136188075 Handbook of Pharmaceutical Generic Development Vol 12 Part 2

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ANDBOOK OF

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HARMACEUTICAL

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ENERIC

D

EVELOPMENT

S

E M I

S

OLIDS

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OLUME

XII

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art

Two

Generic Development Topical Dosage Forms

HANDBOOK OF PHARMACEUTICAL

G E N E R I C D E V E L O P M E N T

H a n d b o o k o f P h a r m a c e u t i c a l

G e n e r i c D e v e l o p m e n t 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 Technikon

Johannesburg RSA.

Edited:

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

Review Process :

Generic & Innovative Drug Development Division Research Center

Locum International Research

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

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

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

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

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

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

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

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

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

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

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

Handbook of Pharmaceutical Generic Development Vol. 12 - Tablets Oral DR Handbook of Pharmaceutical Generic Development Vol. 13 - Analytical

Part I (Method Validation) & Part II (Analytical Methods 1994-2003) (Top 50 Generic Assay Methods) Handbook of Pharmaceutical Innovative Development Vol. 14 - Tablets Oral

Handbook of Pharmaceutical Innovative Development Vol. 15 - CapsulesOral

H

andbook of Pharmaceutical Innovative Development Vol. 16 - Suspensions Oral

H

andbook of Pharmaceutical Drug Development (1-5) Vol. 17 - MF and MMI (Master Formula & Manufacturing Instructions Parts 1 - 5)

H

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

H

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

E l e c t r o n i c

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H a n d b o o k S e r i e s o f

P h a r m a c e u t i c a l G e n e r i c D e v e l o p m e n t

ISSN 0793 8667 - Electronic Version Handbook Development 24 Volume Series ISSN Series Number 0793 761X - Electronic Version

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

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

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

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

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

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

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

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

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

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

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

Handbook of Pharmaceutical Innovative Development Vol. 12 - Semisolids Handbook of Pharmaceutical Generic Development Vol. 13 - Analytical

Part I (Method Validation) & Part II (Analytical Methods 1994-2003) (Top 50 Generic Assay Methods) Handbook of Pharmaceutical Innovative Development Vol. 14 - Tablets Oral DR Handbook of Pharmaceutical Innovative Development Vol. 15 - Suspensions Oral

H

andbook of Pharmaceutical Innovative Development Vol. 16 - Capsules Oral

H

andbook of Pharmaceutical Innovative Development Vol. 17 - Master Formula

H

andbook of Pharmaceutical Innovative Development Vol. 18 - Master processes

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A N D B O O K

O F

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H A R M A C E U T I C A L

GENERIC DEVELOPMENT

Semisolid

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

VOLUME

XII - Part TWO

S E M I S O L I D D O S A G E F O R M

Jeremy D. Block

B.Sc. MPS. D/Pharm.

I n n o v a t i v e S e r i e s

Handbook of

Pharmaceutical

G e n e r i c

Development

S

S

e m i

s

olids

C

opyright © 1994-00 - Locum Publishing House Inc. All Rights Reserved.

N

either this book nor any part may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, microfilming and recording, or by any information storage and retrieval system, without the permission of the publishers.

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

SERIAL NUMBER - DO NO REMOVE - REGISTERED WITH

HPGD Series

- Semisolid Dosage Forms

First and Second International Edition - 01/02.

First and Second edition published and distributed in UK, US, EU, RSA, Israel and Japan in November 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 in February 2000 by Locum International Publishing House (Houston, Israel, South Africa) in Hard Cover; Soft and Spiral Cover; Electronic Diskette; and e-mail attachment versions. All print 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 44864 Israel. - All right reserved.

ISBN 0793 873X

ISBN 0793 8748 - Electronic Version (Diskette, CD ROM, and Online version)

Handbook Development 24 volume series. General ISSN Series number 0793 7407

General ISSN Series number 0793 7792 - Electronic Issue (Diskette, CD ROM and Online version are identical in size and content to the printed hard or soft cover version.)

Duplication: No part of this publication may be reproduced, stored in a retrieval system or transmitted in any form or by any means, electronic, mechanical, photocopying, microfilming, recording or otherwise, without the prior written permission of the copyright owner or subject to the following conditions:

A

uthorization to photocopy items for internal or personal use or internal or personal use of specific company personnel, is granted by Locum International Publishing House, provided that the base fee of $3 per page is paid directly to the Copyright Clearance Center (CCC) 222 Rosewood Drive, Danvers, MA 01923 USA. For organizations that have been granted a photocopy license by CCC, a separate system of payment has been arranged.

F

or additional information, contact the Publications Department Locum International Publishing House; PO Box 874, 50 Gilad Street, Kochav Yair, 44864 Israel.

