136188075 Handbook of Pharmaceutical Generic Development Vol 12 Part 2

SEMISOLID

TOPICAL DOSAGE FORM

HANDBOOK

OF

PHARMACEUTICAL

GENERIC DEVELOPMENT

S E M I S OLIDS VOLUME XII Part Two Generic Development Topical Dosage Forms

HANDBOOK OF PHARMACEUTICAL GENERIC DEVELOPMENT Handbook of Pharmaceutical Generic Development 24 Volume Series

Handbook of Pharmaceutical

[email protected] http://www.l o c u m u s a . c o m

Generic Development

SEMISOLID

TOPICAL DOSAGE FORM

Handbook of Pharmaceutical Generic Development Series Compiled by :

J. D. BLOCK 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: IAGIM Scientific Committee 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)


Vol. 2 - Capsules



Vol. 3 - Semisolids



Vol. 4 - Liquids



Vol. 5 - SG Capsules



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


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

Handbook of Pharmaceutical Innovative Development Handbook of Pharmaceutical Innovative Development Handbook of Pharmaceutical Innovative Development Handbook of Pharmaceutical Drug Development (1-5)

Vol. 12 - Tablets Oral DR Vol. 13 - Analytical (Top 50 Generic Assay Methods)

Vol. 14 - Tablets Oral Vol. 15 - Capsules Oral Vol. 16 - Suspensions Oral Vol. 17 - MF and MMI

(Master Formula & Manufacturing Instructions Parts 1 - 5)

Handbook of Pharmaceutical Drug Development (6-10)

Vol. 18 - MF and MMI

(Master Formula & Manufacturing Instructions Parts 6 - 10)

Handbook of Pharmaceutical Innovative Development

Vol. 19 - SOPs/PAI-Checklist

Part I, Part II & Part III.(Development, Manufacturing & Engineering)

Handbook of Pharmaceutical Drug Development

Vol. 20 - Sterile Injections

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

p p ppp Handbook of Pharmaceutical


Generic Development

SEMISOLID

TOPICAL DOSAGE FORM

Electronic < Handbook Series of Pharmaceutical Generic Development ISSN 0793 8667 - Electronic Version Handbook Development 24 Volume Series ISSN Series Number 0793 761X - Electronic Version


Vol. 1 - Tablets



Vol. 2 - Capsules



Vol. 3 - Semisolids



Vol. 4 - Liquids



Vol. 5 - SG Capsules



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 - Semisolids


Vol. 13 - Analytical

Part I (Method Validation) & Part II (Analytical Methods 1994-2003)

(Top 50 Generic Assay Methods)


Vol. 14 - Tablets Oral DR


Vol. 15 - Suspensions Oral

Handbook of Pharmaceutical Innovative Development Handbook of Pharmaceutical Innovative Development Handbook of Pharmaceutical Innovative Development Handbook of Pharmaceutical Innovative Development

Vol. 16 - Capsules Oral Vol. 17 - Master Formula Vol. 18 - Master processes Vol. 19 - SOPs/PAI-Checklist

Part I, Part II & Part III.(Development, Manufacturing & Engineering) Available either on Online, CD ROM or via electronic mail attachment. Additional Drug Specific Volumes in Preparation An on-going electronic and print series

p p ppp



Generic Development

SEMISOLID

TOPICAL DOSAGE FORM

HANDBOOK OF PHARMACEUTICAL GENERIC DEVELOPMENT

Semisolid

TOPICAL DOSAGE FORM VOLUME XII SEMISOLID

-

Part TWO

DOSAGE

F O R M

Jeremy D. Block B.Sc. MPS. D/Pharm.

International Euro Edition. L O C U M

P U B L I S H I N G

H O U S E

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



Generic Development

SEMISOLID

TOPICAL DOSAGE FORM

Handbook of Pharmaceutical G e n e r i c Development

Innovative Series

Part

Two

Semi

s olids

ANDA Development

Copyright © 1994-00 - Locum Publishing House Inc.

All Rights Reserved.

Neither this book nor any part may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, microfilming and recording, or by any information storage and retrieval system, without the permission of the publishers. Locum International

Publishers


A

L o c u m

H o u s e


P u b l i c a t i o n

Generic Development

SEMISOLID

HPGD Series

TOPICAL DOSAGE FORM

-

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: Authorization 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. For 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 http://www.locum.co.il http://www.locumeuro.com http://www.locumusa.com handbooks@l o c u m u s a . com sales@l o c u m u s a . com

Current Printing (last digit) : 10 9 8 7 6 5 4 3 SERIAL NUMBER - DO NO REMOVE - REGISTERED WITH

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


Ö PRINTED IN USA PRINTED IN ISRAEL PRINTED IN IRELAND PRINTED IN REPUBLIC OF SOUTH AFRICA


Generic Development

SEMISOLID

TOPICAL DOSAGE FORM

EDITORIAL PREFACE Handbook of Generic Drug Development - Semisolid Dosage Forms

T

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. This 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 eformat is up-dated annually to association members of IAGIM.

This 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

An on-going series Additional Volumes in Preparation

General Series ISSN 0793 7407 Electronic Series ISSN 0793 7792

0793 7407 International Print Edition

ppp LOCUM

ppp



Generic Development

SEMISOLID

TOPICAL DOSAGE FORM

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. °

To Doribelle for her years of support and help to Sean for his expert knowledge on computerization to David and Ari for running the project's computers and lastly to Pat for his inestimable contribution.

Third International Edition. 2000

L O C U M

P U B L I S H I N G

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Í

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H O U S E

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Generic Development

HANDBOOK OF GENERIC DRUG DEVELOPMENT

SECTION I

ANDA DEVELOPMENT

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: Indicate Type:Change being Effected Expedited review requested Preapproval Supplement SUPAC Supplement

ü Purpose of Submission ü Type of Submission Ü (Original ANDA) Ü (Supplement) Ü (Amendment) Ü (Annual Report) Ü (Re-submission)

Compare OLD & NEW Data

ü Name of Applicant ü Title of Applicant ü Signature of Applicant (original ink) ü Proprietary name (if any) ü Generic name of Drug ü Number of volumes submitted.

SUPAC Changes:þ Describe Change þ Reference Exact SUPAC Guidance & Guidance Section þ Cover letter Header "This Submission is based on a SUPAC DOCUMENT"

þ Methods Validation Post Approval Commitment . þ Electronic Format Statement (portion or whole submission). þ Sterility Assurance Data Statement (Indicate that submission contains SAD) þ - NEW 1999/2000 Requirements

24 Volume V Drug Development Series

Sect: 1.1

ANDA DEVELOPMENT


ANDA DEVELOPMENT

SECTION I

SECTION 1

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

COVER LETTER

Letter Header For SUPAC submissions only.

Date: ______________

(Place on envelop as well)

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.

Clear Brief Introductory Statement

ORIGINAL ABBREVIATED NEW DRUG APPLICATION [Generic name] Specific Oral Dosage Form [USP] Dear Sir, We 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) Enclosed 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. We furthermore commit to fully resolve any appropriate post approval issue identified in the methods validation process. The 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. The Application does/does not contain Sterility Assurance Data in section XXII We look forward to your review and comment. Yours Sincerely. Specify - Type of Bioequivalence Our Best Wishes, Ö Results of Study Signature ÖResults of Multiple Dose Study Name of Responsible Person. Dated -__________________ Dissolution Data Regulatory Affairs Director - Waiver Request Enclosures - Nine files 24 Volume V Drug Development Series

Sect: 1.2

ANDA DEVELOPMENT


ANDA DEVELOPMENT

SECTION I

SECTION 1


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 .2

Section Page (with Color Section TAG) and brief descriptor of the section. 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 .5

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


Sect: 1.3

ANDA DEVELOPMENT


ANDA DEVELOPMENT

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)


Sect: 1.4

ANDA DEVELOPMENT


ANDA DEVELOPMENT

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


.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 .9

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


Sect: 1.5

ANDA DEVELOPMENT


ANDA DEVELOPMENT

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

.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).


(Suppliers Release Certificate)

Sect: 1.6

ANDA DEVELOPMENT


ANDA DEVELOPMENT

SECTION I

SECTION 1

Application/ Table of Contents TABLE OF CONTENTS SECTIONS IX - Description of Manufacturing Facility 9.1


.2

Statement of commercial

- Site address of Manufacture(s).

.3


- Packaging & Labeling - site address.

.4


- 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 .2

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

.6

SECTIONS XI Proposed Manufacturing and Processing Instructions 11.1 .2

Title Page (with TAG) and brief narrative statement of what this section contains. Outlines of Manufacturing, equipment listing and Packaging SOP.

.3

Summary of In-process controls and reprocessing statement.

.4

Flow Chart of Manufacturing Procedure.

.5

Blank forms for Intended Production runs for LARGEST commercial batch size with processing equipment specified (Note 1:10 pivotal ratio).

.6

Blank forms should include the full manufacturing process such as:

-

Blank forms - Master Formula (Commercial batch size) Blank forms - Manufacturing Procedures (English translations) Blank forms - In-process specifications sheet for final blend. Blank forms - In-process control sheets (English translations). Blank production forms for in-process weight controls Blank forms for production yields and weighing print-outs attachments


Sect: 1.7

ANDA DEVELOPMENT


ANDA DEVELOPMENT

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 Equipment, QC, Production Operating Personnel, SOPs).

.10

Reprocessing statement.

(Formulation,

SECTIONS XII Pivotal Manufacturing and In-Process Controls 12.1 .2 .3 .4 .5 .6 .7 .8 .9 .10 .11 .12 .13 .14 .15 .16 .17 .18 .19 .20 .21 .22

Title Page (with TAG) and brief narrative statement of what this section contains. Outline of In-process SOPs. In Process Controls and sampling plan summary. Executed Manufacturing Procedure Flow Chart. Pivotal Batch Title page Pivotal Batch Records.

