENDRONATE TABLETS 5.0 /10 MG LOT: IA97-06


Step 1.IDENTIFY the equipment in room number [ ] and verify theequipment and room cleanliness prior to use.

PART ONE

Step 2.PLACE into an appropriate blender [Sigma or Ribbon Blender](state specify Type & No) the ingredients in the following order:

Microcrystalline Cellulose NF - (Avicel PH-200)Lactose Monohydrate NF - (Spray dried lactose)Alendronate Sodium

MIX for 8 minutes at 20 (± 2) rpm .Record the mixing time:-Mixing time - Start _______Mixing time - Stop _______Total Mixing Time is 8 minutes.

PART TWOStep 3.Put into the blender [Sigma or Ribbon Blender] (Type & No) thebalance ingredients in the following order:

Microcrystalline Cellulose NF - (Avicel PH-200)Lactose Monohydrate NF - (Spray Dried Lactose)Povidone USP - (PVP K-30)Sodium Starch Glycolate NF - (Primojel)

and mix for 15 minutes at 20 (± 2) rpm .

Record the mixing timeMixing time - Start _______Mixing time - Stop _______

Total Mixing Time is 23 minutes.

Edition Number:02


SPDS 01DD/MM/200Y _____________ __________ _______________ _________/________






ALENDRONATE TABLETS 5.0 /10 MG LOT: IA97-06MANUFACTURING INSTRUCTIONS Machine Sign Date

Step 4.DISCHARGE and transfer the contents of the blender [Sigma orRibbon Blender] from step 3 into a Y-cone / twin shell blender orFlow bin (Type & No) and blend for [15] minutes. Speed: 10.0 (±2) rpm.Record the blending timeMixing time - Start _______Mixing time - Stop _______Total blending Time is 15 minutes.

Step 5.SIFT the Magnesium Stearate NF through a vibrating sieve (Type& No) fitted with a 100.0 mesh screen.

Step 6.ADD the sieved material Magnesium Stearate NFfrom step 5 to the twin shell blender / Flow bin (Type & No).

Step 7. ADD the Silicon Dioxide NF (Aerosil 200) to the blender /Flow bin and blend for [5] minutes. Speed: 10.0 (± 2) rpm.Record the blending timeMixing time - Start _______ Mixing time - Stop _______Total blending Time is 20 minutes.

Step 8. Collect 10 samples, each equivalent to the approximateweight of three tablet (300 [5mg tab] or 600mg [10mg tab]) inlabeled sample containers. Collect samples from upper, middleand lower part of the blender. Send the samples to the QClaboratory for Blend Uniformity Testing.

Step 9. Weigh the final blended materialNo. of containers _____. Actual weight: [ ] Kg.Theoretical Weight [100.0] Kg. Yield ___________ %

(Yield Limits: NLT 98% of total actual weight including the dryingredients added at stage 5 & 6).

Immediately add the batch number to the scale print-out, attach tothe manufacturing instructions after dating and signing it.Number of Bins __________Edition Number:

02Effective Date: APPROVED

Ed. Status:SPDS 01

DD/MM/200Y _____________ __________ _______________ _________/________ Department R &D RA QC / QA






PART THREE - STORAGE

Step 10.Discharge the material into drums lined with two polyethylene bags or into theFlow-Bin

PART FOUR - COMPRESSIONCAUTION - IMPORTANT NOTEEnsure that the relative moisture of the air in the compartment doesnot exceed 50% - remove vacuum line from the rotating table of thetabletting machine

Step11.Tabletting - Compression unit, room number [ ]. Identify and verifythe cleanliness of the tabletting equipment in use.

Step12Compress the final blend according to the written productspecificationsTabletting machine: (Type & No).Target Machine Speed _______ Tablets per hourLimit of rpm NLT 70 % of rpm ; NMT 120 of target rpm

Step13Weigh the tablets:Actual production weight: [100.0] Kg - 5mg TabsActual production weight: [200.0] Kg - 10mg Tabs.Weight of Samples taken: [ ] Kg.Vacuum and rejects Weight: [ ] Kg.Total weight [ ] KgNo of Bulk Containers [ ]Theoretical Weight [ ] Kg.

Calculate the actual production yield:Yield ___________ %(Yield Limits: NMT 2% unexplained loss compared to the finalblend weight from Step 8.

Step14.Seal the double PE plastic bags (clear inner, black outer) withplastic ties then close all containers, and attach (bar coded) labelsto the Bulk Containers for transport to the holding area.

Edition Number:01

Effective Date: APPROVEDEd. Status

NewDD/MM/200Y _____________ __________ _______________ _________/________


HANDBOOK of GENERIC DRUG DEVELOPMENT ANDA DEVELOPMENT




ALENDRONATE TABLETS 5.0 /10 MG LOT: IA97-06


Mixing TimeAttachment # 1 Mixing time Print-Out - Step 2Attachment # 2 Mixing time Print-Out - Step 3

Final BlendAttachment # 3 Mixing time Print-Out of the intermediate Blend - Step 4Attachment # 4 Mixing time Print-Out of the Final Blended material - Step 7Attachment # 5 Weight Print-Out of the Final Lubricated material - Step 9

Compressed TabletsAttachment # 6 Weight Print-Out of the bulk tablets - Step 13





IN-PROCESS CONTROL SPECIFICATION - BLENDED MATERIAL

SUMMARY OF YIELD AND LIMIT VALUES FOR

ALENDRONATE TABLETS 5.0 /10 mg LOT: IA97-06

MANUFACTURING INSTRUCTIONS FOR COMMERCIAL PRODUCTION

Product: ALENDRONATE TABLETS 5.0 /10mg LOT: IA97-06

Quantity 1000 000

YieldsFinal Blend Yield Limit: NLT 98.0%




Tabletting Yield NMT 2.0% unexplained loss from theprevious final blend step.






Proposed Manufacturing Instructions IN-PROCESS CONTROL SPECIFICATION

TABLET þþ / CORES ýýMANUFACTURING INSTRUCTIONS FOR COMMERCIAL PRODUCTION

Product: ALENDRONATE TABLETS 5.0 /10 mg LOT: IA97-06

Labeled Amount: Each tablet contains ALENDRONATE 5.0 or 10.0 mg.

In-process tablet specifications

Punch Diameter 5.0mg 6.5 mmPunch Diameter 10.0mg 8.00 mm

Punch No - 5.0 mg [P044]Die No. - 5.0 mg [D044]

Punch No - 10.0 mg [P025]Die No. - 10.0 mg [D125]

Description White to off-white round biconvex tablet debossed with the number /letters [5 or 10 ] on one face of the tablet

Scoring [not scored]

Core Diameter 5mg Nominal 6.5 mm Limit: 6.4 - 6.6 mmCore Diameter 10mg Nominal 8.0 mm Limit: 7.9 - 8.1 mm

5 mg TABLETIndividual core weight (±7.5%) Nominal 100.0 Limit: 92.5 - 107.5 mg:Average core weight (±5.0%) Nominal 100.0 Limit: 95.0 - 105.0 mg:

10 mg TABLETIndividual weight (±7.5%) Nominal 200.0 Limit: 185.0 - 215.0 mg:Average weight (±5.0%) Nominal 200.0 Limit: 190.0 - 210.0 mg:

Thickness 5.0mg Nominal 3.0 Limit: 2.80 - 3.80 mmThickness 10.0mg Nominal 4.0 Limit: 3.80 - 4.80 mm

Hardness 5.0mg Target: 8 SCU NLT 6.0 - NMT 14 SCU.Hardness 10.0mg Target: 10 SCU NLT 8.0 - NMT 16 SCU.





Proposed Manufacturing InstructionsRELEASE SPECIFICATION FOR TABLETS

PRODUCT: ALENDRONATE TABLETS 5.0 / 10 mg LOT: IA97-06

Labeled Amount: Each tablet contains ALENDRONATE 5.0 or 10.0 mg

DescriptionWhite to off-white) round biconvex tabletdebossed with the number /letters [5 or 10 ]on one face of the tablet



5 mg TABLETIndividual weight (±7.5%) Nominal 100.0 Limit: 92.5 - 107.5 mg:Average weight (±5.0%) Nominal 100.0 Limit: 95.0 - 105.0 mg:10 mg TABLETIndividual weight (±7.5%) Nominal 200.0 Limit: 185.0 - 215.0 mg:Average weight (±5.0%) Nominal 200.0 Limit: 190.0 - 210.0 mg:


Dissolution Equipment: USP App. 2 (Paddle)Media: 900 mL, 37 C. Deaerated WaterpH 6.8 RPM 100 Tolerance: NLT [80]% (Q) of the labeledis dissolved in [30] minutes.

Impurities /Degradation(1) 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 Limit: 95.0 - 105.0% of labeled amount5mg Equal to [4.75] - [5.25] mg / Tablet.

Assay Limit: 95.0 - 105.0% of labeled amount10 mg Equal to [9.5] - [10.5] mg / Tablet.

(1)Vendor or approved supplier dependent.