UK Fax: +(44) 207-900 2096 US Fax: +(1) 435-408 1665 Fax: +972-97-494 532

E-mail: info@locum. co. il

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

h t t p : / / w w w . l o c u mu s a. c o m

handbooks@l o c u mu s a. com

sales@l o c u mu s a. com Current Printing (last digit) :

10 9 8 7 6 5 4 3

EDITORIAL PREFACE

Handbook of Generic Drug Development - Semisolid Dosage Forms

his handbook represents the third International Edition for Europe of the ongoing 24 volume series of Generic Drug Development and appears under the cumulative title of the Handbook series of Generic Drug Development. The ongoing series is updated annually at the end of each year. This is an ongoing process as new data, specifications and process techniques are added on a continual and expanding basis. This handbook is fact, never fully complete, as each new annual edition brings an enlarged and extended profile in the drug development process, as well as new agency rules, guidelines and guidance to industry which continue to be added year by year as the global product data base expands. Currently over 150 scientific publications and drug development conferences are annually referenced in the 24 volume Handbook series of Generic Drug Development.

T

his mammoth task presents a continual ongoing commitment by the scientific review committee to the improvement of the technical databases and the product specific drug development requirements and know-how technology accessed through the world wide IAGIM joint ventures and know-how projects currently active in over 15 countries.

The Handbook is available in electronic format (Online and CD ROM) and the e-format is up-dated annually to association members of IAGIM.

T

his third international edition of the Handbook has been redesigned and updated to meet the January 1999 Guidance for Industry - Organization of an Abbreviated New Drug Application and an Abbreviated Antibiotic Application as well as all current approved and draft FDA guideline requirements of the Center of Drug Evaluation

and Research (CDER). Editor-in-Chief.

ISSN 0793 873X A 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 n

General Series ISSN 0793 7407 Electronic Series ISSN 0793 7792

Acknowledgments

I.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 Guidelines Library 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 io n t 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 rs 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 e c o n t r i b u t i o n .

Third International Edition. 2000

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

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 and should state:

ü

ü

Purpose of Submission

ü

ü

Type of Submission

Ü

(Original ANDA)

Ü

(Supplement)

Ü

(Amendment)

Ü

(Annual Report)

Ü

(Re-submission)

ü

ü

Name of Applicant

ü

ü

Title of Applicant

ü

ü

Signature of Applicant (original ink)

ü

ü

Proprietary name (if any)

ü

ü

Generic name of Drug

ü

ü

Number of volumes submitted.

þ

þ

Methods Validation Post Approval Commitment .

þ

þ

Electronic Format Statement (portion or whole submission).

þ

þ Sterility Assurance Data Statement (Indicate that submission contains

Compare

OLD & NEW

Data

Indicate

Type:-Change being Effected Expedited review requested

Preapproval Supplement SUPAC Supplement

SUPAC Changes:-þ Describe Change

þ Reference Exact SUPAC Guidance & Guidance Section

þ Cover letter Header "This Submission is based on a

SECTION I

SECTION 1

Application/ Table of Contents

'This Submission is based on a SUPAC Document'

COVER LETTER

Date

: ______________ Office of Generic Drugs

CDER, Food and Drug Administration Document Control Room - No. 150 Metro Park North II

7500 Standish Place

ROCKVILLE MD 20855-2773.

ORIGINAL ABBREVIATED NEW DRUG APPLICATION

[Generic name] Specific Oral Dosage Form [USP] Dear Sir,

W

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

E

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

W

e furthermore commit to fully resolve any appropriate post approval issue identified in the methods validation process.

T

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

T

he Application does/does not contain Sterility Assurance Data in section XXII We look forward to your review and comment.

Yours Sincerely. Our Best Wishes,

Signature

Name of Responsible Person. Dated __________________

Clear Brief

Introductory Statement

Letter Header

For SUPAC submissions

only.

(Place on envelop as well)

Specify - Type of Bioequivalence

Ö Results of Study

ÖResults of Multiple Dose Study

SECTION I

SECTION 1

Application/ Table of Contents

TABLE OF CONTENTS

SECTIONS I

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

.2 Signed Application Form (Form FDA 356h or 3439) with original ink signature. .3 Table of Contents - to CDER Guide to Industry Format, (April 1997).

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

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

SECTIONS II

2.1 Section Page (with Color Section TAG) and brief descriptor of the section. .2 Basis for ANDA Submission

SECTIONS III

3.1 Section Page (with TAG) and brief descriptor of the section. .2 Patent Certification statement - (Paragraph I, II, III or IV)

.3 ‘Little VIII’ Patent statement - i.e. no labeling claims on a new indication. .4 Exclusivity Statement with reference to the RLD.

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

SECTIONS IV - Generic vs. RLD Comparison

4.1 Section Page (with TAG) and brief descriptor of the section. .2 Comparison between Generic and Reference Listed Drug (RLD).

.3 Tabulate to show proposed product is the same as listed product namely:

-Use; Active Ingredients; inactive ingredients: Route: Dosage Form; Strength .4 Rx or OTC Marketing Statement for proposed Generic Product.

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

.7 Certification that proposed labeling is the same as listed drug. .8 Innovators labeling - (obtain latest insert from FDA FOI).