Executed Batch with signatures -

Master Formula for pivotal size Executed forms - Master Formula (Commercial batch size). Executed forms - Manufacturing Procedures (English translations.) Executed forms - In-process control sheets (English translations). Documentation for manufacturing procedures, including production yields). - Executed forms - In-process manufacturing specifications for bulk material. - Executed forms - In-process product specifications for bulk material. - Executed forms - In-process test result sheet of the bulk material - Certificate of Batch Homogeneity (showing test results.) - Executed forms - In-process specifications. - Executed forms - In-process test results sheet. - FILL weight Verification study and results - Executed forms for production yields and weighing print-outs attachments. Executed forms production forms for in-process weight controls (translations) Finished Product Release Specifications Manufacturing (Mnf's) Deviation Reports (MDRs) - (translations)


Sect: 1.8

ANDA DEVELOPMENT


ANDA DEVELOPMENT

SECTION I

SECTION 1

Application/ Table of Contents TABLE OF CONTENTS 12.23 .24

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

.25

Manufacturing (Mnf's) Deviation Reports (MDRs)

- (translations)

.26

Production Packaging Work Sheets

- (translations)

.27

Production Packaging Control Forms

.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.)

- (translations)

SECTION XIII Description & Characteristics of Packaging Components Packaging and labeling Procedures 13.0


.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 .4 .5 .6

Description of Packaging Components - pack sizes for each strength. i. LoA from manufacturer referencing their container DMF #. ii. LoA from resin mnf. referencing their resin DMF # used in container - (Obtain separate letters for each resin type used in plastic containers.) 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 .8

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

.9

Batch Compliance Results


Sect: 1.9

ANDA DEVELOPMENT


ANDA DEVELOPMENT

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


.24

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

.25

Batch Compliance Statement.


Sect: 1.10

ANDA DEVELOPMENT


ANDA DEVELOPMENT

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


.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 .2

Title Page (with TAG) and brief narrative statement of what this section contains. State if drug product is: - Compendial and test methods Œ 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 - 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


Sect: 1.11

ANDA DEVELOPMENT


ANDA DEVELOPMENT

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 Œ used are USP - Non-Compendial and test methods in-house and validated. - Non-Compendial and test methods based on• and validated.

Active material .2

Active Ingredient Test Method

.3

Active Ingredient Test Method Validation

In-process Material .4

Final Blend Test Methods (especially Uniformity of Content)

Finished Product .5

Finished Product Test Methods

(QC Release

- physical tests - chemical tests - microbiological tests .6

Finished Product Test Methods - (Stability Check) - stability Indicating Test Methods. - impurity limit tests. - Preservative Efficacy Test Method (Validation and stability Studies).

.7

Finished Product Analytical Validation methodology - stability Indicating Assay. - impurity limits or specific impurity quantitation and detection levels (LQ & LD). - microbiological limit tests


Sect: 1.12

ANDA DEVELOPMENT


SECTION I

ANDA DEVELOPMENT

SECTION 1

Application/ Table of Contents TABLE OF CONTENTS Section XVI

Stability of Finished Dosage Form 16.1


.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

RESERVED SECTION NOT FOR CURRENT USE

Section XVIII

Samples of the drug and articles used as components 18.1


.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)


Sect: 1.13

ANDA DEVELOPMENT


SECTION I

ANDA DEVELOPMENT

SECTION 1

Application/Table of Contents TABLE OF CONTENTS. Section XIX ENVIRONMENTAL IMPACT ANALYSIS REPORTS 19.1 19.2

19.3

19.4

19.5

Title Page (with TAG) and brief narrative statement of what this section contains. Environmental Exclusion Assessment - Development Site - Manufacturing Site Applicable Environmental Laws (National / State / Local /Foreign): - Development Site - Manufacturing Site - Contract Manufacturers Site Environmental Certification: - Development Site - Manufacturing Site - Contract Manufacturers Statement on Environmental Compliance: - Development Site - Manufacturing Site - Contract Manufacturers Commercial Plant Manager and QA Director Signatures.

Section XX ADDITIONAL INFORMATION 20.0


20.1


20.2

US Agents Letter of Authorization

Section XXI ADDITIONAL INFORMATION 21.1


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

1

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


Sect: 1.14

ANDA DEVELOPMENT


SECTION I

ANDA DEVELOPMENT

SECTION 1


FDA FORM 3439 or

FDA FORM 356h [REVISED] Jan 8, 1998

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

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

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


Sect: 1.15

ANDA DEVELOPMENT


ANDA DEVELOPMENT

NOTES


Sect: 1.16

ANDA DEVELOPMENT


ANDA DEVELOPMENT

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

4 24 Volume V Drug Development Series

Sect: 2.1

ANDA DEVELOPMENT


SECTION II

ANDA DEVELOPMENT

SECTION 2

Basis for ANDA Submission BASIS FOR ABBREVIATED NEW DRUG APPLICATION

[a] Listed Drug. This applications refers to the Reference Listed Drug [NAME] qSemisolid qTablet / 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.

Furthermore

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

Furthermore

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. A copy of the FDA letter approving the ANDA SUITABILITY PETITION is attached in section II of this application (page [00]) 24 Volume V Drug Development Series

Sect: 2.2

ANDA DEVELOPMENT


ANDA DEVELOPMENT

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]

T

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])

T

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]

[Two typical examples of this section are given below]


Sect: 2.3

ANDA DEVELOPMENT


ANDA DEVELOPMENT

SECTION II

SECTION 2

Basis for ANDA Submission EXAMPLE 1: Listed Drug. This applications refers to the Reference Listed Drug [RLD] Miconazole1 / Miconazole USP2 Generic q Semisolid qTablet / qCapsule (delete 3 where necessary) manufactured by [RLD Company Name Inc. / Ltd.] . A copy of the Orange Book 20th (2000) Edition listing is enclosed herewith. According to the information published in the 20th Edition List, the reference listed drug is covered by [þ þ no / one / two] use patent which is addressed in Section III of this application. Exclusivity. There are [ONE] / [two] / þ [no] exclusivity’s for the listed drug. I-184 - expires Sept 24, 2000 I-185 - expires Sept 24, 2000


-----------------------------------------


Date


[Applicant Company Name Inc. / Ltd.]


-----------------------------------------


Date


[Applicant Company Name Inc. / Ltd.] 1

INNOVATOR NAME COUNTRY US or EU USA RLD 375 / 500 mg - Application Number 000000 3 INNOVATOR 2


Sect: 2.4

ANDA DEVELOPMENT


ANDA DEVELOPMENT

SECTION II

SECTION 2

Basis for ANDA Submission EXAMPLE 2: Listed Drug. This applications refers to the Reference Listed Drug [RLD] Miconazole1 / Miconazole USP2 q Semisolid / qTablet / qCapsule manufactured by [RLD Innovator Company Name Inc. / Ltd.]3. (delete where appropriate) A copy of the Orange Book 20th (2000) Edition listing is 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 [no] exclusivity’s for the listed drug. I-000 - expires MM DD, 2000 I-000 - expires MM DD, 2000 [Signature of Responsible Person] ------------------------------------------------

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Date


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

-----------------------------------------


Date


[Applicant Company Name Inc. / Ltd.] 1 INNOVATOR 2 USA RLD IS REGISTERED AS STRENGTH 0 mg +00 mg INNOVATOR Application Number [00000] 3 INNOVATOR


Sect: 2.5

ANDA DEVELOPMENT


ANDA DEVELOPMENT

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)


-----------------------------------------


Date



[ANDA SUITABILITY PETITION APPROVAL LETTER attached in Section XXII]


Sect: 2.6

ANDA DEVELOPMENT


ANDA DEVELOPMENT

End of Section 2.


Sect: 2.7

ANDA DEVELOPMENT


ANDA DEVELOPMENT

SECTION III

SECTION 3

Patent Certification / Exclusivity TABLE OF CONTENTS (Overall ANDA Guideline Requirements for this Section).

S

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


4


Sect: 3.1

ANDA DEVELOPMENT


SECTION III

ANDA DEVELOPMENT

SECTION 3

Patent Certification / Exclusivity

Patent Certification Statement Paragraph I Certification [21 CFR 314.94(a)(12)(i)]

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].

W

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

T

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).


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Date




Sect: 3.2

ANDA DEVELOPMENT


ANDA DEVELOPMENT

SECTION III

SECTION 3


Patent Certification Statement Paragraph II Certification

I


W

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

T

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


-----------------------------------------


Date


[Applicant Company Name Inc./Ltd.]


Sect: 3.3

ANDA DEVELOPMENT


ANDA DEVELOPMENT

SECTION III

SECTION 3


Patent Certification Statement Paragraph III Certification

I


W

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

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.


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Date



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


Sect: 3.4

ANDA DEVELOPMENT


ANDA DEVELOPMENT

SECTION III

SECTION 3

Patent Certification / Exclusivity Alternative Certification

Patent Certification Statement Paragraph III Certification

T

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 .


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Date



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.

4


Sect: 3.5

ANDA DEVELOPMENT


ANDA DEVELOPMENT

SECTION III

SECTION 3


Patent Certification Statement Paragraph IV Certification

I


W

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

----------------------------------------Date

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 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® 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).


Sect: 3.6

ANDA DEVELOPMENT


ANDA DEVELOPMENT

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

I

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)

Concurrently

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] ------------------------------------------------

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Date



♦ 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 Certification Oct. 1999: "if they don't sue - they're brain dead"). In truth, branded RLD Company need to honestly address the overall ethics question of this [now] standard litigation action which is based purely on the profit and greed motive and is designed to evade, side-step and elude the spirit and intention of the law for the benefit of the general public at large - Editor-in-Chief.


Sect: 3.7

ANDA DEVELOPMENT


SECTION III

ANDA DEVELOPMENT

SECTION 3


' No relevant Patent ' Statement 21 CFR 314.94(a)(12)(ii)

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

T

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).

W

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.


-----------------------------------------


Date


[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.

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


Sect: 3.8

ANDA DEVELOPMENT


SECTION III

ANDA DEVELOPMENT

SECTION 3


Method of Use Patent Statement 21 CFR 314.94(a)(12)(iii)

T

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

I

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]

W

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 [000000-00] .