50%

50%

50%

50%

ALENDRONATE TABLETS 5.0 /10 mg LOT: IA97-06

Manufacturing Flowchart [II]

Tumbler Y-cone5 min @10 rpm

Blender8 min @ 20 rpm

Blender15 min @ 20 rpm

COMPRESSTarget 80 000 tabs/hr

DC TABLETS

LACTOSE(49%)

Active Material(6.525%)

LubricantAEROSIL (0.75%)

Mag. stearate (0.75%)

MICROCRYSTALLINECELLULOSE (17%)

Sieve100 MESH

SODIUM STARCHGLYCOLATE (5.5%)

Sieve(Where necessary)

0.8 mm

To Filling

IPQCID

Content Uniformity

QCWeight uniformity

ThicknessHardness

Disintegration

PVP K30 (3. 5%)

MICROCRYSTALLINECELLULOSE (17%)

Tumbler Y-cone15 min @ 10 rpm

RELEASEID

AssayContent Uniformity

Dissolution





COMPARISON OF EXECUTED (PIVOTAL) AND PRODUCTION FORMULAE

ALENDRONATE TABLETS 5.0 /10 mg

LOT: IA97-06

Ingredient

Amount pertablets(mg)

Executed Batch1 000,000

tablets(kg)

Production Batch2 000 000 tablets

(kg)

Alendronate Sodium 6.525 6.525 13.050

Microcrystalline cellulose

NF

34.000 34.000 64.000

Lactose monohydrate Spray

Dried NF

49.000 49.000 98.000

Povidone K30 USP 3.475 3.475 6.950

Sodium Starch Glycolate NF 5.500 5.500 11.000

Colloidal Silicon Dioxide

NF

0.750 0.750 1.500

Magnesium Stearate NF 0.750 0.750 1.500

Total 100.000 100.000 200.000




Proposed Manufacturing InstructionsGENERAL PACKAGING OPERATION DESCRIPTION

TABLETS [USP] - SCHEMATIC PRESENTATION

Stage One.PACKAGING COMPONENTS:

1. Bulk Product 2. HDPE Containers 3. Package Insert / Outsert (Product Leaflets) 4. Desiccant (Silica Gel) 5. Container Label 6. Master Cartons 7. Carton Shipping Labels

Stage TwoPACKAGING PROCEDURE:

HDPE Container & Bulk Line Feed

⇓

HDPE Container CleaningProcess

(Air and Vacuum)

⇓Tablet Count & Fill

⇓Cotton Coil

⇓Insert / Leaflet

Capping (Screw or CRC)

⇓Closure Torque Test

⇓or Outsert Attaching

⇓Container Label

⇓

Packed in Master ShippingCartons




Proposed Manufacturing InstructionsSCHEMATIC PACKAGING OPERATION - EQUIPMENT LISTING:


No. Machine Operation Manufacturer

Supplier

Type Serial # OutputCONTAINERS

per min (2)

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 Lakso Counting &

Filling Tablets

Lakso MA US SLAT

FILLER(1)

L-333

L-334

Count

4 RSP Coiler Dessicant

Insertion

H.G. Kalish Inc.,

Canada

5329 2169-

0003

50 Low

100 High

5 RSP Coiler Cotton

insertion

H.G.Kalish Inc.,

Canada

KOTNR-120-

8440

2234-

9987

50 Low

100 High

6 Groninger Capping Groninger & Co

Germany

DFVK

6000

2232-

2234

50 Low

100 High

7. Groninger Outserter Groninger & Co

KarlsHeim,

Germany

DFVK

3000

5664 50 Low

100 High

8. 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 Tablet Slate Filler rate.

50 10050* 100*





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] Date

Director 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

Tablet WeightTablet HardnessTablet ThicknessTablet FriabilityTablet Dissolution at lower hardness limitTablet Dissolution at target hardness limitTablet Dissolution at upper hardness limitAt 3 months stability station (40o C / 60% 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 the reworking of Stage Two (slugging and Milling) may berepeated once as shown, without affecting or impacting on the products physicalparameters as 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.]





Set of Instructions for each strengthA complete set of manufacturing instructions must be provided for eachstrength of dosage form.

If the dosage form has 5 strengths e.g. 10mg, 20mg, 30mg, 40mg, 80mg -five sets of manufacturing and packaging instructions is presented in theANDA file.

Set of specifications for each strengthA complete set of specifications (in-process, tablet cores and film coatedtablets) must be provided for each strength of dosage form.

If the dosage form has 5 strengths e.g. 10mg, 20mg, 30mg, 40mg, 80mg -five sets of specifications are presented in the ANDA file.

Set of Tables for each strengthA complete set of Tables (equipment listing, comparison of equipment etc.) mustbe provided for each strength of the dosage form.

If the dosage form has 5 strengths e.g. 10mg, 20mg, 30mg, 40mg, 80mg -five sets of Tables are presented in the ANDA file.

File TIP.REMEMBER THIS PRINCIPLE APPLIES TO SECTION 12 AS WELL WHERE ACOPY OF THE ACTUAL EXECUTED BATCH RECORD INCLUDING ALLSPECIFICATIONS PER STRENGTH IS PROVIDED.

REMEMBER IF ANY DOCUMENTS ARE PROVIDED FOR ONE DOSAGESTRENGTH - THEN THE SAME DOCUMENT SET MUST BE PROVIDED FOR ALLOTHER DOSAGE STRENGTHS APPLIED FOR.



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

SPECIAL NOTE

Delete specific data or delete whole sections which are not applicable tothis Section 12 of the ANDA

Note the use of bold and square brackets 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 Record

• Packaging Records

• Summary of Tablet Hardness Verification

• Packaging and Disbursement Summary

4





OUTLINE OF STANDARD OPERATING PROCEDURES 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 Tablets.

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

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

4




Pivotal Manufacturing and ControlsIN-PROCESS CONTROLS DURING TABLET COMPRESSION

In-process testing is conducted independently by both production and quality controltrained personnel. The tests specified in the underlying tables are performed in accordwith the in-process product specifications. When, a test is not required, according tothe written specifications, it will not be performed.

Production personnel test the physical specifications of random samples accordingto the individual product specifications: A minimum sampling frequency is tabulated foreach eight hour (shift) period.

Production In-process Testing Schedule:

TestPERFORMED

SampleSize

Frequencyper shift (1) (min)

AcceptanceCriteria (2)

Average Weight 10 At 15 min. intervals. Within specified range.

Thickness 10 3 times(1)

NMT 2 tablets out of the 10 testedcan deviate from productspecifications.No deviation is allowed fromDouble Limits(4) specification.

Hardness 10 3 times(1)

NMT 2 tablets out of the 10 testedcan deviate from productspecifications.No deviation is allowed fromDouble Limits(3) specification.

Friability20 or 40

According toeach product

TwiceNo deviation from productspecifications is permitted.

Disintegration 6 Twice No deviation from productspecifications is permitted.

KEY:

(1) The testing frequency is performed twice when the overall compression time is less than fourhours.

(2) Deviations from specifications and acceptance criteria, arising during the in-process controls,shall determine the corrective action to be performed on the tableting machinery during thecompression stage.

(3) Double Limits for Tablet Hardness Test are defined as c-±20% from the minimum andmaximum product specifications limits. When, there is a NLT 10 SCU Hardness specification, thedouble limits may not exceed a minimum value of 8 SCU. (Not go below 8 SCU).

(4) Double Limits for Tablet Thickness Tests are defined as c-± 0.1 mm from the minimum andmaximum values in the specifications. C is the limit value




Pivotal Manufacturing and ControlsQuality Control personnel test the physical specifications of random samplesaccording to the individual product specifications sheets: A minimum samplingfrequency is tabulated for each eight hour (shift) period.

Quality Control - In-process Testing Schedule:

TestPERFORMED

SampleSize

(Tablets)

Frequencyper shift (1)

(min.)

AcceptanceCriteria (2)

Individual Tablet

Weight

20 (1) Twice NMT 2 tablets out of the 20 tested candeviate from product spec. No deviationis allowed from Double Limits(3) spec.

Thickness 10 (1) Twice NMT 2 tablets out of the 10 tested candeviate from product spec. No deviationis allowed from Double Limits(4) spec.

Hardness 10 (1) Twice NMT 2 tablets out of the 10 tested candeviate from product spec. No deviationis allowed from Double Limits(5) spec.

Diameter3 (1) Once

at startNo deviation from product specificationis allowed.

Friability 20 -40 (1)

According toproduct

TwiceNo deviation from product specificationis allowed

Disintegration 6 (1) Twice No deviation from product specificationis allowed

KEY:

(1) Samples are taken, independently by QC personnel for batch release purposes, at least onceper hour throughout the tableting run, producing a total representative sample quantity of 300 -500 tablets. This representative sample lot is for QC batch release purposes .

(2)Deviations from specifications and acceptance criteria, arising during the in-process controls,shall determine the corrective action to be performed on the tabletting machinery during thecompression stage.

(3)Double Limits for the Individual Tablet Weight test are defined as the double value from theminimum or maximum limit in relation to the nominal tablet value (i.e. target weight value).

(4) Double Limits for Tablet Thickness Tests are defined as c-± 0.1 mm from the minimum andmaximum specification limit values. Where C = limit value.

(5) Double Limits for Tablet Hardness Test are defined as c-±20% from the minimum andmaximum product specifications limits. When, there is a NLT 10 SCU Hardness specification, the double limits may not exceed aminimum value of 8 SCU. (Not go below 8 SCU) .

Target Value Upper limitLower LimitDouble this value Double this value

DOUBLE VALUES





OUTLINE OF STANDARD OPERATING PROCEDURES FOR:SAMPLING PLAN OF PIVOTAL LOTS FOR STABILITY STUDIES

AND BIOAVAILABILITY STUDIES.

tandard Operating Procedures are in place at the commercial manufacturingfacility, defining the packaging procedures for pivotal lots and sampling ofrepresentative packages for stability and bioavailability studies. Theseprocedures are summarized below.

The entire pivotal lot (100%) is packaged in the commercial production packagingdepartment, using production equipment, operated by the routine productionpersonnel.

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 packaging sampled, is calculated in order obtainapproximately equal numbers of each package 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 stability studies andbioavailability studies.

The sampling plan is representative of the entire pivotal batch.