SECTION I

SECTION 1

Application/ Table of Contents

TABLE OF CONTENTS

SECTIONS V - LABELING

5.1 Section Page and cover statement

.2 Innovators labeling - (obtain latest insert from FDA FOI). .3 Proposed Generic labeling

.4 Side-by-side comparison of insert. .5 Side-by-side comparison of label.

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

1Strongly recommended - but not a legal or statutory requirement

2Strongly recommended to repeat sections 5.4 & 5.5 in section 4 as 4.5 & 4.6 (new reg.)

SECTIONS VI -

BIOAVAILABILITY / BIOEQUIVALENCE STUDY

6.1 Title Page and brief summary statement of what this section contains. .2 Formula Composition of GENERIC product

.3 Percent Composition of Formula

.4 Comparative Ingredients List between Innovator & Generic .5 Certificates of Analysis of Generic Drug Product - (all strengths) .6 Certificates of Analysis for Innovator’s Product - (all strengths)

.7 Comparative Diffusion Profile using 6 dosage units each - (all strengths) .8 Comparative Diffusion Profile (CDP study results, statistics, tables and graphs) .9 Request for Waiver for Biostudy for other strengths (multiple strength application) .10 Outline of packaging container closures - proposed marketing packs.

.11 Schematic Trail of all packed units

.12 Topical Bioequivalence protocol and study reports conducted on pivotal batch *(Biostudy = Bioavailability / Bioequivalence Study required in selected cases)

SECTION I

SECTION 1

Application/ Table of Contents

TABLE OF CONTENTS

SECTIONS VII - Components and Composition

7.1 Title Page (with TAG) and brief narrative statement of what this section contains. .2 List of Components - in order of manufacture (name & grade).

.3 Formula Composition of Generic Product .4 Percent Composition of Generic Product.

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

SECTIONS VIII - RAW MATERIAL CONTROL

Active ingredients & Chromatographs

8.1 Title Page (with TAG) and brief narrative statement of what this section contains. .2 Outlines of SOP for handling Raw Materials including Retest Procedure/Period .3 VENDORS Certificates of Analysis (CofA) ; Specifications and Test Results

.4 GENERIC FIRM'S Certificates of Analysis (CofA) ; Specifications and Test Results .5 Disclosure of Active ingredients Source. (Type II DMF Authorization Letter)

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

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

SECTIONS VIII - RAW MATERIAL CONTROL

Inactive ingredients

8.8 Title Page and brief summary statement of what this section contains. .9 CoA from Generic Firm’s QC laboratory, plus supporting:

SECTION I

SECTION 1

Application/ Table of Contents

TABLE OF CONTENTS

SECTIONS VIII - CONTINUED

SECTIONS VIII - RAW MATERIAL CONTROL

Inactive ingredients

.10 CoA from Active Manufacturer, - plus supporting: - Identification IR or UV spectra of Active

- HPLC chromatograms (Assay - Impurities) - label peaks - Photocopy of TLC chromatograms (Assay - Impurities)

.11 IR Identification Spectra of Reference Standard (Pharmacopoeial). Physical Specifications from Active Manufacturer:

- Bulk Density

- Particle Size (note: water insoluble material) .12 Physical and analytical test methods.

.13 Material Data Safety Sheet - source of data for manufacturing cautions. .14 Monographs of each non-active from Generic QC lab

.15 Coating Colors and Dyes - US Source with Batch Certification .16 - Composition of Approved Pigments and Dyes

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

.18 CoA from Approved Manufacturer (Suppliers Release Certificate) .19 Routine Testing Protocol and Frequency of tests for Active Material .20 Routine Testing Protocol and Frequency of tests for Inactive Material

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

.22 SOP Outline of vendor qualification requirements (outlines are unsigned) .23 SOP Outline of retesting procedures and schedule (micro. NMT 12 months) .24 SOP Outline of RM environmental storage temperatures (15o-25 o (30o C).

SECTION I

SECTION 1

Application/ Table of Contents

TABLE OF CONTENTS

SECTIONS IX - Description of Manufacturing Facility

9.1 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 equipment

and key personnel (no personnel CVs).

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

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

SECTIONS X

Outside 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 XI

Proposed 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)

SECTION I

SECTION 1

Application/ Table of Contents

TABLE OF CONTENTS

11.7 _{Finished Product Release Specifications.}

.8 _{Outline Packaging Operations and packaging equipment listing} .9 _{Blank Packaging Records.}

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

.10 _{Reprocessing statement.}

SECTIONS XII

Pivotal Manufacturing and In-Process Controls

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 Title page

.6 Pivotal Batch Records.

.7 Executed Batch with signatures

.8 - Master Formula for pivotal size

.9 - Executed forms - Master Formula (Commercial batch size). .10 - Executed forms - Manufacturing Procedures (English translations.) .11 - Executed forms - In-process control sheets (English translations).

Documentation for manufacturing procedures, including production yields). .12 - Executed forms - In-process manufacturing specifications for bulk material. .13 - Executed forms - In-process product specifications for bulk material.