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Date




Sect: 3.9

ANDA DEVELOPMENT


ANDA DEVELOPMENT

SECTION III

SECTION 3

Patent Certification / Exclusivity Exclusivity Statement 21 CFR 314.94(a)(3)(ii)

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

T

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

A

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] ------------------------------------------------

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Date



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.

4 End Section III


Sect: 3.10

ANDA DEVELOPMENT


ANDA DEVELOPMENT

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: • • •

4.3

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) 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

4 24 Volume Drug Development Series

Sect: 4.1

Topical SEMISOLID


ANDA DEVELOPMENT

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

000.0 mg 000.0 mg 000.0 mg 000.0 mg

000.0 mg 000.0 mg 000.0 mg 000.0 mg

Number of Strengths

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. 2)

Product are packed in different size containers.

24 Volume Drug Development Series

Sect: 4.2

Topical SEMISOLID


ANDA DEVELOPMENT

SECTION IV

SECTION 4

Rx / OTC Statement [Generic name] SEMISOLID [USP] [All strengths]

Prescription Drug (Rx)

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

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Sect: 4.3

Topical SEMISOLID


ANDA DEVELOPMENT

NOTES


Sect: 4.4

Topical SEMISOLID


SECTION V

ANDA DEVELOPMENT

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).

4


Sect: 5.1

Topical SEMISOLID


ANDA DEVELOPMENT

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


Sect: 5.2

Topical SEMISOLID


ANDA DEVELOPMENT

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 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] Lot No Mfg. Date: Use Before:

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


Sect: 5.3

Topical SEMISOLID


ANDA DEVELOPMENT

SECTION V

SECTION 5

Labeling PROPOSED GENERIC PACKAGE INSERT LABELING

SIDE-BY-SIDE COMPARISON GENERIC PACKAGE INSERT

INNOVATIVE PACKAGE INSERT

Present full Generic package insert identical to innovators (caution restrictions on indications still on patent - these may not be included )

Present full Innovative package insert of innovators (restrictions on indications still on patent are included and shown as a difference ) - latest edition of package insert must be used - obtain from FOI services

Use point size 7 and highlight the differences in the GENERIC PACKAGE INSERT - use line side bars where differences appear as shown:

Use point size 7 and highlight the differences in the INNOVATIVE PACKAGE INSERT - use line side bars where differences appear.

NOTE:The differences in the package insert should be restricted to Generic product name and different addresses for Applicant Manufacturer, Distributor and Product reference Numbers.

NOTE:The differences in the package insert should be restricted to Innovative product name and different addresses for Applicant Manufacturer, Distributor and Product reference Numbers

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


Sect: 5.4

Topical SEMISOLID


ANDA DEVELOPMENT

SECTION V

SECTION 5

Labeling PROPOSED GENERIC CONTAINER LABEL LABELING

SIDE-BY-SIDE COMPARISON

GENERIC CONTAINER LABEL

INNOVATIVE CONTAINER LABEL

Present full Generic CONTAINER LABEL identical to innovators (caution restrictions on indications still on patent - these may not be included )

Present full CONTAINER LABEL of innovators (restrictions on indications still on patent are included and shown as a difference ) - latest edition of package CONTAINER LABEL must be used - obtain from FOI services

Use point size 12 and highlight the differences in the GENERIC PACKAGE CONTAINER LABEL - use line side bars where differences appear as shown:

Use point size 12 and highlight the differences in the INNOVATIVE CONTAINER LABEL - use line side bars where differences appear.

NOTE:The differences in the CONTAINER LABEL should be restricted to Generic product name and different addresses for Applicant Manufacturer, Distributor and Product reference Numbers.

NOTE:The differences in the CONTAINER LABEL should be restricted to Innovative product name and different addresses for Applicant Manufacturer, Distributor and Product reference Numbers

NOTE: Examine innovators labeling carefully and reproduce wording meeting all regulatory requirements


Sect: 5.5

Topical SEMISOLID


ANDA DEVELOPMENT

SECTION V

SECTION 5

Labeling PROPOSED GENERIC CONTAINER ADHESIVE LABELING

000 g [GENERIC Name] Semisolid [USP] (Show ALL dosage and fill sizes)

NDC [0000-0000-00]

[GENERIC Name] Semisolid [USP] 000 mg per g. Each gram contains: [Active Material] [000] mg Caution: Federal law prohibits dispensing without prescription

000g [GENERIC Name] Semisolid [USP] 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 MEDICATION OUT OF REACH OF CHILDREN.

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

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

4


Sect: 5.6

Topical SEMISOLID


ANDA DEVELOPMENT

SECTION V

SECTION 5

Labeling INNOVATIVE CONTAINER ADHESIVE LABELING

000 g [GENERIC Name] Semisolid [USP] (Show ALL dosage and fill sizes)

NDC [0000-0000-00]

[INNOVATIVE Semisolid [USP] 000 mg per g Each gram contains: [Active Material] [000] mg Caution: Federal law prohibits dispensing without prescription

000 g [RLD Name] Semisolid [USP]

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 MEDICATION OUT OF REACH OF CHILDREN.

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

NOTE: Examine innovators labeling carefully and reproduce meeting all regulatory requirements

4


Sect: 5.7

Topical SEMISOLID


ANDA DEVELOPMENT

SECTION V

SECTION 5

Labeling Certification Statement [GENERIC Name] Semisolid [USP] [000] mg per g

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


-----------------------------------------


Date



444


Sect: 5.8

Topical SEMISOLID


ANDA DEVELOPMENT

SECTION VI

SECTION 6

Bioavailability / Bioequivalence

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

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

•

Formula Composition of Generic product

•

Percent Composition of Formula

•

Comparative Ingredients List between Innovator & Generic (all strengths)

•

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

•

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

•

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

•

Outline of packaging container closures - proposed marketing packs.

•

Packaging trail of all packed units.

•

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

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

4


Sect: 6.1

Topical SEMISOLID


ANDA DEVELOPMENT

SECTION VI

SECTION 6


T

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

Generic Product Chosen: [Generic name] Semisolid [USP] [000.0] mg/g. Lot: 000 was manufactured at [Generic Company Name Inc./Ltd.] [Address] facility, utilizing the production area and incorporating standard production staff, procedures and equipment. The Batch size was: Batch size: 150 Kg equal to [150 000] one gram dosage applications of the Semisolid Dosage Form

Reference Product Chosen: [RLD Company Name Inc./Ltd.], [RLD] Semisolid Dosage Form [USP] [000.0] mg/g Lot: AA000 Expiry Date: Month Year.

This Section contains: ♦ Statement of composition of the Generic Product strengths - [Generic Name] Semisolid [USP] [000.0] mg/g ♦ Percent composition of the Generic Product [Generic Name] Semisolid [USP] [000.0] mg/g - (give all strengths where appropriate.) ♦ Qualitative comparative Ingredient List of the Reference Listed Product (RLD) and Generic Product - (give all strengths where appropriate.) ♦ Certificates of Analysis for both products used in the Topical Bioequivalence. ♦ Certificates of Analysis for both products requested in the waiver


Sect: 6.2

Topical SEMISOLID


ANDA DEVELOPMENT

SECTION VI

SECTION 6

Bioavailability / Bioequivalence Products used in Topical Biostudy: PRODUCT

Table 1 Strength

Batch No:

C o A No:

REFERENCE

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

Lot: AA000

R000

GENERIC

[Generic name] Semisolid [000.0] mg/g

Lot: OO0

G000

Products in Study Waiver Request: PRODUCT

Table 2 Strength

Batch No:

C o A No:

REFERENCE

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

Lot: AA000

R001

REFERENCE

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

Lot: BB000

R002

GENERIC


Lot: OO0

G001

GENERIC


Lot: OO0

G002

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


Sect: 6.3

Topical SEMISOLID


ANDA DEVELOPMENT

SECTION VI

SECTION 6

Bioavailability / Bioequivalence FORMULA COMPOSITION Composition of the drug, stating the name and amount of each ingredient, whether active or not, contained in a stated quantity of the drug, in the form in which it is to be distributed.

PERCENT COMPOSITION OF THE PRODUCT [Generic name] FORM [USP] Table 3.

FORMULA

Amount in mg

INGREDIENTS

per gram mg

Miconazole USP Micronized

20.00

Pegoxol 7 Stearate [Tefose 63™]

180.00

Heavy Mineral OIL NF

44.80

Benzoic Acid USP

2.00

Butylated Hydroxyanizole Peglico 5 Oleate

000.05

1

EMULGENT OIL BASE PRESERVE ANTIOXIDANT EMULGENT

1.50

CHEALATE

721.65

AQ. PHASE

Edetate Disodium USP

TOTAL

ACTIVE1

30.00

[LABRAFIL M 1944™]

Purified Water USP

PURPOSE

1000.00

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

4


Sect: 6.4

Topical SEMISOLID


ANDA DEVELOPMENT

SECTION VI

SECTION 6

Bioavailability / Bioequivalence QUALITATIVE COMPARATIVE INGREDIENTS LIST Table 4. [Generic name] Form [USP]

[RLD] Form [USP]

[Active Material]

[Active Material]

[Generic Company Name Inc. / Ltd.]

[RLD Company Name Inc. / Ltd.]*


Miconazole USP





Benzoic Acid USP

Benzoic Acid USP

Butylated Hydroxyanizole


Peglico 5 Oleate

Peglico 5 Oleate




Purified Water USP

Purified Water USP

* Reference Source

-

PDR 1998/1999

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


Sect: 6.5

Topical SEMISOLID


ANDA DEVELOPMENT

SECTION VI

SECTION 6


CERTIFICATES OF ANALYSIS REPRESENTING THE DRUG PRODUCTS USED IN BIOEQUIVALENCY STUDY The analytical results of the Certificates of Analysis for [Generic Company Name Inc. / Ltd.] and [RLD Company Name Inc. / Ltd.] Drug Product lots were obtained from the Analytical Research Laboratories at [Generic Company Name Inc. / Ltd. & Address].