4

S




Pivotal Manufacturing and ControlsEXECUTED PIVOTAL BATCH MANUFACTURING INSTRUCTIONS

Product name: [Generic name] Tablets USP [000.0] mg.Batch Number: [IA-000-00]Department: ______________ Batch Size: 000-000 unitsPrecautions: �� Sub-lot No: þ1 þ 2 ý 3Caution: �� Manufacture Date: Month DD, YYYYCat./Formula No: # IAG0000 Cores þ : Coated þ Tablets þBased on PQ: Batch # IAG0000 þ PIVOTAL BATCH

þþ Validation Lot ý Commercial LotChange 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%

Note:

(Manufacturing process for film-coated tablets is provided as an exampleof how to prepare the manufacturing instructions. This specific set ofmanufacturing instructions was chosen as it represents the written detailrequired to produce clear manufacturing instructions).

Edition Number:01


New DD/MM/YY _____________ __________ ____________ _________/________





Pivotal Manufacturing and ControlsEXECUTED PIVOTAL BATCH MASTER FORMULA

[Generic name] Tablets USP [000.0] mg. [IA-000-00]Batch No: Weighing Date:

PerUNITmg


RM.LotNo


weigh.Dept.

Kg g mg L mL A BPART ONE - GRANULATIONSUBLOT ONE

00.0 [Active Ingredient] 00 00000.0 [Intra-granular excipient NF] 00 00000.0 [Intra-granular excipient NF] 00 000

GRANULATING SOLUTION 1- [Purified Water USP] 00 000 - [Purified Water USP] q.s. 00 000



PART ONE - GRANULATIONSUBLOT TWO

[Active Ingredient] 00 00000.0 [Intra-granular excipient NF] 00 00000.0 [Intra-granular excipient NF] 00 000

GRANULATING SOLUTION 2- [Purified Water USP] 00 000- [Purified Water USP] q.s. 00 000



PART TWO - BLENDINGSUBLOTS: ONE + TWO

000.0 Combined Granulates - Sublots 1 +200.0 [Extra-granular Disintegrant NF] 00 00000.0 [Extra-granular Glidant NF] 00 00000.0 [Extra-granular Lubricant NF] 00 000


Edition Number: 01 Effective Date APPROVEDEd. Status:

New DD/MM/YY _____________ __________ ____________ _________/________





Pivotal Manufacturing and ControlsEXECUTED PIVOTAL BATCH MASTER FORMULA

[Generic name] Tablets USP [000.0] mg. [IA-000-00]Batch No:Weighing Date:

PerUNITmg

%Excess

Raw Material Names RM.LotNo


weigh.Dept.

PART THREE - AQUEOUS FILMCOAT SUSPENSION ¹

- 00 Aqueous Film Coating Suspension - -- Purified Water USP 00 000

00.0 0PADRY OY-S-0000 [color] 00 000- Theoretical End Weight. 00 000

PART FOUR - FILM COATING,SUBLOT 11

000.0 [Name] Tablets [000] mg CORES 000


000


PART FIVE - FILM COATING,SUBLOT 22


000


000


PART SIX - FILM COATING,SUBLOT 33


000


000



New DD/MM/YY _____________ __________ ____________ _________/________


¹ Aqueous film coat suspension contains 00.% solids² Solids remaining in film coat






1 Identify the equipment and verify the cleanliness prior to use.

PART ONEStage 1.2. Put into the [Diosna 000] (Type & No) the ingredients in the followingorder:

[Active Material][DRY INGREDIENT NF][DRY INGREDIENT NF]and mix for [ 0 ] minutes at mixer speed I / II and Chopper I / II .

Stage 2.3. Granulation Solution Preparation(i) Weigh [00] Kg [PURIFIED WATER USP] into a stainless steel vesselfitted with a roller mixer. (#0)(ii) Operate the mixer and add the [INGREDIENT NF] and mix until fullydissolved.(iii) While mixing, add the [ALCOHOL USP 95%].Stage 2a.4. Add the granulating solution in the set time to the [Diosna 000] (Type& No) while mixing at mixer speed II and chopper speed II. Total MixingTime is 45 seconds.

Time of adding Solution - [40] secondsTime of mixing - [ 5] seconds

5. If necessary, add the [ALCOHOL USP 95%]. q.s. and/or mix at thesame conditions as in stage 4.Amount of additional [ALCOHOL USP 95%]: __________ Kg.Additional mixing time ___________Seconds

6. Discharge the wet granulate to the FBD mobile bed (Type & No) whilemixing at mixer speed I.Stage 3.Dry the wet granulate in the FBD (Type & No) under the followingsettings:Inlet Air Temperature NMT 00ºC (Target: 00ºC)Outlet Air Temperature NMT 00ºC (Target: 00ºC)

Attach the temperature graph of the FBD (Type & No). to themanufacturing instructions. Immediately add the batch number to thetemperature graph and date and sign it.Stage 4.7. Mill a 1Kg. Check portion the dried granulate through a OSCILLATINGGRANULATOR (Type & No). fitted with a [0.0 mm] screen.


New DD/MM/YY _____________ __________ ____________ _________/________







7b. Check the milled granulate portion for Loss on Drying (LOD) Use(Type & No) IR machine with temperature set at 00ºCRecord first result: __________[ 0.0%] LOD Limits: [0.0 to 0.0%] 7c. If necessary, continue to dry the bulk granulate under the sameconditions as stage 6, until the LOD is close to the midpoint of the givenrange limits and check moisture again.Record second result: __________[ 0.0%]

Attach the temperature graph of the FBD (Type & No) to themanufacturing instructions. Immediately add the batch number to thetemperature graph and date and sign it.

8. Pass the remainder of the dry granulate through an OSCILLATINGGRANULATOR (Type & No) fitted with a [0.0 mm] screen into a [000]liter container / bin.

9. Weigh the milled granulate ______Kg. Immediately add the batchnumber to the scale print-out, attach to the manufacturing instructionsafter dating and signing it.

10. Theoretical Weight [00.0] Kg. Yield ___________ %(Yield Limits: NLT 95% of Theoretical Weight.) Bins ___________

PART TWOStage 5.11. Transfer the milled granulate from stage 10 of both sub lots to a twinshell blender / Flow bin (Type & No).

12. Add to the twin shell blender / Flow bin (Type & No).[INGREDIENT NF]

13. PASS the following material through a sieve (Type & No) fitted with a[00.0] mm screen.[GLIDANT INGREDIENT USP][DISINTEGRATING AGENT USP]Stage 6.14. Add the sieved materials from stage 13 to the blender / Flow bin(Type & No) from stage 12 and mix/blender for [00] minutes. Speed:[00.0] rpm.Mixing Start Time: _________ Mixing Stop Time: _________

15. Collect 10 samples, each equivalent to the approximate weight ofone tablet (000 mg) in labeled sample containers. Collect samples fromupper,middle and lower part of the container. Send the samples to theQC laboratory for Blend Uniformity Testing.

16. Weigh the final blended material No. of containers _____ .Actual weight: [00.0] Kg.Theoretical Weight [00.0] Kg. Yield ___________ %(Yield Limits: NLT 98% of total actual weight from the (2) / (3) sublots,including the dry ingredients added at stage 12 & 14).Edition Number: 01 Effective Date APPROVED

Ed. Status:New

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






PART THREEStage 7.Tabletting - Compression17. Identify and verify the cleanliness of the tabletting equipment in useCompress the final blend according to the written product specifications

Tabletting machine: (Type & No).Machine Speed _______ Tablets per hourLimit of rpm NLT _______ rpm ; NMT _______ rpm

18. Weigh the tablets:Actual production weight: [00.0] Kg.Weight of Samples taken: [00.0] Kg.Vacuum and rejects Weight: [00.0] Kg.Total weight [00.0] KgNo of Bulk Containers [ 0 ]Theoretical Weight [00.0] Kg. Yield ___________ %(Yield Limits: NMT 2% unexplained loss compared to the final blendweight from stage 16.

19. Seal the double PE plastic bags (clear inner, black outer) with plasticties then close all containers, and attach (bar coded) labels to the BulkContainers for transport to the holding area.

PART FOUR

20. Identify and verify the cleanliness of the coating equipment.Weigh [00] Kg PURIFIED WATER USP into a stainless steel vesselfitted with a roller mixer. (#0)

21. ADD gradually while mixing the [OPADRY S-0000 - Color] to thePURIFIED WATER USP and mix to a uniform dispersion - about 45minutes Mixing time ________minutes.

22. PASS the AQUEOUS FILM COATING SUSPENSION through a [00]mesh screen into a stainless steel container and close well.

23. SPLIT the AQUEOUS FILM COATING SUSPENSION into twoequal sublots and label with (bar-coded) batch number and Sublotnumber.

24. STIR the AQUEOUS FILM COATING SUSPENSION continuouslyduring the coating process.


New DD/MM/YY _____________ __________ ____________ _________/________







PART FOURStage 8.Coating Procedure:25. Identify and verify the cleanliness of the coating equipment in useSublot Size ________ Kg. Equal to ___________ tablets. SUB LOT No 1.PREHEATING OF CORES:Coating machine (Type & No) : Extraction Air Temperature: 00ºC - 00ºCIncoming Air Temperature: 00ºC - 00ºCTotal Warming time: [0] MinutesDrum Speed: _________ rpm (minimum speed)Jogging cycle: One cycle every [0] minutes.Limit of rpm: NLT _[0]_ rpm: NMT _[0]_ rpm.


26. Coat tablet cores at a drum speed of [0] - [0] rpm and a spray rate of[000]-[000] g/min until the target COATED tablet weight of [000] mg isobtained. COATING COMPLETION PROCEDURE27. Reduce drum speed to minimum rpm and perform the following:- Reduce set point of incoming air temperature to 00ºC- on reaching this temperature - close the inlet air- continue drum speed until the Extraction Air Temp. reaches 00ºC - 00ºC




New DD/MM/YY _____________ __________ ____________ _________/________







PART FIVECoating Procedure:25. Identify and verify the cleanliness of the coating equipment in useSublot Size ________ Kg. Equal to ___________ tablets. SUB LOT No 2.PREHEATING OF CORES:Coating machine (Type & No) : Extraction Air Temperature: 00ºC - 00ºCIncoming Air Temperature: 00ºC - 00ºCTotal Warming time: [0] MinutesDrum Speed: _________ rpm (minimum speed)Jogging cycle: One cycle every [0] minutes.Limit of rpm: NLT _[0]_ rpm: NMT _[0]_ rpm.