.14 - Executed forms - In-process test result sheet of the bulk material .15 - Certificate of Batch Homogeneity (showing test results.)

.16 - Executed forms - In-process specifications. .17 - Executed forms - In-process test results sheet. .18 - FILL weight Verification study and results

.19 - Executed forms for production yields and weighing print-outs attachments. .20 Executed forms production forms for in-process weight controls (translations) .21 Finished Product Release Specifications

SECTION I

SECTION 1

Application/ Table of Contents

TABLE OF CONTENTS

12.23 Executed forms production forms for in-process weight controls (translations) .24 Finished Product Release Specifications

.25 Manufacturing (Mnf's) Deviation Reports (MDRs) - (translations) .26 Production Packaging Work Sheets - (translations) .27 Production Packaging Control Forms - (translations) .28 Distribution of Pivotal lot into various container-closures systems (Packaging) .29 Pivotal Batch Packaging Trail - (overall disposition of UNITS i.e. net yield, QC

sampling, reserve samples, stability samples, Biostudy, Packaging formats.)

SECTION XIII

Description & Characteristics of Packaging Components

Packaging and labeling Procedures

13.0 Title Page (with TAG) and brief narrative statement of what this section contains. .1 Outlines for Packaging and Labeling Procedures

.2 Blank Packaging Forms and Packaging reconciliation.

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

CONTAINERS, GLASS OR THERMOPLASTIC

(REQUIREMENTS FOR EACH CONTAINER.) .3 Description of Packaging Components - pack sizes for each strength. .4 i. LoA from manufacturer referencing their container DMF #.

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

.6 Manufacturer's Container Specifications or Certificate of Conformance, including; - drawings/diagrams and dimensions

- test protocol and Certificates meeting USP and 21 CFR requirements - DSC thermal analysis (for thermoplastic containers only)

- Manufacturer’s Container CoA

.7 Testing Specifications / protocol and test results (CoA) of Generic packaging Lab. .8 CoAs of Containers from Generic packaging Lab.

SECTION I

SECTION 1

Application/ Table of Contents

TABLE OF CONTENTS

METAL CAPS AND THERMOPLASTIC CLOSURES (PER EACH CLOSURE.)

13.09

LoA from closure manufacturer referencing DMF # of cap (+ GMP statement.) .10 _{LoA from resin manufacturer referencing thermoplastic resin DMF #. (Obtain}

separate letters for each resin type used in thermoplastic closures) .11 _{Mnf's Closure Specifications or Certificate of Conformance, including;}

- drawings/diagrams and dimensions

- test protocol and certificates meeting all USP and 21 CFR requirements - DSC thermal analysis (only for thermoplastic closures)

- Manufacturer’s CoA

.12 Testing Specifications / protocol and test results (CoA) of Generic packaging Lab. .13 Batch Compliance Results.

INNER CLOSURE LINER:

13.14 Item description and use - meets current CFR and USP requirements. .15 LoA from manufacturer to applicant referencing their DMF # of inner liner.

.16 Inner liner Specifications or Certificate of Conformance from manufacturers. .17 Testing Specifications / protocol of Generic packaging Lab.

.18 CoA or test results of inner liner from Generic packaging Lab. .19 Batch Compliance Statement.

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

13.20 Item description and use - meets current CFR and USP requirements. .21 LoA from manufacturer to applicant referencing their DMF # of foam seal. .22 Foam seal Specifications or Certificate of Conformance from manufacturers .23 Testing Specifications / protocol of Generic packaging Lab.

.24 CoA or test results of Foam seal from Generic packaging Lab. .25 Batch Compliance Statement.

SECTION I

SECTION 1

Application/ Table of Contents

TABLE OF CONTENTS

TUBES AND NOZZLES/APPLICATORS

13.26 Item description and use - USP requirements.

.27 LoA from manufacturer to applicant referencing their DMF # .28 Specifications or Certificate of Conformance from manufacturers. .29 Testing Specifications / protocol of Generic packaging Lab. .30 CoA or test results from Generic packaging Lab.

.31 Batch Compliance Statement of incoming packaging materials.

Section XIV

- Controls for the Finished Dosage Form

14.1 Title Page (with TAG) and brief narrative statement of what this section contains. .2 State if drug product is:

- Compendial and test methods Πused 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 - CoA for _______ [product] USP [Strength #2] mg + HPLC chromatograms - CoA for _______ [product] USP [Strength #3] mg + HPLC chromatograms - CoA for _______ [product] USP [Strength #4] mg + HPLC chromatograms

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

SECTION I

SECTION 1

Application/ Table of Contents

TABLE OF CONTENTS

Section XV

-

Analytical Methods

15.1 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 Πused are USP

- Non-Compendial and test methods in-house and validated. - Non-Compendial and test methods based on• and validated.