Generic Product: Attached Certificate of Analyses in support of waiver: (3 Batches for antibiotics) Certificate of Analysis Certificate of Analysis Certificate of Analysis Certificate of Analysis Certificate of Analysis Certificate of Analysis

No: No: No: No: No: No:

A01 A02 B01 B02 C01 C02

Lot: A00 [000.0] mg/g Lot: A00 [000.0] mg/g Lot: B00 [000.0] mg/g Lot: B00 [000.0] mg/g Lot: C00 [000.0] mg/g Lot: C00 [000.0] mg/g

Date: MM DD YY Date: MM DD YY Date: MM DD YY Date: MM DD YY Date: MM DD YY Date: MM DD YY

Innovative Product (1 Batch) Certificate of Analyses Certificate of Analysis Certificate of Analysis

No:AA01 No:AA01

Lot: AA02 Lot: AA02

[000.0] mg/g [000.0] mg/g

Date: MM DD YY Date: MM DD YY

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

Ü

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

Ü

The development and validation of an in-vitro release test is not required for approval of an NDA, ANDA or AADA nor is the in vitro release test required as a routine batch-to-batch quality control test.

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

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


Sect: 6.6

Topical SEMISOLID


ANDA DEVELOPMENT

SECTION VI

SECTION 6

Bioavailability / Bioequivalence CERTIFICATE OF ANALYSIS Chromatogram part only. RLD:

Lot No:

Exp. Date:

Analysis Date:

Fill Size

Standard Chromatogram Barr spec.15 14/2/98 12:03 Assay Innovator 000mg Sample D-3400 method SI- 00-00 Tabs. Tag 44 CH: 1 Vial : File 15 RT 3.63 7.61 14.63 15.93 Total

Calc-Method: AREA 445 5553456 645 445

AREA HEIGHT 56 588456 66 96

HEIGHT Conc. 0.0008 99.995 0.0011 0.0008

Conc. BC BB BB BB BB

8 BC

No:

No: 1 2 3 4

Lab book Ref.

GENERIC:

Lot No:

Exp. Date:

Analysis Date:

Fill Size

Standard Chromatogram Barr spec.16 Assay Generic Sample D-3400 method SI- 00-00

14/2/98 13:43 000mg

Tabs Tag 45 CH: 1 Vial :

File 15 Calc-Method: AREA RT AREA HEIGHT 3.63 445 56 7.62 5553456 588456 14.63 445 66 15.93 445 96

HEIGHT Conc. 0.0008 99.995 0.0008 0.0008

BC BB BB BB BB

Conc. No: 1 2 3 4

11 BC

No:

Lab book Ref.


Sect: 6.7

Topical SEMISOLID


ANDA DEVELOPMENT

SECTION VI

SECTION 6

Bioavailability / Bioequivalence REQUEST FOR WAIVER OF IN-VIVO BIOAVAILABILITY STUDIES STATUS OF EACH STRENGTH: [Generic Product] Semisolid 000 mg/g - Bioequivalence Study Submitted in this ANDA. [Generic Product] Semisolid 000 mg/g

- Waiver hereby being requested.

[Generic Product] Semisolid 000 mg/g


[Generic Product] Semisolid 000 mg/g


WAIVER REQUEST [Generic Firm] hereby request a waiver of evidence for a topical bioequivalency with respect to [Generic Product] Semisolid 000 mg/g USP as listed in Table 2. A topical bioequivalency study was conducted on [Generic Product] Semisolid 000 mg/g (Table 1) and a full report of the biostudy is included in Section VI of this ANDA. The [Generic Product] Semisolid 000 mg/g which is the subject of this application, has the same geometric proportional formulation as the [Generic Product] Semisolid mg strengths per gram given in Table 3. MULTI-STRENGTH PREPARATIONS The milligrams per gram Semisolid and comparative percent compositions of the [one/two/three] strengths are shown for purposes of similarity in Table 5 (not shown).

4


Sect: 6.8

Topical SEMISOLID


ANDA DEVELOPMENT

SECTION VI

SECTION 6

Bioavailability / Bioequivalence Biostudy Section of Packaging and Disbursement Summary for Pivotal Lot: 000 Product: [Generic name] SEMISOLID [USP] [000] mg/g - Batch No: 000

60g HDPE Collapsible Tube with cap/nozzle [00 mm] 200 units x 60 g Packaging date: Month DD, 1999

Nov.28, 1996

55 units x 60 g Release & Stability Testing

5 units x 60 g QC Testing

Month DD, 1999

Month DD, 1999

80 units 60 g Balance stored in

BIOSTUDY

Pivotal Warehouse 60 units 60 g Biostudy (European Market)

Month DD, 1999


Nov.28, 1996

10 units x 30 g

25 units x 30 g

QC Testing & Reserve units

Release & Stability Testing

Month DD, 1999

Month DD, 1999

200 units x 30 g

BIOSTUDY

Balance stored in Pivotal Warehouse

65 units x 30 g Biostudy & Retained Samples

Month DD, 1999

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

4


Sect: 6.9

Topical SEMISOLID


SECTION VI

ANDA DEVELOPMENT

SECTION 6

Bioavailability / Bioequivalence FINAL TOPICAL BIOEQUIVALENCE REPORT (Summary Report Here)

FULL BIOEQUIVALENCE PRESENTED IN SEPARATE BINDINGS AS STAND ALONE VOLUME(S) USING FDA BIO JACKET COVERS (RED).

4


Sect: 6.10

Topical SEMISOLID


ANDA DEVELOPMENT

SECTION VI

SECTION 6

Bioavailability/ Bioequivalence

FINAL REPORT TITLE

BIOEQUIVALENCE Evaluation of two Topical [Active Material] Preparations in [00] Healthy Volunteers SPONSOR

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

INVESTIGATION SITE

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

ANALYTICAL CENTER(S)

[CRO Testing Lab Name Inc. / Ltd.] [Address]

BIOMETRICAL CENTER

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

PRINCIPAL INVESTIGATOR

[Name of Principal Investigator] [Principal Investigator Qualifications]

CLINICAL STUDY DATES Start Date Completion date DATE OF COMPLETION OF FINAL REPORT

Month DD, 200Y Month DD, 200Y Month DD, 200Y

Report Code No

S00000


Sect: 6.11

Topical SEMISOLID


ANDA DEVELOPMENT

SECTION VI

SECTION 6


TABLE OF CONTENTS VOLUME ONE 1. 2. 3. 4.

Section Section Section Section

: : : :

5. Section 6. Section 7. Section 8. Section 9. Section 10. Section

: : : : : :

11. Section

:

Project Summary Rationale for [topical] study. Summary of Statistical Analysis Study protocol, Protocol amendments, Informed Consent, IRB Approval, and Clinical Report. Summary of Bioequivalent Data. Individual Linear and Semi-log graphs Statistical report on [Active Material] Analytical Report for[Active Material] Results of [Active Material] Statistical Data of Standards and Quality Control Samples for [Active Material] Chromatograms of [Active Material]

VOLUME TWO 1. 2. 3. 4. 5.

Appendix : Appendix : Appendix : Appendix : Appendix :

Validation of [Active Material] Validation Report for [Active Material] Chromatograms of [Active Material] Statistical Data of Standards and Quality Control Samples Short description of Testing Facilities Testing Facilities in US Testing Facilities in Europe BIOMETRICAL Center in US

VOLUME THREE 1. Appendix : Case Records Forms.


Sect: 6.12

Topical SEMISOLID


ANDA DEVELOPMENT

SECTION VI

SECTION 6


STATEMENT OF STUDY FACILITY STATEMENT ON 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 final report based on the aspects of the investigation performed at the facilities of [Testing Facilities Inc. in US] situated [Address].

Month DD, 1999

[Signature of Responsible Person] [Name of Principal Investigator] Principal Investigator


----------------------------------------Date

Sect: 6.13

Topical SEMISOLID


ANDA DEVELOPMENT

SECTION VI

SECTION 6

Bioavailability/ Bioequivalence STATEMENT OF TESTING FACILITY STATEMENT ON STUDY FACILITY STATUS The undersigned hereby conforms that our testing facility in [Address] operates in compliance 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 of biological samples performed in the Study No [0000] the [Testing Facilities in US] had no current outstanding deficiencies as cited by the FDA or other government agency and that the facility fully met the performance requirements for current Good Laboratory Practice (cGLP) of the US Food and Drug Administration and US Code 21 Federal Register.


---------------------------------

[Name of CEO / President]

Date

CEO / President


Sect: 6.14

Topical SEMISOLID


ANDA DEVELOPMENT

SECTION VI

SECTION 6

Bioavailability/ Bioequivalence STATEMENT OF BIOMETRICAL FACILITY

This report is respectfully submitted to [Applicant Company Name Inc. / Ltd.] [Address] The signature below attests to the content and accuracy of the biometrics part of this final report based on the aspects of the investigation performed at the facilities of [Testing Facilities in US] [Address].

Month DD, 1999


[Name of Principal Investigator] Principal Pharmacokeneticist

-


----------------------------------------Date

Sect: 6.15

Topical SEMISOLID


ANDA DEVELOPMENT

SECTION VI

SECTION 6

Bioavailability/ Bioequivalence PROJECT SUMMARY This report is respectfully submitted to [Applicant Company Name Inc. / Ltd.] [Address]. The objective to determine the bioequivalence of [Generic name] Semisolids [USP] [000.0] mg/g in comparison to a registered preparation of [Innovator name] Semisolids [USP] marketed by [Innovator] in [Country] This project was designed as a randomized, single application, two way, crossover comparative study for evaluating topical bioequivalence / pharmacokinetics of the following test preparations: [Generic name] Semisolid [000.0] mg / g Lot: 000 versus the [RLD] Semisolid [000.0] mg /g. Lot: AA000 THE Study was performed in [00] healthy volunteers who received a [000] mg single application of [Active Material] under controlled study conditions. DETERMINATION of [Active Material] were performed according to SOP 00 on the samples collected, following application of the topical forms. [Active Material] concentration was determined by a validated [GC-MS] / [HPLC] method. BASED on the results of the study the test product is comparable in rate and extent of absorption for the reference product for [Active Material] THE clinical observations were unremarkable. No significant or unexpected changes in vital 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] Principal Investigator


Date

Sect: 6.16

Topical SEMISOLID


ANDA DEVELOPMENT

SECTION VI

SECTION 6

Bioavailability/ Bioequivalence TITLE

BIOEQUIVALENCE Evaluation of two Topical [Active Material] Preparations in [00] Healthy Volunteers

Volume One STUDY DATA VOLUME ONE 1. Section

: Project Summary

2. Section

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

3. Section

: Summary of Statistical Analysis

4. Section

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

5. Section

: Summary of Bioequivalent Data.