New DD/MM/YY _____________ __________ ____________ _________/________






MANUFACTURING INSTRUCTIONS Machine

Sign Date

PART SIXCoating Procedure:25. Identify and verify the cleanliness of the coating equipment in useSublot Size ________ Kg. Equal to ___________ tablets. SUB LOT No 3.PREHEATING OF CORES:Coating machine (Type & No) : Extraction Air Temperature: 00ºC - 00ºCIncoming Air Temperature: 00ºC - 00ºCTotal Warming time: [0] MinutesDrum Speed: _________ rpm (minimum speed)Jogging cycle: One cycle every [0] minutes.Limit of rpm: NLT _[0]_ rpm: NMT _[0]_ rpm.


26. Coat tablet cores at a drum speed of [0] - [0] rpm and a spray rate of[000]-[000] g/min until the target COATED tablet weight of [000] mg isobtained. COATING COMPLETION PROCEDURE

27. Reduce drum speed to minimum rpm and perform the following:- Reduce set point of incoming air temperature to 00ºC- on reaching this temperature - close the inlet air- continue drum speed until the Extraction Air Temperature reaches 00ºC -00ºC

28. TRANSFER coated tablets into containers lined with two PE plasticbags (clear inner, black outer) Seal bags with plastic ties and closecontainers, and attach (bar coded) labels to the Bulk Containers fortransport to the holding area.

29. Attach the temperature graphs (Type & No) to the manufacturinginstructions. Immediately add the batch / Sublot number to the temperaturegraph(s) and date and sign graph.



New DD/MM/YY _____________ __________ ____________ _________/________







DryingAttachment # 1 Temperature Print-Outs of Drying Process - Sub lots I, II, III

GranulateAttachment # 2 LOD Print-Outs of the Milled Granulate - Sub lots I, II, IIIAttachment # 3 Weight Print-Outs of the Milled Granulate - Sub lots I, II, III

Final BlendAttachment # 4 Mixing time Print-Out of the Final Blend of Sub lots I, II, IIIAttachment # 5 Weight Print-Out of the Final Blend

CoresAttachment # 6 Weight Print-Out of the total cores

Coated TabletsAttachment # 7 Weight Print-Out of the coated tablets sub lot I.Attachment # 8 Weight Print-Out of the coated tablets sub lot II.Attachment # 9 Weight Print-Out of the coated tablets sub lot III.

Temperature ProfileAttachment # 10 Temperature profile Print-Out of the coated tablets sub lot I.Attachment # 11 Temperature profile Print-Out of the coated tablets sub lot II.Attachment # 12 Temperature profile Print-Out of the coated tablets sub lot III





IN-PROCESS CONTROL SPECIFICATION - GRANULATION MATERIAL

SUMMARY

PIVOTAL BATCH

PRODUCT: [Generic name] Tablets USP [000.0] mg. [IA-000-00]

QUANTITY 000000 MNF Date: Month DD, 199Y

YieldsMilled Granulation Yield Limit: NLT 98.0%




Tabletting Yield NMT 2.0% unexplained loss from the previousfinal blend step.







IN-PROCESS CONTROL SPECIFICATION

TABLET CORESSUMMARY

PIVOTAL BATCH

Product: [Generic name] Tablets [USP] [000.0] mg. - CORESLabeled Amount: Each core contains [Active Material] [000.0] mg.

Core in-process Specifications

Punch Diameter 00.00 mmPunch No [00]Die No. [00]

Description [Color] (white to off-white) [shape] (roundbiconvex) core debossed with the number /letters [abc] on one face of the tablet coreand [xyz] on the opposite face.

Scoring [not scored] [scored on one side]

Core Diameter Limit: 000.0 - 000.0 mm: Nominal 000.0 mm


Thickness Nominal 00.0 Limit: 00.0 - 00.0 mm

Hardness Target: 00 SCU NLT 0.0 - NMT00 SCU.


Where the tablet is capsule shaped (i.e. a caplet) provide width, length and thickness





IN-PROCESS CONTROL SPECIFICATIONCOATING PROCESS

SUMMARY

PIVOTAL BATCH

PRODUCT: [Generic name] Tablets USP [000.0] mg. [IA-000-00]

QUANTITY: [000000] MNF Date: Month DD, 199Y

Film Coating Controls Before Coating After Coating¹Theoretical Tablet weight (mg) 000.0 -

¹Target Coated weight (mg) - 000.0

¹Weight of 100 tablets #1 (g) 000.0 000.0¹Weight of 100 tablets #2 (g) 000.0 000.0¹Weight of 100 tablets #3 (g) 000.0 000.0¹Weight of 100 tablets #4 (g) 000.0 000.0¹Weight of 100 tablets #5 (g) 000.0 000.0

¹Average tablet 100 weight (g) 000.0 000.0

¹Average tablet weight (mg) 000.0 000.0

In-Process Yields

¹Yield after coating vs. Pre-coating 00.0%

¹Yield after coating to theoretical 00.0%

¹ Recorded on Statistical Data Tablet Coating Work Sheets.




Pivotal Manufacturing and ControlsRELEASE SPECIFICATION FOR COATED TABLETS [USP]

SUMMARY

EXECUTED PIVOTAL BATCH

Product: [Generic name] Tablets USP [000.0] mg.Labeled Amount: Each tablet contains: [Active Material] [000.0] mg.

Description [Color] (white to off-white) [shaped] (roundbiconvex) Tablet debossed with the number/letters [AA00] on one face of the Tabletand [BB00] on the opposite face.





Dissolution Equipment: USP App. No 1 or 2 (Paddle)Media: 000 mL, 37 C. [00]% of [Sodium laurylSulphate in 0.1N Phosphate Buffer]pH 0.0 RPM 00

Tolerance: NLT [00]% (Q) of the labeledis dissolved in [00] minutes.

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 Limit: 90.0 - 110.0% of labeled amountequal to [00.0] - [00.0] mg / Tablet.

IR = IMMEDIATE RELEASE ER = EXTENDED RELEASE

CR = CONTROLLED RELEASE DR = DELAYED RELEASE.

Where the tablet is capsule shaped (i.e. a caplet) provide width, length and thickness




Pivotal Manufacturing and ControlsMANUFACTURING PROCEDURE FOR EXECUTED BATCHES

[Generic name] Tablets [USP] [000.0] mg. - FLOW CHART

Finished Product

Step 1High Speed Granulator

PREMIX

Step 4Communition stage

MILLING

Step 2High Speed Granulator

GRANULATION

Step 2bHigh Speed Granulator

GRANULATION

Step 3Fluid Bed Dryer

DRYING

[Active Material][intra-granular excipient][intra-granular excipient]

Extra-granularExcipient

[Purified Water USP][Sodium Lauryl Sulfate]

Granulating Fluid

Add sub-lot 2/3

[Alcohol USP 95%]Solvent

[Alcohol USP 95%]if required

Step 6Twin Shell / Flow Bin

Blending

Step 7Compression stage

Tabletting

Step 5Extragranular Addition

pre-blending

Step 8Coating stage

[1/2/3] Sublots

GlidantDisintegrant

Quick Sieve Stage 5Sieve # [0]

IPQC testingBlend UniformitySieve Analysis

IPQC testingPhysical tests

AssayDissolution

IPQC testingcoated tablets- weight

IPQC Testing% LOD analysis

Final BlendYield Analysis

TablettingYield Analysis

Coating YieldsOverall Prod Yield

Yield AnalysisMilled Granulation Yield





BATCH RECORDS FOR EXECUTED BATCH

Tablets Lot No

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

Note for Foreign Manufacturing PlantsTranslation Policy: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 translation isprovided 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 tablets were manufactured on full size production equipment underactual production conditions and SOPs.

The active material is manufactured by [Active Material] Pharmaceutical andChemical Manufacturing Company - [Address].





HARDNESS RANGE VERIFICATIONFOR TABLETS

The following hardness specification were given for the executed (pivotal) batch:

HARDNESS (SCU)

6 - 16

During the manufacture of the executed (pivotal) batch, hardness range verificationtesting was performed.

Results of the 00 mg TABLETThe result demonstrate that compression of 0.0 mg Tablets within the proposed range(minimum 6 SCU, maximum 14 SCU), does not adversely impact on dissolution.The dissolution profile did not change from the original by more than 2.5 %

Results of the 00 mg TABLET

The result demonstrate that compression of 00 mg Tablets within the proposed range(minimum 8 SCU, maximum 16 SCU), does not adversely impact on dissolution.The dissolution profile did not change from the original by more than 2.5 %

COMMERCIAL HARDNESS RANGETherefore, this hardness range will be valid for routine commercial production batch.