Active material

.2 Active Ingredient Test Method

.3 Active Ingredient Test Method Validation

In-process Material

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

Finished Product

.5 Finished Product Test Methods (QC Release - physical tests

- chemical tests - microbiological tests

.6 Finished Product Test Methods - (Stability Check) - stability Indicating Test Methods.

- impurity limit tests.

- Preservative Efficacy Test Method (Validation and stability Studies). .7 Finished Product Analytical Validation methodology

- stability Indicating Assay.

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

RESERVED SECTION NOT FOR CURRENT USE

SECTION I

SECTION 1

Application/ Table of Contents

TABLE OF CONTENTS

Section XVI

Stability of Finished Dosage Form

16.1 Title Page (with TAG) and brief narrative statement of what this section contains. .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 controlled room temperature studies.

.7 Stability Data Summary Report (graphs).

Section XVII

Reserved

17.0 Title Page (with TAG) and brief statement that section is reserved. 17.1 Reserved

Section XVIII

Samples of the drug and articles used as

components

18.1 Title Page (with TAG) and brief narrative statement of what this section contains. .2 Statement on Sample Submission Procedures to FDA on request on

SECTION I

SECTION 1

Application/Table of Contents

TABLE OF CONTENTS.

Section XIX

ENVIRONMENTAL 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 Manufacturers

Commercial Plant Manager and QA Director Signatures.

Section XX

ADDITIONAL INFORMATION

20.0 Title Page (with TAG) and brief narrative statement of what this section contains. 20.1 Certification Pursuant to the Generic Drug Enforcement Act of 1992.

20.2 US Agents Letter of Authorization

Section XXI

ADDITIONAL INFORMATION

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

SECTION I

SECTION 1

Application/ Table of Contents

FDA FORM 3439

or

FDA FORM 356h

[REVISED]

Jan 8, 1998

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

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

SECTION II

SECTION 2

Basis for ANDA Submission

TABLE OF CONTENTS

(Overall ANDA Guideline Requirements for this Section).

2.O Section Page and Title. The information in this section summarizes the four critical 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

or

2.1.2 Based on an approved ANDA Suitability Petition

and

3.0 Based on Active Ingredient (same as RLD) and current approved labeling

and

4.0 Based on Route of Administration, Dosage Form and Strength

and

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

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

SECTION II

SECTION 2

Basis for ANDA Submission

BASIS FOR ABBREVIATED NEW DRUG APPLICATION

[a]

Listed Drug.

This applications refers to the Reference Listed Drug [

NAME

]

q

Semisolid

q

Tablet

/

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

(delete where necessary)

.

The basis for [Applicant Company Name Inc. / Ltd.] proposed ANDA for Full Generic Drug Name is the approved reference listed drug as above, the subject of ANDA [#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 Drug Products known as the Orange Book 20th (2000) Edition the listing is enclosed herewith.

[b]

Exclusivity.

F

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

or

F

urthermore according to the FDA listed information published in the list of Approved Drug Products [Orange Book] 20th (2000) Edition,

no exclusivity’s for

the 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 is

addressed in Section III of this application.

[d]

APPROVED ANDA SUITABILITY PETITION

The basis for [Applicant Company Name Inc. / Ltd.] proposed ANDA is further based on the approval of the suitability petition pursuant to the 21 Code Federal Register (CFR) # 505[j][2][c] and 21 CFR 314.93 that requested a change from the above listed drug in subparagraph 1[a] as above.

Docket No [00000]

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

SECTION II

SECTION 2

Basis for ANDA Submission

BASIS 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

q Semisolid / qTablet / qCapsule (delete where necessary) is the same as that

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

ROUTE OF ADMINISTRATION DOSAGE FORM AND STRENGTH

21 CFR 314.94 [A][5][i]

he Route of Administration, Dosage Form and Strength [Applicant Company's Name Inc. / Ltd.] of Generic q Semisolid / qTablet / qCapsule (delete where necessary) is the same as for [RLD brand name]

Again we refer the reviewer to [Applicant Company Name Inc. / Ltd.] annotated labeling and the current approved labeling of the RLD as shown in Section IV-05 of this 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

q Semisolid / qTablet / q Capsule Name] (delete where necessary) was

successfully conducted in terms of current approval parameters 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] Date

Regulatory Affairs Director

[Applicant Company Name Inc. / Ltd.] [Signature of Responsible Person]

T

SECTION II

SECTION 2

Basis for ANDA Submission

EXAMPLE 1:

Listed Drug.

This applications refers to the Reference Listed Drug [RLD]

Miconazole

1

/

Miconazole USP

2

Generic

q

Semisolid

q

Tablet

/

qCapsule

(delete where necessary)

manufactured by

[RLD Company Name Inc. / Ltd.]

3

.

A copy of the Orange Book

20

th (

2000

) Edition listing is enclosed

herewith.

According to the information published in the

20

th Edition List, the

reference listed drug is covered by

[

þ no / one / two]

þ

use patent which is

addressed in Section III of this application.

Exclusivity.

There are

[ONE] / [two]

/

þ

þ

[no]

exclusivity’s for the listed drug.