6. Section

: Individual Linear and Semi-log graphs

7. Section

: Statistical report on the [Active Material]

8. Section

: Analytical Method Report for [Active Material]

9. Section

: Analytical Method Validation for the [Active Material]

10. Section

: Test Results of [Active Material]

11. Section

: Analytical Chromatograms of the [Active Material]

12. Section

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


Sect: 6.17

Topical SEMISOLID


ANDA DEVELOPMENT

SECTION VI

SECTION 6


BIOEQUIVALENCE Evaluation of two TOPICAL [Active Material] Preparations in [00] Healthy Volunteers

Volume Two APPENDIXES

1. Appendix : Validation of [Active Material] 2. Appendix : Validation Report for [Active Material]a 3. Appendix : Chromatograms of [Active Material] in Plasma 4. Appendix : Statistical Data of Standards and Quality Control Samples 5. Appendix : Short description of Testing Facilities Testing Facilities in US [Address] Testing Facilities in Europe [Address] BIOMETRICAL Center in US [Address]


Sect: 6.18

Topical SEMISOLID


ANDA DEVELOPMENT

SECTION VI

SECTION 6


BIOEQUIVALENCE Evaluation of two TOPICAL [Active Material] Preparations in [00] Healthy Volunteers

Volume Three Case Records Forms

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

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


Sect: 6.19

Topical SEMISOLID


ANDA DEVELOPMENT

SECTION VI

SECTION 6

Bioavailability/ Bioequivalence BRIEF OVERVIEW

TYPES OF BIOEQUIVALENT STUDIES FOR SEMISOLIDS IN VIVO BIOEQUIVALENCE STUDIES The design of in vivo bioequivalence studies for semisolid dosage forms varies depending on the pharmacological activity of the drug and dosage form. A brief general discussion of such tests follows.

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

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

ÜGlucocorticoids (FDA, Topical Dermatological Corticosteroids: In Vivo Bioequivalence, June 2, 1995.)

ÜComparative clinical trial or any other appropriate validated bioequivalence study (e.g., dermatopharmacokinetic study) for the topical dermatological drug product.

Analytical Method: The assay methodology selected should ensure the following Ü Specificity Ü Accuracy Ü Inter-day precision (ruggedness) Ü Intra-day precision (ruggedness) Ü Linearity of standard curves Ü Adequate sensitivity Ü Recovery Ü Stability of the samples under the storage and handling conditions associated with the analytical method.


Sect: 6

Topical SEMISOLID


ANDA DEVELOPMENT

SECTION VI

SECTION 6


NOTES


Sect: 6

Topical SEMISOLID


ANDA DEVELOPMENT

SECTION VII

SECTION 7

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

7.1 Section Page (with Color Section TAG) and brief descriptor of the section. A complete statement of components and composition is provided in this section. A comparison 7.2 List of Components - in order of manufacture (name & grade) 7.3 Formula Composition of Generic Product 7.4 Percent Composition of Generic Product

This section contains: •

List of components

•

Formula Composition

•

Percent Composition

FDA's Published January 1999 ANDA Guideline requirements 1.

Components and Composition Statement

4


Sect: 7.1

Topical SEMISOLID


ANDA DEVELOPMENT

SECTION VII

SECTION 7

Components and Composition LIST OF COMPONENTS Following is a full list of the articles used as components of the drug product:

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

1. Miconazole USP Micronized 2. Pegoxol 7 Stearate [Tefose 63™] 3. Heavy Mineral OIL NF 4. Benzoic Acid USP 5. Butylated Hydroxyanizole 6. Peglico 5 Oleate [LABRAFIL M 1944™] 7. Edetate Disodium USP 8. Purified Water USP

4


Sect: 7.2

Topical SEMISOLID


ANDA DEVELOPMENT

SECTION VII

SECTION 7

Components and Composition FORMULA COMPOSITION Composition of the drug, stating the name and amount of each ingredient, whether active or not, contained in a stated quantity of the drug in the form in which it is to be distributed.

[Generic name] Semisolids [USP] FORMULA

Amount in mg

INGREDIENTS

per gram mg

MATERIALS


20.00


180.00


44.80

Benzoic Acid USP

2.00

Butylated Hydroxyanizole Peglico 5 Oleate

000.05

EMULGENT OIL BASE PRESERVE ANTIOXIDANT EMULGENT

1.50

CHEALATE

721.65

AQ. PHASE


TOTAL

ACTIVE

30.00


Purified Water USP

PURPOSE

1000.00

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

4


Sect: 7.3

Topical SEMISOLID


ANDA DEVELOPMENT

SECTION VII

SECTION 7

Components and Composition PERCENT COMPOSITION OF THE PRODUCT [Generic Name] Semisolids [USP]

Formula

Amount in %

Ingredients

per gram 2.000


18.000

[Pegoxol 7 Stearate Tefose 63™] Heavy Mineral OIL NF

4.480

Benzoic Acid USP

0.200


0.005

Peglico 5 Oleate [LABRAFIL M 1944™]

3.000


0.150

Purified Water USP

72.165 100.000 %

TOTAL

4


Sect: 7.4

Topical SEMISOLID


ANDA DEVELOPMENT

SECTION VIII

SECTION 8

Raw Material Control TABLE OF CONTENTS (Overall ANDA Guideline Requirements for this Section). Active Ingredient(s) 8.1 Title Page and brief summary statement of what this section contains 8.2 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 Source 8.4 DMF of Manufacturer via Letter of Access from Active Manufacturer (Type II) 8.5 Active Monograph supplied by QC laboratory 8.6 CoA from Generic Firm’s QC laboratory, plus supporting - Identification IR or UV spectra of Active - HPLC chromatograms (Assay - Impurities) - label peaks - Photocopy of TLC chromatograms (Assay - Impurities) 8.7 CoA from Active Manufacturer, - plus supporting - Identification IR or UV spectra of Active - HPLC chromatograms (Assay - Impurities) - label peaks - Photocopy of TLC chromatograms (Assay - Impurities) 8.8 IR Identification Spectra of Reference Standard (Pharmacopoeial) 8.10 Physical Specifications from Active Manufacturer - Bulk Density, - Particle Size (note: water insoluble material) - Physical and analytical test methods 8.11 Outline of Material Data Safety Sheet (MDSS) (source of data for manufacturing instructions precautions).

8.12 8.13

Inactive Ingredients Testing Specifications (ID and characterization) Suppliers Certificate of Analysis (Specifications and Test Results)

4


Sect: 8.1

Topical SEMISOLID


ANDA DEVELOPMENT

SECTION VIII

SECTION 8

Raw Material Control This section contains: •

Outline of the Standard Operating Procedures for Raw Materials

•

Summary of Lot Numbers of Active and Inactive Ingredients

•

Disclosure of Active Ingredient Source (approved supplier)

•

Active Ingredient DMF Authorization Letter

•

Active Ingredient Certificates of Analysis

•

Active Ingredient Supporting Data (Spectra)

•

Outline of Material Data Safety Sheet (MDSS)

•

Inactive Ingredient Testing Monographs & Test Procedures

•

Inactive Ingredient Certificates of Analysis

•

Routine Testing Protocols - retest schedules

FDA's Published January 1999 ANDA Guideline requirements:Section VIII. Raw Materials 1. Active ingredient(s). a. Synthesis listing manufacturer/supplier (Type II DMF authorization letters) b. Certificates of analysis specifications and test results from drug substance manufacturers c. Testing specifications and data from drug product manufacturer(s) d. Spectra and chromatograms for reference standards and test samples e. Retesting period 2. Inactive ingredients (§ 3l4.94(a)(9)) a. Testing specifications (including identification and characterization) b. Suppliers' certificates of analysis (specifications and test results) c. Retest schedule

4


Sect: 8.2

Topical SEMISOLID


ANDA DEVELOPMENT

SECTION VIII

SECTION 8

Raw Material Control 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 and primary stability batches, must be supplied by approved vendors. The approval of vendors is a shared responsibility of the QA Department of the plant and the Purchasing Department. For pilot batches, the R&D Department is responsible. The Purchasing Dept. submits an application to approve a vendor to the QA Department, specifying the full details of the vendor and samples identified by the manufacturer, including the Certificates of Analysis of the manufacturer. The manufacturer must have a DMF (Drug Master File) submitted to the FDA. The QC Laboratory tests must confirm that the Certificate of Analysis, which must accompany the raw material, meets the raw material requirements. In the absence of a pharmacopoeia monograph, compliance to an approved inhouse monograph 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 the ANDA, is subject to the prior approval of the FDA. After obtaining satisfactory results, and if required the approval of the appropriate health authority, the QA Unit approves the new vendor. 2. Acceptance Criteria All raw materials are quarantined after receipt at the firms warehouse, pending tests and 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 in which the goods arrived is full examined. All lots are sampled. Each lot must have a manufacturer’s Certificate of Analysis for the 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 the vendor is approved, the use of an abbreviated monograph is evaluated. A full compendial monograph is performed every 6 months on all incoming raw material lots. On receipt, each sample undergoes at least one (1) identification test. Further routine tests are performed as required by the respective testing program.