4



HARDNESS RANGE VERIFICATION - Lot No:

SAMPLE LOW HARDNESS HIGH HARDNESS

NO. TabletWeight (mg)

TabletThickness

(mm)

TabletHardness

(SCU)

Friability(%)

Tablet Weight (mg)

TabletThickness

(min)

TabletHardness

(SCU)

Friability(%)

123456789

1011121314141617181920

AVG.RSD %

USLLSL



TARGET HARDNESSINTERVAL SAMPLE

NoTabletWeight

(mg)

TabletThickness

(mm)

TabletHardness

(SCU)

Friability(%)

1 11 199 201 3.1 3.2 9 8 0.4 0.32

12 199 200 3.1 3.1 9 9 0.4 0.5

3 13 198 200 3.1 3.1 8 8 0.5 0.44 14 198 201 3.1 3.1 9 9 0.4 0.4

1 5 15 197 201 3.1 3.1 8 8 0.3 0.4

6 16 199 200 3.1 3.1 9 8 0.3 0.57 17 200 203 3.1 3.1 8 10 0.3 0.58 18 202 202 3.1 3.1 8 9 0.4 0.59 19 199 202 3.1 3.1 8 9 0.5 0.310 20 202 201 3.1 3.1 8 8 0.5 0.3

1 11 199 201 3.1 3.2 9 8 0.4 0.32

12 199 200 3.1 3.1 9 9 0.4 0.5

3 13 198 200 3.1 3.1 8 8 0.5 0.44 14 198 201 3.1 3.1 9 9 0.4 0.4

2 5 15 197 201 3.1 3.1 8 8 0.3 0.4

6 16 199 200 3.1 3.1 9 8 0.3 0.57 17 200 203 3.1 3.1 8 10 0.3 0.58 18 202 202 3.1 3.1 8 9 0.4 0.59 19 199 202 3.1 3.1 8 9 0.5 0.3

10 20 202 201 3.1 3.1 8 8 0.5 0.3

1 11 199 201 3.1 3.2 9 8 0.4 0.3

2

12 199 200 3.1 3.1 9 9 0.4 0.5

3 13 198 200 3.1 3.1 8 8 0.5 0.44 14 198 201 3.1 3.1 9 9 0.4 0.4

3 5 15 197 201 3.1 3.1 8 8 0.3 0.4

6 16 199 200 3.1 3.1 9 8 0.3 0.57 17 200 203 3.1 3.1 8 10 0.3 0.58 18 202 202 3.1 3.1 8 9 0.4 0.59 19 199 202 3.1 3.1 8 9 0.5 0.310 20 202 201 3.1 3.1 8 8 0.5 0.3

AVG. RSD %USLLSL





TABLET TRAILPACKAGING AND DISBURSEMENT

Tablets [USP] [10] mg

Batch No. Lot: [IA-00-00]

Bulk Material in Polyethylene Bags:

1,800,050 tablets packed in :

10 bulk containers x 180,050 tablets


2 bulk containers


Month DD, 200Y

8 bulk containers

Balance stored in

Pivotal Warehouse




Pivotal Manufacturing and ControlsPACKAGING AND DISBURSEMENT

[Active Material] TABLETS [USP] [20] mgBatch No. Lot: [IA-00-00]

30cc HDPE ContainerChild Resistant Cap Closure [33 mm]

30cc HDPE ContainerMetal Cap Closure [33 mm]

590 Units x 30 tablets = 17,900 tablets


Nov.28, 1996

10 units x 30 tabs


Month DD, 200Y

50 units x 30 tabs


Month DD, 200Y

530 units x 30 tabs

Balance stored in

Pivotal Warehouse



Nov.28, 1996

10 unit x 100 tabs


Month DD, 200Y

30 units x 100 tabs


Month DD, 200Y

960 units x 100 tabs

Balance stored in

Pivotal Warehouse





[Active Material] TABLETS [USP] [20] mg - Batch No. Lot: [IA-00-00]





5 unit x 180 tabs


Month DD, 200Y

15 units x 180 tabs


Month DD, 200Y


Balance stored in

Pivotal Warehouse



5 unit x 1000 tabs


Month DD, 200Y



Month DD, 200Y


Balance stored in

Pivotal Warehouse





PACKAGING AND DISBURSEMENT

[Active Material] TABLETS [USP] 40 mg - Batch No. Lot: [IA-00-00]





Nov.28, 1996

5 units x 30 tabsQC Testing

Month DD, 200Y

40 units x 30 tabsBiostudy (European Market)

Month DD, 200Y

400 units x 30 tabsBalance stored in

Pivotal Warehouse

55 units x 30 tabsRelease & Stability Testing

Month DD, 200Y



Nov.28, 1996

9 units x 100 tabs


Month DD, 200Y

25 units x 100 tabs


Month DD, 200Y

40 units x 100 tabs

Biostudy & Retained Samples

Month DD, 200Y

60 units x 100 tabs

Balance stored in

Pivotal Warehouse




Pivotal Manufacturing and Controls[Active Material] TABLETS [USP] 40 mg - Batch No. Lot: [IA-00-00] (continued)





5 units x 180 tabs


Month DD, 200Y

15 units x 180 tabs


Month DD, 200Y


Balance stored in

Pivotal Warehouse



7 units x 1000 tabs


Month DD, 200Y



Month DD, 200Y


Balance stored in

Pivotal Warehouse


Stability (European Market)

Month DD, 200Y



SECTION XIII SECTION 13

Packaging and Labeling Procedures


This Section contains information on the container-closure systems, including type IIIDMF 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 an ANDAsubmission. 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, the workstation is re-inspected and full In-Process Control checks are carried out prior torestarting 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 cotton wool 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

Additive Regulations (21 CFR).

NOTE:Moisture permeability - USP <661>: Max 10mg/day/Liter.Container closing Torque - USP <671>: Should establish a good seal at target torque.

4






Cotton Coil

(required for coiler )Solid oral dosage forms.

FROM THE GENERIC FIRM:

48 Testing Specifications or protocol and test results (CoA) of Genericpackaging Lab.

49 CoA of Cotton Coil from the QC Packaging Lab50 Batch Compliance Statement of applicants acceptance tests

FROM THE COTTON COIL MANUFACTURERS :-

51 Purified Cotton Coil Specifications (including)52 - Tests performed on Cotton Coil53 - Partial Compliance to USP requirements54 - Complies to 21 CFR requirements55 - Certificate of Analysis (include moisture content)

LETTERS OF AUTHORIZATION - (LOA)

LoA from Cotton Coil manufacturer referencing their facility DMF #.56 LoA from manufacturer referencing their Cotton Coil DMF #.

STATEMENTS OF COMPLIANCE57 Cotton Coil manufacturer's: Statement of GMP Compliance58 Statements of Compliance with Applicable Sections of the Indirect Food

Additive Regulations (21 CFR).Note:ØØ Fillers (cotton coil and rayon coil etc.) are Primary Packaging Material (inimmediate contact with dosage form). Specify coiler as 9g or 20g weight.ØØ Desiccants (e.g. '2:1' silica gel) requires documentation similar to cotton or rayoncoilers. Desiccants should differ in size and shape from solid dosage form.ØØ Cotton USP (as filler) - exempted from USP monograph sterility, absorbency andfiber length testsØØ Rayon USP (as filler) - exempted from USP monograph absorbency and fiberlength testsØØ Rayon (Coiler as filler) - do not use for Hard Gelatin Capsules (impacts ondissolution.)





This section contains:Ü Package Characteristics for container-liner-closure systems

Ü Package Description concerning container-liner-closure systems

Ü Technical Specifications (Diagrams &Drawings) of each component.

Ü Certificates of Analysis of [Generic Company Name Inc./Ltd.] packages.

Ü DMF Referral Letters

Ü Statements of Compliance with applicable sections of the Indirect Food AdditiveRegulations (21 CFR).

Ü USP XXIV Testing Results of the closure system.

Ü Documents for container-liner-closure system include the following:

Certificates of Analysis outlining the components used for packages containing;

30 / 60 Tablets in HDPP with child-resistant cap

1000 Tablets in HDPP with metal screw cap.

4





PACKAGE CHARACTERISTICS

ORAL CAPSULES [00.0] mg LOT: IA00-00

Pivotal Lot

The container closure system used consists primarily of high density polyethylene(HDPE) container using plastic or metal caps (child resistant where required), witha non-reactive filler and an self adhesive internal tamper-evident seal covering theopening of the container.

Amount 30 Units 60 Units 1000 Units 1000 UnitsCONTAINERmanufacturer

Drug Plastics & Glass Drug Plastics & Glass Drug Plastics &Glass

Drug Plastics &Glass

CONTAINERsize

30 cc round, whiteHDPE bottle




CONTAINERcomposition

HDPE resin:Quantum LR-7340-43

HDPE resin:Quantum LR-7340-43

HDPE resin:Quantum LR-7340-

43

HDPE resin:Quantum LR-7340-

43CONTAINERcolor/pigment

Ampacet White 11078PE,

DMF # 8354

Ampacet White 11078PE,

DMF #4162

Ampacet White11078 PE,

DMF # 8354

Ampacet White11078 PE,

DMF #4162

Capmanufacturer

Owens-Illinois U.S. CAN Owens-Illinois U.S. CAN

Cap type Child resistant cap Child resistant cap Metal screw cap Metal screw cap

Cap size 29 mm 33 mm 53 mm 53 mm

Closure linermanufacturer

Tekni-Plex Inc. Tekni-Plex Inc. Tekni-Plex Inc. Tekni-Plex Inc.

Closure Linercomposition Foam seal PS 22 Foam seal PS 22

1.Tekniseal RVT+LF 2.Foamseal PS

22

1.Tekniseal X-14(p/poly)

2.Foamseal PS 22Pharmaceutical

Cotton CoilManufacturer

American

White Cross

American

White Cross

American

White Cross

American

White Cross

Cotton

Coil

SnopureCotton Coil - 9 g




Desiccantmanufacturer

United Desiccant United Desiccant United Desiccant United Desiccant

Desiccant type Humi cap 0.75gSilica gel

Humi cap 0.75gSilica gel







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 safe foruse in contact with a drug product - generally accepted as safe (Appear inthe 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:

30 & 60 Units

CHILD RESISTANT - CLOSURE

Description Child Resistant cap, 38 mm / 400 White, Unlined PolypropyleneCap with Pressure 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











1000 Units

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






30 /60 / 1000 Units

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








PACKAGING COMPONENT DESCRIPTION FORINCLUSIONS USED IN ALL CONTAINER SYSTEMS

Description :: Snopure Cotton Coil

Type :: 9 or 20 grams

Manufacturer :: American White Cross

DMF of MNF :: American Fiber and Finishing, DMF # 4343

Product DMF :: DMF # 4164 / DMF # 4343

LoA :: Month DD, YYYY

American White Cross (formerly National Patent Medical), DMF # 4164 or AmericanFiber and Finishing, DMF # 4343

PACKAGING COMPONENT DESCRIPTION FORDESICCANT USED IN ALL CONTAINER SYSTEMS

(where used)

Description : Humi cap 0.75 g silica gel.