I-184 - expires Sept 24, 2000

I-185 - expires Sept 24, 2000

[Signature of Responsible Person]

---

---[Name of Responsible Person] Date

Regulatory Affairs Director

[Applicant Company Name Inc. / Ltd.]

[Signature of Responsible Person]

---

---[Name of Responsible Person] Date

Regulatory Affairs Director

[Applicant Company Name Inc. / Ltd.]

1

INNOVATOR NAME COUNTRY US or EU 2

USA RLD 375 / 500 mg - Application Number 000000 3

SECTION II

SECTION 2

Basis for ANDA Submission

EXAMPLE 2:

Listed Drug.

This applications refers to the Reference Listed Drug [RLD]

Miconazole

1

/

Miconazole USP

2

q

Semisolid /

q

Tablet

/

qCapsule manufactured by

[RLD Innovator Company Name Inc. / Ltd.]

3

.

(delete where appropriate)

A copy of the Orange Book

20th

(

2000

) Edition listing is enclosed

herewith.

According to the information published in the

20th

Edition List (

2000

), the

reference listed drug [RLD] is covered by

[

þ

þ 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 Orange

Guide (

2000

), there are

[one] / [two]

/

þ

þ

[no]

exclusivity’s for the listed

drug.

I-000 - expires MM DD, 2000 I-000 - expires MM DD, 2000

[Signature of Responsible Person]

---

---[Name of Responsible Person] Date

Regulatory Affairs Director

[Applicant Company Name Inc. / Ltd.] [Signature of Responsible Person]

---

---[Name of Responsible Person] Date

Regulatory Affairs Director

[Applicant Company Name Inc. / Ltd.]

1 INNOVATOR

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

SECTION II

SECTION 2

Basis for ANDA Submission

ANDA SUITABILITY PETITION APPROVAL LETTER

Date:

Office of Generic Drugs

CDER, Food and Drug Administration Document Control Room - No. 150 Metro Park North II

7500 Standish Place

ROCKVILLE MD 20855-2773.

ORIGINAL ABBREVIATED NEW DRUG APPLICATION

[Generic name] Dosage Form Dear Sir,

We submit herewith the ANDA SUITABILITY PETITION APPROVAL LETTER

for the drug product [Generic name q Semisolid / qTablet / qCapsule [000 / 000] mg. (delete where necessary)

[Signature of Responsible Person]

---

---[Name of Responsible Person] Date

Regulatory Affairs Director

[Applicant Company Name Inc. / Ltd.]

[ANDA SUITABILITY PETITION APPROVAL LETTER

SECTION III

SECTION 3

Patent Certification / Exclusivity

TABLE OF CONTENTS

(Overall ANDA Guideline Requirements for this Section).

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 (if applicable) are the statements concerning the required notices to the patent owners and NDA holder. These statements are in accord with the FD&C Act as amended September 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

SECTION III

SECTION 3

Patent Certification / Exclusivity

Patent Certification Statement

Paragraph I Certification

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

n accord with the Food, Drug and Cosmetic Act as amended September 24, 1984 and with the final regulations effective November 2 1994 Patent certification is hereby provided for our Abbreviated New Drug Application for [Generic Drug Name].

e the undersigned hereby certify to the best of our knowledge and in [Generic Company 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 I the 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

I

W

T

SECTION III

SECTION 3

Patent Certification / Exclusivity

Patent Certification Statement

Paragraph II Certification

n accord with the Food, Drug and Cosmetic Act as amended September 24, 1984 and with the final regulations effective November 2 1994 Patent certification is hereby provided for our Abbreviated New Drug Application for [Generic Drug Name].

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 listed drug [RLD] DRUG Name[USP] [000.0] mg. NDA # 00-000 expired on 31 December 1999

his certification is made in accordance with Section 505 (j)(2)(A)(vii)(I) of Title I the Food, Drug and Cosmetic Act, as amended September 24, 1984 and pursuant to 21 CFR 314.94 (a)(12)(i)(A)(1).

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

[Signature of Responsible Person]

---

---[Name of Responsible Person] Date

Regulatory Affairs Director

[Applicant Company Name Inc./Ltd.]

I

W

T

SECTION III

SECTION 3

Patent Certification / Exclusivity

Patent Certification Statement

Paragraph III Certification

n accord with the Food, Drug and Cosmetic Act as amended September 24, 1984 and with the final regulations effective November 2 1994 Patent certification is hereby provided for our Abbreviated New Drug Application for [Generic Drug Name].

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 listed drug [RLD] DRUG Name [USP] [000.0] mg. NDA # 00-000 will expire on [31 December 1999.]

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

n 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

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

[Signature of Responsible Person]

---

---[Name of Responsible Person] Date

Regulatory Affairs Director

[Applicant Company Name Inc. / Ltd.]