Sect: 8.3

Topical SEMISOLID


ANDA DEVELOPMENT

SECTION VIII

SECTION 8

Raw Material Control Rejected Batches: Raw materials samples not approved for use by the laboratory will be marked by a laboratory issued red Rejected label, affixed to the sample by a quality assurance unit, and transferred to the Rejected area of the warehouse. Rejected materials will remain in the Rejected area until a final decision is reached whether 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 previous date of analysis. Retest period for highly sensitive materials (actives and excipients) and materials requiring microbiological testing, is 12 months. All other active and excipient materials are retested after 24 months, or as stipulated in the laboratory documents. [Active Material] (Approved Supplier) will be retested after 12 months. 4. Storage Quarantine Storage 1. Raw materials shall be stored in controlled environmental areas under monitored environmental 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 the quarantine area, pending QC release. 3. The quarantine for raw materials requiring cooling or freezing shall be stored in controlled and routinely monitored refrigerators or deep freezers, capable of maintaining 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 or in appropriate refrigerated units. 5. The raw materials shall remain in the quarantine area throughout the QC Analytical Laboratory material acceptance testing. Release from Quarantine 1. Raw materials released by the QC laboratory for use in production, shall receive a green Released label. The label is printed by the QC Lab computer and attached over 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 the QC lab computer. Materials having a green Released label will be transferred to the released materials storage area. 3


Sect: 8.4

Topical SEMISOLID


ANDA DEVELOPMENT

SECTION VIII

SECTION 8

Raw Material Control Summary of Batch Numbers of Active & Inactive Raw Materials Used in the Executed (Pivotal) Batch - Lot: 000 Raw Material

Raw Material Batch Numbers Used for MNF of Lot:

Representative

Lot: 1002

Certificate of Analysis(a)

Miconazole USP [micronized Lot # material]

CoA #

Pegoxol 7 Stearate [Tefose 63™] Butylated Hydroxyanizole

Lot #

CoA #

Lot #

CoA #

Benzoic Acid USP

Lot #

CoA #

Peglico 5 Oleate [LABRAFIL M 1944™] Heavy Mineral OIL NF

Lot #

CoA #

Lot #

CoA #


Lot #

CoA #

Purified Water USP

Lot #

CoA #

(a)

A Certificates of Analysis is provided for each ingredient lot used in the manufacture of the Executed Pivotal batch - Lot: 002. In cases where full monograph testing has not been performed on the specified lot used in the pivotal batch, a representative Certificate of Analysis (that is, within a six month period from 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 methods and limits stated in this application. • Any batch lot of ACTIVE MATERIAL remaining in warehouse stock for a period exceeding 12 months shall be fully re-tested to a full monograph prior to manufacture.


Sect: 8.5

Topical SEMISOLID


ANDA DEVELOPMENT

SECTION VIII

SECTION 8

Active Material Control The manufacturer and approved supplier of the active ingredient

[Active Material] (Approved Supplier) is:

Approved Supplier: [Name] Pharmaceutical and Chemical Company Address: [Name] Pharmaceutical and Chemical Company Street Town

State

Zip Code

Country

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

Commitment to Compendial Requirement Testing THE COMPANY commits to perform future pharmacopoeial analyses in accordance with all compendial testing (or otherwise approved testing) at the time the active material are used in the manufacture of [Generic name] SEMISOLIDS [USP] [000.0] mg per g containing the [Active Material] from (Approved Supplier name.) Any batch lot of [Active Material] which remains in stock for a year will be fully retested prior to use.3


Sect: 8.6

Topical SEMISOLID


ANDA DEVELOPMENT

SECTION VIII

SECTION 8

Active Material Control Physical Specifications of Active Materials TEST

PHYSICAL SPECIFICATIONS

METHODS

[ACTIVE MATERIAL] SPECIFICATIONS

TEST RESULTS

TEST METHOD

Bulk Density Suppliers CoA - C0000

06-07g/cc

Complies

SI-A076-01

Particle Size Suppliers CoA - C0000

d90 < 250µ

Complies

SI-A076-02

Bulk Density In-house CoA - C0000

06-07g/cc

Complies

SI-A076-01

Particle Size In-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. CERTIFICATE OF ANALYSIS Included (ref. page [00-00]) are the drug substance manufacturers certificate of analysis, specifications and test results including identification and assay IR and HPLC specta and chromatograms as used in Lot # [00-0000] used by the applicant to manufacture the ANDA batch used in the bioequivalent study supporting this ANDA. LETTER OF AUTHORIZATION A letter of authorization to access DMF# [00-00] for the active material is attached to section XXI (ref. page [00). Please refer to DMF for the complete description of the drug substance including physical, chemical ,microbiological and stability parameters, where appropriate.


Sect: 8.7

Topical SEMISOLID


ANDA DEVELOPMENT

SECTION VIII

SECTION 8

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

Certificate of Analysis and Spectra Numbers. Material Supplied by:

Certificate number

Remarks

Approved

# [C076-98]

In-house CoA

# [C076-98]

Suppliers CoA

ý

ý

In-house Ref. Material

[Active Material]

Approved

# [C076-98]

In-house I R

I R Spectra (or UV)

Supplier ý

[Active Material]

Approved

# [C076-98]

Suppliers I R

I R Spectra (or UV)

Supplier ý

[Active Material]

Approved

Ref. F

I R Spectra (or UV)

Supplier ý

In-house Ref. material

[Active Material]

Approved

# [C076-98]

In-house HPLC

# [C076-98]

Suppliers HPLC


Ref. G

In-house HPLC

Approved

# [C076-98]

In-house TLC

# [C076-98]

Suppliers TLC

Ref. G

In-house TLC

[Active Material] CoA


Supplier ý Approved Supplier ý


Typical HPLC Spectra

[Active Material] Typical HPLC Spectra

[Active Material] Typical HPLC Spectra

[Active Material] Typical TLC Photocopy







Sect: 8.8

Topical SEMISOLID


ANDA DEVELOPMENT

SECTION VIII

SECTION 8

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.


-

Typical HPLC Spectra

-

as per table.


-

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)


Sect: 8.9

Topical SEMISOLID


ANDA DEVELOPMENT

SECTION VIII

SECTION 8

Active Material Control BULK MANUFACTURERS STATEMENT OF GMP [Active Material Company Name Inc. / Ltd.] [Active Material Company Name Inc. / Ltd.] certifies that the methods used in, and the facilities and controls used for, the manufacture, processing, packaging and storage of drugs at our [Active Material Company Name Inc./Ltd.] manufacturing plant conform to Current 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] Last inspection date was MM/DD/YYY

and/or [Active Material Company Name Inc. / Ltd.] certifies that the methods used in, and the facilities and controls used for, the manufacture, processing, packaging and storage of actives/intermediates at [Third Party Company Name Inc. / Ltd.] plant conform to Current 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] Last inspection date was MM/DD/YYY [Signature of Responsible Person] ------------------------------------------------

-----------------------------------------


Date

Plant General Manager Pharmaceutical Manufacturing Division [Active Material Company Name Inc. / Ltd.] [Signature of Responsible Person] ------------------------------------------------

-----------------------------------------


Date

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

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


Sect: 8.10

Topical SEMISOLID


ANDA DEVELOPMENT

SECTION VIII

SECTION 8

Raw Material Control Non active Ingredients CERTIFICATES OF ANALYSIS

T

he following section contains Certificates of Analysis for the lots of inactive ingredients used to produce the pivotal batch. In the case where the lot used in manufacture 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 the ingredient is provided as a representative CoA.

Hence, in some cases there are more than one set of THE COMPANY’S Certificates of 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 the full compendial or in-house monograph CoA.

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

Commitment to Compendial Requirement Testing

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

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


Sect: 8.11

Topical SEMISOLID


ANDA DEVELOPMENT

SECTION VIII

SECTION 8

Raw Material Control Summary of Certificate of Analysis Numbers of Non-active Raw Materials Used in the Executed (Pivotal) Batch. RAW MATERIAL

Certificate of Analysis (CoA) Numbers. Approved

Used in MNF.

Representative

Suppliers

Lot: [ICA00-00]

C of A’s

[COMPANY]

[CA0326-98]

[CA388-98]

2. Butylated Hydroxyanizole

[CA0526-98]

[CA237-98]

3. Benzoic Acid USP

[CA0136-98]

[CA0637-98]

4. Peglico 5 Oleate [LABRAFIL M 1944™] 5. Heavy Mineral OIL NF

[CA0325-98]

[CA0224-98]

[CA0024-98]

-

6. Edetate Disodium USP

[CA0076-98]

[CA0572-98]

7. Purified Water USP

[CA0126-98]

[CA0637-98]

1. Pegoxol 7 Stearate [Tefose 63™]

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

þYes q No. all Routine Certificates of Analysis precede pivotal MNF date þYes q No.

- all Representative Certificates of Analysis in date -

Note : Approved NON ACTIVE Suppliers are not an FDA OGD requirements at the time of publishing (December 1999), but is strongly recommended. NON ACTIVE SUPPLIERS List non-active suppliers only


Sect: 8.12

Topical SEMISOLID


ANDA DEVELOPMENT

SECTION VIII

SECTION 8

Raw Material Control Non active Ingredients Attachments. CoAs • Seven (7) Certificates of Analysis attached as per table. (Presented in the order of tabulation). Supporting Documentation • Seven (7) Testing Monographs of non-active materials • Seven (7) Routine Testing Protocols (List of Routine tests Performed on non-active materials)

Page References: CoAs

Page No. ___ to Page No: ___ .

Testing Monographs


Routine Testing Protocols


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


Sect: 8.13

Topical SEMISOLID


ANDA DEVELOPMENT

SECTION VIII

SECTION 8

Raw Material Control - Non active Ingredients ROUTINE TESTING Routine testing performed on each batch of inactive ingredients.