Manufacturer : United Desiccant

DMF of MNF :: DMF [0000]

Product DMF :: DMF [0000]

LoA : Month DD, YYYY

4




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.


24 VOLUME DRUG DEVELOPMENT SERIES: Sect: 14.1 Oral Oral TABLETS

SECTION XIV SECTION 14

Finished Dosage Form Controls


State if drug product is:-

ØØ Compendial and test methods¡ used are USP XXIV

ØØ Non-Compendial and test methods¡ are validated in-house methods

ØØ Non-Compendial and test methods¡ based on published analyticalmethods² and fully validated.

Certificate of Analysis and analytical spectra for the finished dosage form, representingeach container-closure system of the Pivotal Batch(es), including:

Ø HPLC, TLC, GC, UV chromatograms and spectra for all pivotal strengths made.

Ø Certificate of Analysis for each pivotal lot strength plus the corresponding HPLCassay chromatogram of actual batch manufactured.

¡ Stability Indicating AssayImpurity Limit Tests Dissolution AssayUSP Monograph tests

² USPC Inc. Pharmacopeial ForumPublished Reference Works


Section XIV. Controls for the Finished Dosage Form1. Test procedures2. Testing specifications and data (COA)




Finished Dosage Form Controls

This section contains:THE DRUG PRODUCT IS NON-COMPENDIAL.

Certificates of Analysis for the finished drug product [Generic name] TABLETS [0.00]mg (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] TABLETS [0.00]mg (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,dissolution and purity of the finished drug product during the entire shelf life period ofthe drug.

Note:Additionally, separately bound copies of all non-compendial methods have beenprovided in accordance with 21 CFR 314.50(e)(2)(i).




Finished Dosage Form ControlsRELEASE SPECIFICATION FOR FINISHED PRODUCT

SUMMARY

Product: [Generic name] TABLETS [000.0] mg

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

Description [Color] white-to-off white [size in mm]tablet printed/embossed with the number /letters [000] on the face and [0000] on theobverse.

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.

Moisture (LOD / KF) Target 0.0 Limit: 0.0 - 0.0

Weight Individual (±7.5%) Target 000 Limit: 000 - 000 mg

Weight Average (±5.0%) Target 000 Limit: 000 - 000 mg

Uniformity of Dosage Units: Conforms to the current USPContent Uniformity

Microbial Limit test Conforms to the current USP (where required)

Dissolution (Select Conditions) Equipment: USP App. No 1 or 2 (Paddle) Media: 900 mL, 37 C. pH 0.0 RPM 00 Tolerance: NLT [00]% of the labeled is dissolved in [00] min.Impurities /Degradation Products determination- Each unknown: NMT 0.09% of the labeled amount- Any identified: NMT 0.5% of the labeled amount- Total: NMT 2.0% of the labeled amount

Residual SolventsIsopropyl alcohol NMT 1.0 %Acetone NMT 500 ppmEthanol NMT 1000 ppm

Assay Limit: 95.0 - 105.0% of labeled amount00.0] - [00.0] mg

Note:IPC Limits

may betightened to

5.0%

The release Assay should allow for themaximum degradation during the

entire product's shelf life. It may be96% - 105% or even 97% - 105%.All overages (5%) added must be

scientifically justified.Total impurity profile shouldnot exceed 2% unless theinnovative brand leader

product exceeds the 2% limit(i.e. the impurities are nottoxic or probably inert)

Assay decimals arealways reported as one

significant decimal place.




Finished Dosage Form ControlsSTABILITY SPECIFICATION FOR FINISHED PRODUCT

SUMMARY

Product: [Generic name] TABLETS [000.0] mg

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

Description [Color] white to off-white [size in mm]tablet printed / embossed with the number /letters [000] on the face and [0000] on theobverse.

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.

Moisture (LOD / KF) Target 0.0 Limit: 0.0 - 0.0

Unit weight Individual (±7.5%) Target 000 Limit: 000 - 000 mg

Unit weight Average (±5.0%) Target 000 Limit: 000 - 000 mg

Uniformity of Dosage Units: Conforms to the current USPContent Uniformity

Microbial Limit test Conforms to the current USP (where required)

Dissolution (Select Conditions) Equipment: USP App. No 1 or 2 (Paddle) Media: 900 mL, 37 C.

pH 0.0 RPM 00 Tolerance: NLT [00]% of the labeled is dissolved in [00] min.

Impurities /Degradation Products determination- Each unknown: NMT 0.09% of the labeled amount- Any identified: NMT 0.5% of the labeled amount- Total: NMT 2.0% of the labeled amount

Residual SolventsIsopropyl alcohol NMT 1.0 %Acetone NMT 500 ppmEthanol NMT 1000 ppm

Assay Limit: 90.0 - 110.0% of labeled amount00.0] - [00.0] mg

Note:Limits to official

parameters, which differmay from the release QC

parameters

Select color to complywith the full 2 -3 yearshelf life of the tablet

under market conditions

Total impurity profile shouldnot exceed 2% unless theinnovative brand leader

product exceeds the 2% limit(i.e. the impurities are nottoxic or probably inert)




Finished Dosage Form ControlsSUMMARY OF CERTIFICATE OF ANALYSES AND

ANALYTICAL SPECTRA :

Pivotal Batch C of A No.

Executed LotPivotal Lot No: [000-01] [60.0] mg C 000-01

Pivotal Lot No: [000-02] [90.0] mg C 000-02



G C SPECTRAPivotal Lot No: [000-01] [00.0] mg S 000-01

Pivotal Lot No: [000-02] [00.0] mg S 000-02



UV SPECTRA

Pivotal Lot No: [000-01] [00.0] mg U 000-01

Pivotal Lot No: [000-02] [00.0] mg U 000-02

Pivotal Lot No: [000-03] [000.0] mg


U 000-03

U 000-04

HPLC SPECTRA

Pivotal Lot No: [000-01] [00.0] mg H 000-01

Pivotal Lot No: [000-02] [00.0] mg H 000-02



H 000-03

H 000-04

TLCPivotal Lot No: [000-01] [00.0] mg T 000-01Pivotal Lot No: [000-02] [00.0] mg T 000-02Pivotal Lot No: [000-03] [000.0] mgPivotal Lot No: [000-04] [000.0] mg

T 000-03T 000-04

(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.




Finished Dosage Form ControlsSUMMARY 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 Product -Dissolution Method

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

D = A Dissolution 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. Thus QC-025-00 is in fact, a combination of SI-A23-00 & SI-A24-00.


Ed 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)



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).



NewDD/MM/YY _____________ __________ _______________ _________/________





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 SI-2000-01

Finished Product Release

QC Release Assay SI-4000-01


Content Uniformity SI-4000-01

Dissolution Assay SI-4000-01

Finished Product Stability Methods

Stability Indicating Assay SI-5000-01


Validation of Stability Indicating Assay SI-5000-01

Dissolution Assay SI-5000-01

Validation of Dissolution Assay method SI-5000-01

(All Analytical Methods Placed Here)



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.



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



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.



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



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



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



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).



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.



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.



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



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.



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.



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



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)


.

24 V24 Volume DDrug DDevelopment SSeries Sect: 16.1 OralOral TABLETS

SECTION XVI SECTION 16

Stability of Finished Dosage Form


• Section Page and Title.

• Expiration Dating Period Statement

• Stability Protocol for Post Approval Production Batches (ANDA commitment)

• Stability Reports indicating results of Pivotal lot from 3 months accelerated and controlled room temperature studies

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

• Stability Protocol used for Pivotal lot

• Stability Data Summary Report (plus graphs).

4





This section contains:♦ Proposed expiration date and stability commitment

♦ Stability protocol for post-approval production batches

♦ Summary of Stability summary

♦ Stability reports containing data from 3 month accelerated and 6 months controlledroom temperature studies

♦ Package Characteristic of pivotal batch

OVERVIEW

Stability testing is performed on the largest and smallest container-closure systemsproposed for marketing; i.e. in each material type, namely plastic (HDPE/HDPP), glass, orpush-through blister packs.

When more than one closure for the same container material type (e.g. glass bottle) isused in the proposed marketing containers, the largest and smallest container-closureconfiguration is tested, - for both accelerated and long term studies.

In cases where plastic bottles of the same size range and shape are manufactured fromdifferent thermoplastic resins, they exhibition different storage characteristics and thus areconsidered as completely separate container-closure systems.

The number of stability tests conducted can be quite large in such cases. The examplebelow for the following packaging configuration highlights the number of stability testsneeded. Tests can be reduced using a matrix stability protocol.

1. Glass bottle with plastic Child Resistant Cap (CRC) and metal-screw cap2. HDPP (1) container with plastic Child Resistant Cap and a HDPE screw-on cap3. HDPP (2) container with plastic Child Resistant Cap and a HDPE screw-on cap

when tested in the largest and smallest container-closure configuration at accelerated andlong term testing will produce 24 separate stability protocols.

Calculation.(3 containers x [largest & smallest size] x 2 closures x [25–C+40–C] = 24 studies).

4





Proposed Expiration Date and Stability Commitment

ll stability data support the proposed expiration period of 2 years when the product isstored at room temperatures.