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

I

W

SECTION III

SECTION 3

Patent Certification / Exclusivity

Alternative Certification

Patent Certification Statement

Paragraph III Certification

he undersigned hereby certifies to the best of our knowledge and in [Generic Company 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, YYYY US. Patent No. 0-0000-0000 expiring MM DD, YYYY

I

n 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 will

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

[Signature of Responsible Person]

---

---[Name of Responsible Person] Date

Regulatory Affairs Director

[Applicant Company Name Inc. / Ltd.]

Attached:

Page Number:

[00]

The Prescription Drug Product List of the APPROVED DRUG PRODUCTS WITH THERAPEUTIC EQUIVALENCE EVALUATIONS EDITION 20th - 2000 US Department of Health and Human Sciences.

SECTION III

SECTION 3

Patent Certification / Exclusivity

Patent Certification Statement

Paragraph IV Certification

n accord with the Food, Drug and Cosmetic Act as amended September 24, 1984 and with the final regulations effective November 2 1994 Patent certification is hereby provided for our Abbreviated New Drug Application for [Generic Drug Name].

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 be infringed] / [ is invalid] / [is unenforceable]1 _{by the manufacturer [Generic Company}

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

[Signature of Responsible Person]

---

---[Name of Responsible Person] Date

Regulatory 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

S

pecial Note of Notification:

I

f the owner of the patent, subject to a paragraph IV Certification, is a person or entity other than the registered NDA holder, then the applicant, is required to notify, under separate cover, both parties - namely the Patent Holder and the NDA Holder.

(Certified mail return receipt cards often get damaged in the mail - thus avoid use, as system is ineffective. Where Fedex® , UPS® or DHL® etc. is used to advise of a notification it is essential to obtain the recipient approval to use Fedex® , UPS® or DHL®

I

SECTION III

SECTION 3

Patent Holder & NDA Holder

Statement Concerning Notice

To 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, as amended 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 from the FDA of an acknowledgment letter stating that this ANDA is sufficiently complete to 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 [RLD

Company Name Inc./Ltd.] the holder of the approved application for the Branded Product, [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) and 21 CFR 314.95 (c)

C

oncurrently with mailing the notice to the [RLD Company Name Inc./Ltd.] the pertaining to the Branded Product - [RLD] DRUG Name] the [Generic Company Name 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 been provided to each person identified under CFR 314.95(a) and that the notice met the contents of CFR 314.95(c).

[Signature of Responsible Person]

---

---[Name of Responsible Person] Date

Regulatory Affairs Director

[Applicant Company Name Inc./Ltd.]

♦

♦

It has become standard practice for the large RLD (Innovative) Companies to delay for as long as possible, by means of costly litigation action, the newly applied Generic registration, if submitted under 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 the general public is overridden by the Innovative Companies desire to look for continued extra-legal patent protection even thought the innovator has indeed received its fair and proper share of protection under the law during its full marketing period. The branded RLD Company simply immediately sues the generic applicant as a matter of routine practice, using its huge financial leverage to suppress the potentially lesser generic company. (Quote Brussels Conference on Patent

SECTION III

SECTION 3

Patent Certification / Exclusivity

' No relevant Patent ' Statement

21 CFR 314.94(a)(12)(ii)

n accord with the Food, Drug and Cosmetic Act as amended September 24, 1984 and with the final regulations effective November 2, 1994. Patent certification clarification is hereby provided for our submitted Abbreviated New Drug Application for [Generic Drug Name].

his certification is made in accordance with Section 505 (j)(2)(A)(vii)(I) of Title I the 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 [Generic Company 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.

[Signature of Responsible Person]

---

---[Name of Responsible Person] Date

Regulatory Affairs Director

[Applicant Company Name Inc. / Ltd.]

Background

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

I

T

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SECTION III

SECTION 3

Patent Certification / Exclusivity

Method of Use Patent Statement

21 CFR 314.94(a)(12)(iii)

his certification is made in accordance with Section 505 (j)(2)(A)(vii)(I) of Title I the Food, Drug and Cosmetic Act, as amended September 24, 1984 and pursuant to 21 CFR 314.94 (a)(12)(i)(A)(1).

Method of Use Patent

n accord with the Section 505 (j)(2)(A)(viii) of Title I the Food, Drug and Cosmetic Act, 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], submitted by [RLD Company Name Inc./Ltd.] for listing in respect to [RLD Branded Drug Name], that of Use Patent No [000-000-00] does not claim a use for which [Generic Company Name Inc./Ltd.] is seeking approval for [Generic Drug Name]

e the undersigned hereby certify to the best of our knowledge that of Use Patent 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 in this ANDA, as evident by the attached proposed labeling (Refer to Page [00]), is for use indication _________, which is beyond the reach of claims of Patent No [000-000-00] .

[Signature of Responsible Person]

---

---[Name of Responsible Person] Date

Regulatory Affairs Director

T

I

SECTION III

SECTION 3

Patent Certification / Exclusivity

Exclusivity Statement

21 CFR 314.94(a)(3)(ii)

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

he undersigned hereby certifies to the best of our knowledge and in [Generic Company Name Inc./Ltd.] opinion the listed drug [RLD] DRUG Name [USP] [000.0] mg. NDA # 00-000 is not covered by any exclusivity.