PEGOXOL 7 STEARATE (Trade Name™)

Description Identification Test Viscosity Microbial Limits BUTYLATED HYDROXYANIZOLE (Trade Name™)

Description Identification Test BENZOIC ACID USP Description Identification Test PEGLICO 5 OLEATE (Trade Name™)

Description Identification Test Viscosity Microbial Limits HEAVY MINERAL OIL NF Description Identification Test Viscosity Microbial Limits EDETATE DISODIUM USP

LIBRARY OF USP XXIII TESTS Description Solubility Identification Test Assay Impurities Related substances Ash 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 OF USP XXIII / NF TESTS RELEVANT TO THIS APPLICATION

(Trade Name™)

Description Identification Test PURIFIED WATER USP Per week - Microbial Testing Per month - Full USP Monograph


Where absent from USP / NF add BP or Pharm Eur. Tests

Sect: 8.14

Topical SEMISOLID


ANDA DEVELOPMENT

SECTION IX

SECTION 9

Description of Manufacturing Facility


Section Page (with Color Section TAG) and brief descriptor of the section. The manufacturer of the final dosage form of the new drug for which this application is submitted is [Generic Company Name Inc. / Ltd.]. The applicant performs all of the manufacturing, packaging, testing and stability test functions of the submitted drug product. [Generic Company Name Inc. / Ltd.] does not manufacturer the active drug substance, the excipients or the container closure system used in the manufacturing and packing operations for the finished dosage forms. Details concerning the bulk active drug substance appears in section VIII as those of the excipients while details for 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 personnel CV’s). 9.6 Statement on the GMP Certification of Compliance Central File Number (CFNs) at manufacturing site.

FDA's Published January 1999 ANDA Guideline requirements Section IX. Description of Manufacturing Facility 1. Full address(es) of the facility(ies) for the manufacturing process, testing, and stability testing 2. Brief description of the facility. 3. For description of the facility sterile products, see Section XIV. 4. CGMP certification 5. Central File Number (CFNs)


Sect: 9.1

ANDA DEVELOPMENT


SECTION IX

ANDA DEVELOPMENT

SECTION 9

Description of Manufacturing Facility This section contains:Addresses of RESEARCH Facilities [Generic Company Name Inc. / Ltd.] • Description of Facility • Responsible Personnel (Key Staff) • List of Production Equipment • Blueprint of Facility • GMP Certification Statement

Addresses of Scale-up Facilities [Generic Company Name Inc. / Ltd.] • Description of Facility • Responsible Personnel (Key Staff) • List of Production Equipment • Blueprint of Facility

Addresses of Manufacturing Facilities [Generic Company Name Inc. / Ltd.] • 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 the specific site (such as analytical or stability testing) need to describe these facilities in section VIII and X. A separate GMP certificate for that specific site needs to be included in the application.

4


Sect: 9.2

ANDA DEVELOPMENT


ANDA DEVELOPMENT

SECTION IX

SECTION 9

Description of Research Facility Research & Scale-up Facilities LIST OF RESPONSIBLE PERSONNEL (A) List of research facilities key personnel in the situation where the ANDA research site is geographically separated from the proposed manufacturing site (i.e. in another city, state or country.)

List of Small Scale Manufacturing Equipment (B) List of research and small scale facilities equipment in the situation where the pivotal batch was manufactured at a site other 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 the proposed manufacturing site are required to be validated. [In addition - to the above OGD's requirements, lot validation may be initialized¡ at the remote or foreign site]. ¡ Process Qualification Batch and/or Pivotal Batch

4


Sect: 9.3

ANDA DEVELOPMENT


ANDA DEVELOPMENT

SECTION IX

SECTION 9

Description of Manufacturing Facility LIST 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


Sect: 9.4

ANDA DEVELOPMENT


ANDA DEVELOPMENT

SECTION IX

SECTION 9

Description of Manufacturing Facility BLUEPRINT OF MNF FACILITY Manufacturing, Testing and Storage Areas blueprints - showing facilities layout.

ADDRESSES OF FACILITIES Manufacturing, processing, bulk packaging, bulk labeling, handling and storage of the bulk [Generic name] DRUG [USP] [000.0] mg. will take place at the pharmaceutical manufacturing facility identified below: [Generic Company Name Inc. / Ltd.] Pharmaceutical Manufacturing Division Industrial 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 identified below: [Generic Company Name Inc. / Ltd.] Pharmaceutical Packaging Division Industrial 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 Division Industrial 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 in accord with the Division of Generic Drugs Policy and Procedure Guide at: [Generic Company Name Inc. / Ltd.] Analytical Research / QC Laboratories Industrial Area [Street] [Town] [State] [Zip Code] [Country]. (Additional information on these sites is provided herein.)

4


Sect: 9.5

ANDA DEVELOPMENT


ANDA DEVELOPMENT

SECTION IX

SECTION 9

Description of Manufacturing Facility

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

[Generic Company Name Inc. / Ltd.] certifies that the methods used in, and the facilities and controls used for, the manufacture, processing, packaging and storage of drugs at our [Generic Company Name Inc./Ltd.] manufacturing plant conform to Current 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 the facilities and controls used for, the manufacture, processing, packaging and storage of drugs at our [Third Party Company Name Inc. / Ltd.] plant conform to Current 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] [Signature of Responsible Person] ------------------------------------------------

-----------------------------------------


Date

Plant General Manager Pharmaceutical Manufacturing Division [Generic Company Name Inc. / Ltd.] [Signature of Responsible Person] ------------------------------------------------

-----------------------------------------


Date

QA Manager Pharmaceutical Manufacturing Division [Generic Company Name Inc. / Ltd.] (Signed GMP statement required for all processing, warehousing and testing sites.)

4


Sect: 9.6

ANDA DEVELOPMENT


ANDA DEVELOPMENT

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 Laboratories 1. Full address 2. Functions 3. CGMP certification/GLP

4


Sect: 10.1

ANDA DEVELOPMENT


ANDA DEVELOPMENT

SECTION X

SECTION 10

Outside firms and Contract Facilities Contract Facilities [Generic Company Name Inc./Ltd.] does not intend the use of any outside manufacturing contract facilities at the prevailing time. If a contract outside facility is desired 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 testing laboratories facilities at the prevailing time. If a contract laboratory or outside laboratory is required in the future, the appropriate CBE documentation according to PAC-ALTS (Post-approval Changes - Analytical testing Laboratory Sites, April 1998) will be submitted to this ANDA.


-----------------------------------------


Date

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


-----------------------------------------


Date

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


Sect: 10.2

ANDA DEVELOPMENT


SECTION X

ANDA DEVELOPMENT

SECTION 10

Outside firms and Contract Facilities (or where used)

Contract Testing Laboratories The following contract testing laboratory was used during the development of [Drug Product] [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 Company Name Inc. Ltd.] and the active raw material for the pivotal batches was tested according 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 drug establishment for the year 200Y.


-----------------------------------------


Date

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


-----------------------------------------


Date

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

4


Sect: 10.3

ANDA DEVELOPMENT


SECTION X

ANDA DEVELOPMENT

SECTION 10

Outside firms and Contract Facilities ADDRESSES OF FACILITIES Manufacturing, processing, bulk packaging, bulk labeling, handling and storage of the bulk [Generic name] Drug [000.0]mg [USP]. will take place at the pharmaceutical manufacturing facility identified below: [Third Parties Company Name Inc. / Ltd.] Pharmaceutical Manufacturing Division Industrial 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 identified below: [Third Parties Company Name Inc. / Ltd.] Pharmaceutical Packaging Division Industrial 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 Division Industrial 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 in accord with the Division of Generic Drugs Policy and current Procedure Guides [Third Parties Company Name Inc. / Ltd.] Analytical Research / QC Laboratories Industrial Area [Street] [Town] [State] [Zip Code] [Country]


Sect: 10.4

ANDA DEVELOPMENT


ANDA DEVELOPMENT

SECTION X

SECTION 10


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 and storage of drugs at our [Third Parties Company Name Inc. / Ltd.] plant conform to Current Good Manufacturing Practice in accord with 21 CFR Parts 210 and 211.


-----------------------------------------


Date

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


-----------------------------------------


Date

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

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


Sect: 10.5

ANDA DEVELOPMENT


ANDA DEVELOPMENT

Generic Drug Enforcement Act - 1992

Third Party Letterhead

STATEMENT Where Company has NO previous convictions AND does not use a debarred person in connection with the ANDA

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

O

n behalf of [3rd Party Company Name Inc. / Ltd.], we hereby certify, pursuant to 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 any capacity 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 types of crimes set forth in Section 2(a) and Section 2(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, nor has any person affiliated with our contracting firm, who is responsible in whole or in part, for the development or the submission of this application been convicted of any crime of the type listed in Section 2(a) and Section 2(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] -------------------------------------------------

---------------------------------------


Date


[3rd Party Company Name Inc. / Ltd.]

[Signature of Responsible Person] __________________________

______________________


Date

Director Quality Assurance Unit Pharmaceutical Manufacturing Division



Sect: 10.6

ANDA DEVELOPMENT


ANDA DEVELOPMENT


Third Party Letterhead

STATEMENT Where Company has a previous conviction but does not use a debarred person in connection with the ANDA


O

n behalf of [3rd Party Company Name Inc. / Ltd.], we hereby certify, pursuant to 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 any capacity 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 the following conviction for the types of offenses as set forth in Section 2(a) and Section 2(b) of the Generic Drug Enforcement Act of 1992, 21 USC 335a (a) and/or (b), Date of Conviction MM/DD/YY Nature 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 person affiliated with the applicant, who is responsible in whole or in part, for the development or the submission of this application has been convicted of any offense of the type listed in Section 2(a) and Section 2(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] -------------------------------------------------

---------------------------------------


Date



4 End of Section 10. 24 Volume V Drug Development Series

Sect: 10.7

ANDA DEVELOPMENT


ANDA DEVELOPMENT

SECTION X

SECTION 10


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


-----------------------------------------


Date

QA Manager Pharmaceutical Manufacturing Division

[Generic Company Name Inc./Ltd.]