Stability commitmentLong term commercial stability studied in accordance with the approved stability protocolshall be carried out by [Generic Company Name Inc. / Ltd.] The stability results ofthese studies shall be submitted in the annual ANDA Reports filed on the anniversarydate of the submitted product.

[Generic Company Name Inc. / Ltd.] commits to remove any batch promptly from themarket place any material falling outside the products check specifications.

Extensions to the expiration date will be made via the annual ANDA Reports asacceptable long term stability data is obtained,

[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] TABLETS [USP] [000.0] mg. [Batch No: [IA00-00-00]

FINISHED PRODUCT STABILITY PROTOCOLPackage sizes: Smallest and largest containersStorage ConditionsControlled 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 approved application

Stability Testing.All test results will be subjected to compliance with current official requirements of theapproved applications and all supplements approved thereafter.Test parameters will include:

TEST PROCEDURE TEST METHOD& ED. NUMBER

SPECIFICATION

1 Appearance SI-P-000-01 Conforms

2 Assay SI-A-000-01 90.0 - 110.0% of labeled amount

IMPURITIES / DEGRADATION PRODUCTS

3 - Each Individual- Any other Individual- Total:

SI-A-000-01SI-A-000-01SI-A-000-01

NMT 0.5% of the labeled amountNMT 0.5% of the labeled amountNMT 2.0% of the labeled amount

4 Dissolution SI-D-000-01 NLT 00% (Q) in 00 min.

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 STUDIES

The 3 months accelerated (40° ±2°C / 75 RH ±5% ) and 6 months room temperature (25°±2°C / 60 RH ±5%) stability data were examined for [Generic name] TABLETS [USP] [000.0] mg.

The data indicate that the formulation is stable, with no observed degradation, under testconditions. No significant change in either chemical or physical attributes was noted inany sample under any of the storage conditions.

The attached tables and graphs are summaries of the results for the parameters used toestablish the stability profile of [Generic name] TABLETS [USP] [000.0] mg.

[Generic name] TABLETS [USP] [000.0] mg. were stored at accelerated conditions (40°±2°C / 75% RH ± 5%) and at room temperature (25° ±2°C/ 60% RH ±5%) in the proposedmarket container/closure system.

All stability data support the proposed expiration period of 2 years when the product isstored at room temperatures.





SUMMARY OF STABILITY STUDY RESULTS.

HDPE Container Closure liner system 25°C 60%RH 40°C 75%RH

Small Large Small Large

30cc HDPE Metal Screw Cap þþ qq þþ qq

30cc Child Resistant Closure (CRC Cap) þþ qq þþ qq

300cc Child Resistant Closure (CRC Cap) qq þþ qq þþ

300cc HDPE Metal Screw Cap qq þþ qq þþ

GLASS CONTAINER CLOSURE LINER SYSTEM

ýý ýý

ýý ýý

ýý ýý

ýý ýý

Blister packagingýý ýý

ýý ýý

ýý ýý

ýý ýý

BULK PACKAGING

Bulk Packaging þþ þþ

Number of Studies Performed 10

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.2 Fill size 100 Tablets [USP]3 Site of Manufacture NJ MNF SITE4 Batch or lot number [IA-0000-00]5 Batch size (type) 200 000 Tablets [USP]6 Batch manufacturing Date and Packaging Date Month DD, 200Y / Month DD, 200Y7 Manufacturer of Active Material (approved supplier) LEK Chemical Co. dd8 Date placed on stability Month DD, 199Y9 Batch number or receiving number of Active Material LK 232310 Full details of container/closure system (type, material, resin) 100cc HDPP (LR-7340-43) Screw-on

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 þPivotal Batch14 Site where stability test conducted US PA MAN Site15 Number of units to be sent for testing in each time interval 2 x 10016 Analytical method number and Edition Number for each stability indicating testS-I A00-22-24 / S-I A0023 Ed . 0117 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

Appearance ASSAY Percentage

D I S S O L U T I O NPercentage of label claim dissolved in 45 minutes

SPECIFIC-ATIONS

Months White toOff-White

90.0 % -110.0%

NLT 80% (Q) in 45 minutes

Method # S-I 551 -02 S-I 555 -03 S-I 1234 Ed. 03 Mean C.V.

0 1/6/96 conforms 100.3 98.2 99.8 95.2 98.2 99.5 98.395.2 94.2 96.2 98.3 99.1 99.8 96.4 2.1

1 15/7/96 conforms 99.8 95.2 94.2 99.2 98.3 99.1 99.895.9 94.2 99.0 96.2 98.3 99.1 97.5 2.4

2 16/8/96 conforms 101.3 95.7 94.2 99.2 96.2 98.3 99.197.2 94.2 99.2 96.8 98.3 99.1 98.1 1.7

3 15/9/96 conforms 101.4 95.6 94.2 96.2 98.3 99.1 99.294.2 99.2 96.5 99.1 99.8 101.5 99.0 2.2

21. Product Formula On Stability (Formula No: S000).Active material 23.60

Povidone USP 9.00 Colloidal Silicon Dioxide NF 2.10 Starch NF 5.30

Starch NF (Redried) 27.00 Anhydrous Lactose NF 230.00 Magnesium Stearate NF 3.00 Purified Water USP (Processing Solvent Only)




Stability of Finished Dosage FormSTABILITY REPORT 1 Product name, dosage form and strength. [Generic name] [000.0] mg. 2 Fill size 100 Tablets [USP]3 Site of Manufacture NJ MNF SITE4 Batch or lot number P-54325 Batch size (type) 200 000 Tablets [USP]6 Batch manufacturing Date and Packaging Date DD/MM/YY / May 28, 200Y7 Manufacturer of Active Material (approved supplier) LEK Chemical Co. dd8 Date placed on stability June DD, 200Y9 Batch number or receiving number of Active Material LK 232310 Full details of container/closure system (type, material, resin) 100cc HDPP (LR-7340-43) Screw-on

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 þPivotal Batch14 Site where stability test conducted US PA MNF Site15 Number of units to be sent for testing in each time interval 2 x 10016 Analytical method number and Edition Number for each stability indicating testS-I A-0323/34/35 / S-I 0024 Ed . 0117 Stability specifications indicating names of test required. Tabulated18 Number of packages placed on stability 7019 Testing intervals required 0, 1, 2, 3 6months

20 Stability storage conditions 25degreesC/60% RH

Stability Parameters

Storage Period

Date ofAnalysis

Appearance ASSAY Percentage

D I S S O L U T I O NPercentage of label claim dissolved in 45 minutes

SPECIFIC-ATIONS

Months White toOff-White

90.0 % -110.0%

NLT 80% (Q) in 45 minutes

Method # S-I P022 -02 S-I A024 -03 S-I D024 Ed. 03 Mean C.V.

0 1/6/96 conforms 100.3 98.2 99.2 95.2 98.2 99.5 98.395.2 94.2 99.0 98.3 99.1 99.8 96.4 2.1

3 15/8/96 conforms 99.8 95.2 94.2 99.2 96.2 98.3 99.195.9 94.2 99.0 96.2 98.3 99.1 97.5 2.4

6 6/11/96 conforms 101.3 95.7 94.2 99.2 96.2 98.3 99.197.2 94.2 99.2 96.8 98.3 99.1 98.1 1.7

9 15/2/97 conforms 101.4 95.6 94.2 99.3 96.2 98.3 99.194.2 99.2 98.0 99.1 99.8 101.5 99.0 2.2

12 5/5/97 conforms 100.4 98.2 95.2 96.2 98.3 99.1 99.299.0 96.2 98.3 99.1 99.8 101.5 99.0 1.2

18 5/119724 5/5/98

21. Product Formula On Stability (Formula No: S000).Active material 23.60

Povidone USP 9.00 Colloidal Silicon Dioxide NF 2.10 Starch NF 5.30

Starch NF (Redried) 27.00 Anhydrous Lactose NF 230.00 Magnesium Stearate NF 3.00 Purified Water USP (Processing Solvent Only)





PACKAGE CHARACTERISTICS

[Generic name] TABLETS [USP] [000.0] mg. [Batch No: [IA00-0000]

Pivotal Lot Packaging Characteristics

Amount 30 Tablets 100 tablets 30 tablets 100 tablets

Containermanufacturer

Drug Plastics & GlassCo Inc.

Drug Plastics & GlassCo Inc.

BROCKWAY Glass BROCKWAY Glass

Containersize

60 cc round, WhiteHDPE container

60 cc round, WhiteHDPE container

50 cc amber glassbottle

50 cc amber glassbottle

Resin Type HDPEQuantum LR-7340-43

HDPEQuantum LR-7340-43

--- ---

11087 PE White

Masterbatch

White Ampacet 11078Polyethylene

White Ampacet 11078Polyethylene

Amber Glass Amber Glass

CapManufacturer

Owens-Illinois U.S. CAN(Penn-WheelingClosure Corp.)

Owens-Illinois U.S. CAN(Penn-WheelingClosure Corp.)

Cap Type Child Resistant Cap Metal Screw Cap Child Resistant Cap Metal Screw Cap

Cap Size 31 mm 31 mm 31 mm 31 mm

Closure LinerManufacturer

Tekni-Plex Inc. Tekni-Plex Inc. Tekni-Plex Inc. Tekni-Plex Inc.