OR

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

ccording to the information as published in the 'Orange Book' [Approved Drug

Products 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 31 2002.

[Generic Company Name Inc./Ltd.] does not intend to introduce its drug product subject to this ANDA, prior to the expiration of this exclusive marketing period.

[Signature of Responsible Person]

---

---[Name of Responsible Person] Date

Regulatory Affairs Director

[Applicant Company Name Inc./Ltd.]

Attached:

Page Number: [00]

The Prescription and OTC Drug Product Patent and Exclusivity Data of the APPROVED DRUG PRODUCTS WITH THERAPEUTIC EQUIVALENCE EVALUATIONS EDITION 20 (2000) - US Department of Health and Human Sciences.

T

SECTION IV

SECTION 4

Generic and RLD Comparison

TABLE 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 capsules 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 requirements

Section 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 Industry Organization of an ANDA' it was appropriate to place the side-by-side labeling comparison in section V on the ANDA. The new February 1999 'Guide' indicates that the side-by-side labeling comparison should appear in Section IV-5. Applicants may place the comparison in both section IV-5 and V until the FDA are conversant with the new guideline

SECTION IV

SECTION 4

Generic and RLD Comparison

Information required under 314.94 (a)(4) through (6) of the ANDA Regulations final rule issued April 28 1992 and February 1999 Guidance to Industry.

[RLD] SEMISOLID [Generic name] SEMISOLID

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

Conditions of Use The conditions of use prescribed or recommended or suggested for [RLD] SEMISOLIDS [USP] may be

found in the package insert (see section V).

The conditions of use prescribed, recommended or suggested for [Generic name] SEMISOLIDS [USP]] are the same for [RLD] SEMISOLIDS [USP] and may be found in the package insert (see Section V).

Active Ingredient [Active Material] [Active Material]

Dosage Form SEMISOLIDS [USP] (Topical dosage form)

SEMISOLIDS [USP] (Topical dosage form)

Administration

Topical

Topical

Strengths Number of Strengths 000.0 mg 000.0 mg 000.0 mg 000.0 mg 000.0 mg 000.0 mg 000.0 mg 000.0 mg

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

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

SECTION IV

SECTION 4

Rx / OTC Statement

[Generic name] SEMISOLID [USP]

[All strengths]

Prescription Drug

(R

_x)

This drug is limited in its labeling and by this application to use under the

professional supervision of a practitioner licensed by law to administer the

prescription drug.

or

Over-the-Counter (OTC) Drug

This drug is limited in its prescribed labeling and by this application for

use as an Over-the-Counter (OTC) Drug.

[Signature of Responsible Person]

---

---[Name of Responsible Person] Date

Regulatory Affairs Director

SECTION V

SECTION 5

Labeling

TABLE OF CONTENTS

(Overall ANDA Guideline Requirements for this Section).

1. Section Page and cover statement

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

3. Proposed Generic Insert / Outsert

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

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

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

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

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

SECTION V

SECTION 5

Labeling

PROPOSED GENERIC CONTAINER PANEL LABELING

000 g [Name] SEMISOLID [USP]

Main Panel NDC [0000-0000-00]

[Generic Name] Semisolid [USP]

000

mg per g

_________________________ Contains:

[Active Material] 000 mg per g

Caution: Federal law prohibits dispensing without prescription

000 g Semisolid [USP]

[Applicant Company Name Inc. / Ltd.]

Side Panel Usual dosage : Apply four times a day.

See package for full prescribing information. KEEP OUT OF REACH OF CHILDREN

Keep tightly closed. Store at controlled room temperature 15º -30º C (59º - 86º F).

Protest from exposure to temperatures above 40º C (104º F) and moisture.

KEEP THIS AND ALL MEDICATIONS OUT OF REACH OF CHILDREN

6/YY.

MANUFACTURED BY

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

Distributed By:

SECTION V

SECTION 5

Labeling

PROPOSED GENERIC CONTAINER PANEL LABELING

000 g [Name] SEMISOLID [USP]

Main Panel NDC [0000-0000-00]

[Generic Name] Semisolid [USP]

000

mg per gram

_________________________ Contains:

[Active Material] 000 mg / g

Caution: Federal law prohibits dispensing without prescription

000 g [Name] Semisolid [USP]

[Applicant Company Name Inc. / Ltd.]

Side Panel Usual dosage : Apply four times a day.

See package for full prescribing information. KEEP OUT OF REACH OF CHILDREN

Lot No Mfg. Date: Use Before:

Keep tightly closed. Store at controlled room temperature 15º -30º C (59º - 86º F).

Protest from exposure to temperatures above 40º C (104º F) and moisture.

KEEP THIS AND ALL MEDICATIONS OUT OF REACH OF CHILDREN

6/YY.

MANUFACTURED BY

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

Distributed By:

[Distributing Company Name Inc. / Ltd.] [Short Address]