Inner linercomposition

TEKNISEAL RVT+ LF

TEKNISEAL X-14(polyethylene/Kraft

Paper laminate)

- -

Adhesive FoamSeal - Tamper

Evident

Foamseal PS 22 Foamseal PS 22 Foamseal PS 22 Foamseal PS 22

PharmaceuticalCotton coil

Manufacturer

American WhiteCross* or AmericanFiber and Finishing

American WhiteCross* or AmericanFiber & Finishing

American WhiteCross* or AmericanFiber & Finishing

American WhiteCross* or AmericanFiber and Finishing

Cotton Coil Snopure cotton coil(9 or 20 g)

Snopure cotton coil(9 or 20 g)

Snopure cotton coil(9 or 20 g)

Snopure cotton coil (9 or 20 g)





PACKAGE CHARACTERISTICS - BULK

[Generic name] TABLETS [USP] [000.0] mg. [Batch No: [IA00-000]

Pivotal Lot Packaging Characteristics

Fill size [00] kg Bulk

Polyethylenebag

manufacturer(Transparent)

[Manufacturing Company Name Inc. / Ltd.][Address]

Size Ht [00] x Wt [000] cm, [0.0] mm thickness

Composition Low Density Polyethylene [Name]:Resin [000], Transparent

Polyethylenebag

manufacturer(Black)

[Manufacturing Company Name Inc. / Ltd.][Address]

Size Ht [00] x Wt [000] cm, [0.0] mm thickness

Composition Low Density Polyethylene [name]: Resin PE [000]


24 VOLUME DRUG DEVELOPMENT SERIES: Sect: 17.1 Drug Development

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


18.1 Section Page and Title

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


24 VOLUME DRUG DEVELOPMENT SERIES: Sect: 19.1 ANDA ANDA DEVELOPMENT

SECTION XIX SECTION 19

Environmental Impact Analysis Reports


19.1 Section Page and Title

19.2 Environmental Exclusion Assessment

- Development Site

- Manufacturing Site

19.3 Applicable Environmental Laws (National / State / Local /Foreign)

- Development Site


- Contract Manufacturers

19.4 Site Environmental Certification

- Development Site



19.5 Statement on Environmental Compliance

- Development Site



19.6 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 manufacturing environment.

Note:-Where the development and/or the manufacturing of the drug product is performed ina foreign country, the applicable National Environmental laws of the country need tobe 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 longer duration,or for different indications than previously in effect for the listed drug product(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 Name Inc./Ltd.]submits that an Environmental Impact Analysis Statement is not requiredwith this application and, therefore requests that it be categoricallyexcluded from the requirements to submit an Environmental ImpactAnalysis.


___________________________________ _________________[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 in productionat the facility is not expected to affect compliance with current emission requirementsor 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 in fullcompliance 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] Dosage Form [USP][000.0] mg.





333



SECTION XX SECTION 20

Generic Drug Enforcement Act


20.1 Section Page and Title and Color Tag

20.2 Generic Drug Enforcement Act

20.3 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



SECTION XXI SECTION 21

Additional InformationOVERVIEW

his section is used for clarifying the various ADDITIONAL DATAREQUIREMENTS that may apply to the development and the manufacturingprocedures of this application as well as the following four categories

1. References to information that has been previously submitted by applicant2. English translations of literature publications3. Letters of Authorization (when referring to third party data (e.g. DMF) on file withthe FDA) - Always provide TWO copies of actual LOA

4. Field Copy Certification (+proof of delivery - i.e. photocopy of courier Fedex / DHLdelivery Form and date of Fedex / DHL pick-up. Avoid where possible registered mailand postal return (red) cards)

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.

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.

Do not use this section for manufacturing steps that do not require support data andare classified as minor procedures such as fluid bed drying operations that mayrequire additional drying to reach the required target moisture content (LOD %) of thegranule. These conditional procedures are highlighted as standard instructions in themanufacturing method or manufacturing instructions.


1. Reference to previously submitted information (§ 3l4.94(a)(11))2. Literature publication for which English translation is submitted (§ 3l4.94(a)(11))3. Letters of authorization (two copies)4. Field Copy Certification.

T




Additional Information

REFERENCING PREVIOUS SUBMITTED INFORMATION

References to information that has been previously submitted to the FDA by applicantunder 21CFR 314.94 [a][11]

Applicants need to provide precise and detailed Reference Data to the FDA in orderto clearly identify the previously submitted file. Remember any referrals to apreviously submitted file or data will marginally slow down the approval process (referto thirteen commandments Section XXII)

1. Date supplied to FDA MM/DD/YY

2. File Name at FDA

3. Volume Number of File at FDA

4. Reference Number of File at FDA

5. Actual Document Name of File at FDA

6. Page Number where reference data is available






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.• Active material• Specific Excipients• Capsules• Colors/dyes• Film coating color premixes

DMF numbers are required for container/closure materials.Primary Material in direct contact with the drug product e.g.• Plastic containers• Plastic caps• Plastic closures• Plastic liners• Plastic seals• Plastic application nozzles(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• Silica gel drying agent in plastic containers• Measuring caps as an integral part of closure system.

MNF DMFsManufacturing DMF numbers are required for the manufacturing facility supplying theraw material.

LOAsLetters of Access (recent date is essential) are required for all referenced DMFnumbers.




Additional InformationSUMMARY OF DMF NUMBERS USED IN THIS APPLICATION:

Raw Material / Component DMF No.

Active Material(s)

Active material 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) Yes

Color / Pigment (US Certification) Yes

Coating material / Premix DMF

Capsules DMF

Container-closures

HDPE Container DMF

HDPE Container DMF

HDPE Cap DMF

Metal Cap DMF

Cap liner DMF

Adhesive Tamper evident inner-seal DMF

Silica Gel /Other DMF

Cotton Coil DMF

Thermoplastic Resins and Master Batch Dyes

Resin No [A000] DMF

Resin No [B000] DMF

Resin No [C000] 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 for Biostudy and Pivotal LOA

Alternative Supplier LOA

Non active Materials

Capsules LOA

Color / Pigment (US Certification) Cert.

Coating materials LOA

Container-closuresHDPE Container DMF

HDPE Container DMF

HDPE Cap DMF

Metal Cap DMF

Cap liner DMF

Adhesive Tamper evident inner-seal DMF

Silica Gel /Other DMF

Cotton Coil DMF

Thermoplastic Resins and Master Batch Dyes

Resin No [A0000] of THERMOPLASTIC container DMF

Resin No [B0000] of Cap DMF

Resin No [C0000] of CRC OUTER component DMF

Resin No [D0000] of CRC INNER component DMF

Master Batch White DMF

Master Batch color DMF

Resin No [E0000] LOA

Resin No [F0000] LOA

Resin No [G0000] LOA

Master Batch White LOA

Master Batch color LOA

No LOA date greater than two years. Change in Ownership show new DMF Holder.




Additional InformationApplicant or Agent Letterhead

FIELD COPYDate:

District DirectorDistrict OFFICE ADDRESSDistrict ZIP CODEState

FIELD COPY CERTIFICATIONUS Applicants:

Dear District Director,

1. [Applicant Company Name Inc. / Ltd.] has submitted on the MM/DD/YY bycourier an original abbreviated New Drug Application (ANDA) seeking approval to theUS market of the drug product [NAME] Drug Strength [00.0] and [00.0]mg.

2. The [Generic NAME] Drug Strength [00.0]mg are bioequivalent to the ReferenceListed Drug [RLD] as manufactured by [RLD's Inc. Address] pursuant to NDA #00-0000.

3. This FIELD COPY which is a true field copy of the same technical sections(chemistry, manufacturing and controls and including a copy of the 356h form) of theapplication is identical to the original copy that has been submitted to the appropriateOffice of Generic Drugs FDA Maryland. The field copy is submitted in the standardburgundy colored folder.

Please be so kind as to direct written correspondence with regard to this submissionto the undersigned writer. Please direct calls or facsimiles directly to me as percontact numbers shown in the signature line.

Signature Name of Responsible Person. Dated __________________Regulatory Affairs Director[Applicant Company Name Inc. / Ltd.]Tel (Direct) 202-000-000Fax 202-000-001

Note DifferenceAddress is to District Director

District Office(e.g. NJ)




Additional InformationApplicant or Agent Letterhead

FIELD COPY[Field is sent to FDA Headquarters OGD and may be forwarded tot the Office ofCompliance used for overseas PAI foreign inspections]

Date:


Dear Office of Generic Drugs

Foreign Applicants:1. [Applicant Company Name Inc. / Ltd.] has submitted on the MM/DD/YY bycourier an original abbreviated New Drug Application (ANDA) seeking approval to theUS market of the drug product [NAME] Drug Strength [00.0] and [00.0] mg.

2. The [Generic NAME] Drug Strength 00.0 mg are bioequivalent to the ReferenceListed Drug [RLD] as manufactured by [RLD's Inc. Address] pursuant to NDA # [00-0000].

3. This FIELD COPY which is a true field copy of the same technical sections(chemistry, manufacturing and controls and including a copy of the 356h form) of theapplication is identical to the original copy that has been submitted to the appropriateOffice of Generic Drugs FDA Maryland. The field copy is submitted in the standardburgundy colored folder.

Please be so kind as to direct written correspondence with regard to this submissionto the undersigned writer. Please direct telephone calls or facsimiles directly to me asper contact numbers shown in the signature line.

Signature Name of Responsible Person. Dated __________________Regulatory Affairs Director[Applicant Company Name Inc. / Ltd.]Tel (Direct) +972-97-494-965Fax +972-97-494-532

Note DifferenceAddress is FDA Headquarters

Maryland and not one of the FDADistrict Office (e.g. NJ)





LETTERS OF AUTHORIZATION Date:


US Applicants:Certified copies of the relevant LETTERS OF AUTHORIZATION as referenced inthis applications are herewith attached:

TABLE OF LOAs ATTACHEDLetter of authorization Company Referenced LOA Item LOA Date

1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15.

Signature

Name of Responsible Person. Dated __________________Regulatory Affairs Director

4End of Section 21.



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 CMC 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

Drug Ñ2001Ð ManufacturersHigh 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

Drug Ñ2001Ð ManufacturersHigh 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