-----------------------------------------


Date

Production Manager Pharmaceutical Manufacturing Division



Sect: 10.8

ANDA DEVELOPMENT


ANDA DEVELOPMENT

SECTION XI

SECTION 11

Proposed Manufacturing Instructions

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

This section contains:

◊

Description of Manufacturing Process

◊

Manufacturing Procedure Flow Chart

◊ ◊ ◊ ◊ ◊

Blank Master Production Batch Records (largest intended commercial production lots.) Blank Packaging Records (largest intended commercial production lots.) Formula comparison (compares pivotal batch parameters with intended commercial production) Equipment Comparison (compares pivotal batch parameters with intended commercial production) Description of Intended Commercial Packaging Operation

◊

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

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

Section XI. Manufacturing and Processing Instructions 1. Description of the manufacturing process (including microbiological verification in Section XIV, as appropriate) 2. Blank batch records (for largest intended commercial production runs with equipment specified) 3. Reprocessing statement.

4


Sect:11. 1

Topical SEMISOLID


ANDA DEVELOPMENT

SECTION XI

SECTION 11

Proposed Manufacturing Instructions Section contents: • Outlines of process and controls • Description of Manufacturing Process • Manufacturing Procedure Flow Chart • Blank Master Production Batch Records for intended production lots • Blank Packaging Records for intended production lots • Formula comparison between pivotal and intended commercial lots • Equipment Comparison pivotal and intended commercial lots • Description of Packaging Operation • Reprocessing Statement(s)

4


Sect:11. 2

Topical SEMISOLID


ANDA DEVELOPMENT

SECTION XI

SECTION 11

Proposed Manufacturing Instructions OUTLINE OF STANDARD OPERATING PROCEDURES FOR : MANUFACTURING AND PROCESSING

1. 2. 3.

4.

5.

6.

7. 8. 9. 10. 11. 12. 13. 14.

Production Office - Prepares a production order file for each production batch according to the production schedule. Production Office - Assigns batch numbers, according to the existing code procedure, and enters these numbers in the batch numbers log. Production Office - A photocopy of the master formula record and manufacturing instructions is prepared with the specific manufacturing batch number. Production Office - Prepares all forms needed in the manufacturing process which are placed in the product order file. The file is then transferred to the Weighing Center/Dispensing Area. Dispensing Area - Weighs all raw material components according to the master formula record. For each weighing, the raw material receiving logbook number is entered on the master formula record. All materials belonging to one manufacturing batch of the product is placed on a separate pallet and covered with a pallet cover or clear shrink-wrap. As per production schedule the pre-weighed raw material on pallets are transferred to productions, by production personnel, under the responsibility of the department head. Production Depts. - During manufacturing, the product test results are recorded on the control forms which are attached to the master formula and manufacturing instructions batch record. Production Office - forwards a “Standard Packaging Sheet” with the computerized order to the packaging department. Packaging Department - forwards the “Standard Packaging Sheet” and the computer order to the packaging materials warehouse. Packaging Department - Authorizes packaging startup, in-process compliance, on the “Packaging Work Sheet”. After packaging, the packaged goods are transferred to the warehouse/holding area under a quarantine status, pending QC release. The product is tested by the QC analytical laboratory. Production records and test results are analyzed by QA Department and on release the product is moved to the warehouse ready for shipment. The batch records are archived by the Quality Assurance Department. Shipping Department - maintains a complete and traceability record of the dispatches of each product batch number and its final destination.


Sect:11. 3

Topical SEMISOLID


ANDA DEVELOPMENT

SECTION XI

SECTION 11

Proposed Manufacturing Instructions OUTLINE OF STANDARD OPERATING PROCEDURES FOR:

IN-PROCESS CONTROLS 1. At all stages of manufacturing, processing, time limitations and packaging appropriate control procedures are employed in conformity with current good manufacturing practice. 2. Appropriate in-process controls include material testing by quality control and quality assurance personnel. These test cover:

⇒ ⇒

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

3. In-process material testing is performed by Qualified Personnel. 4. The Quality Assurance Department reviews the batch test results and evaluates the acceptance or rejection of each batch lot.

4


Sect:11. 4

Topical SEMISOLID


ANDA DEVELOPMENT

SECTION XI

SECTION 11

Proposed Manufacturing Instructions IN-PROCESS CONTROLS DURING SEMISOLID FILLING In-process testing is conducted independently by both production and quality control trained personnel. The tests specified in the underlying tables are performed in accord with the in-process product specifications. When, a test is not required, according to the written specifications, it will not be performed. Production personnel test the physical specifications of random samples according to the individual product specifications: A minimum sampling frequency is tabulated for each eight hour (shift) period.

Production In-process Testing Schedule: TEST PERFORMED Bulk Description

Sample Size

Frequency per shift (min)

Acceptance

(1)

1

At start.

Fill Weight (Active)

10

At 30 min. intervals.

Cap Torque

6


Criteria (2) Within written specifications. NMT 2 Containers from of the 20 tested may deviate from product spec. No deviation permitted from Double Limits(3) specification. No deviation from product specifications is permitted.

KEY: 1

The testing frequency is performed twice when the overall filling time is less than four hours.

2

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


Sect:11. 5

Topical SEMISOLID


ANDA DEVELOPMENT

SECTION XI

SECTION 11


Q

uality Control personnel test the physical specifications of random samples according to the individual product specifications sheets: A minimum sampling frequency is tabulated for each eight hour (shift) period.

Quality Control In-process Testing Schedule:

TEST

Sample

Frequency

PERFORMED

Size

per shift (min.)

Material Description

1 (1)

Once at start

Individual Fill

No deviation from product specification is allowed.

20 (1)

60 min

NMT 2 Containers from of the 20 tested may deviate from product spec. No deviation permitted from Double Limits(3) specification.

6 (1)

60 min

No deviation from product specification is allowed

Weight

CAP TORQUE

Acceptance Criteria (2)

(1)

KEY: 1

Samples are taken, independently by QC personnel for batch release purposes, at least once per hour throughout the FILL run, producing a total representative sample quantity of 20 - 40 Containers . This representative sample lot is for QC batch release purposes . 2

Deviations from specifications and acceptance criteria, arising during the in-process controls, shall determine the corrective action to be performed on the filling machinery during the filling stage. 3

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


Sect:11. 6

Topical SEMISOLID


ANDA DEVELOPMENT

SECTION XI

SECTION 11

Proposed Manufacturing Instructions BATCH RECORDS FOR POST-APPROVAL PRODUCTION BATCHES

E

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

Translation Policy - for Non English Speaking Areas: Certain manufacturing and process and control documents may be written in [English and the National Foreign language] with some information in English only. Where information is provided in [English and a Foreign language], an authorized English translation is provided preceding the document in [English and the Foreign language]. Where only English is used on a page, no translation is provided.

4


Sect:11. 7

Topical SEMISOLID


ANDA DEVELOPMENT

SECTION XI

SECTION 11

Proposed Manufacturing Instructions MANUFACTURING INSTRUCTIONS FOR COMMERCIAL PRODUCTION

Product name: Batch Number: Department: Precautions: Caution: Cat./Formula No: Based on PQ:

[Generic name] SEMISOLID USP [000.0] mg per g.

000 ______________

•‚ƒ …† # F0000 Batch # PQ-000

Change Control for this document:

Batch Size: 0000 Kg/units Sub-lot No: þ1 ý2 ý3 Manufacture Date: Month DD, YY SEMISOLID þ ý PIVOTAL BATCH ý Validation Lot þ Commercial Lot Original - No Change þ : Change ý

Changes made: - none

KEY: Precautions:

Caution:

•Wear Mask and Gloves ‚Wear disposable overalls ƒUse air stream face visor with AIR filter „Use Mask, Gloves and Safety glasses …Avoid exposure to light / Protect form light †Store in well closed containers ‡Potential danger to pregnant women ˆPregnant women prohibited in this area ‰Do not heat above 00ø øC • Room humidity below 30%

Note: (A modern real life manufacturing process for a SEMISOLID is provided as an example of how to prepare the manufacturing instructions. This specific set of manufacturing instructions was chosen as it represents the most complex example).


Sect:11. 8

Topical SEMISOLID


ANDA DEVELOPMENT

SECTION XI

SECTION 11

Proposed Manufacturing Instructions MANUFACTURING INSTRUCTION COMMERCIAL PRODUCTION [Generic name] SEMISOLID [USP] [000.0] mg/g Lot: 000 Miconazole Cream USP [20.0] mg/gram Batch No:

Weighing Date : Page 1 of 2 pages

Mg Per gram

% Exc ess

Raw Material Names

#

Sign weigh. Dept.

per [150] kg Kg

g

mg

L

mL

A

PART I - OIL PHASE 180.00 25.20 2.00 0.05 207.252

20.00

Pegoxol 7 Stearate [Tefose 63™] Heavy Mineral OIL NF Benzoic Acid USP Butylated Hydroxyanizole

27

000

3

780 300 7

500

Theoretical End Weight. PART II

31

087

500

3 4

000 500

1 1

225 440 500

10

665

108

247

108

247

[Miconazole USP Micronized Peglico 5 Oleate [LABRAFIL M 1944™] Edetate Disodium USP st Heavy Mineral OIL (1 Rinsing) nd Heavy Mineral OIL (2 Rinsing)

30.00 1.50 9.60 10.00

Theoretical End Weight.

PART III - AQUEOUS PHASE 721.650 721.650

Purified Water USP Theoretical End Weight.

500 500

PART: IV MIXING STAGE 1000.0

Combined Phases - [1+2] + 3

150

000

1000.0


150

000

Edition Number: 01 Ed. Status: New

Effective Date: DD/MM/YY

APPROVED _____________ Department


__________ R &D

_______________ RA

Sect:11. 9

_________/________ QC / QA

Topical SEMISOLID

B


ANDA DEVELOPMENT

SECTION XI

SECTION 11

Proposed Manufacturing Instructions MANUFACTURING INSTRUCTION COMMERCIAL PRODUCTION [Generic name] SEMISOLID [USP] [000.0] mg/g Lot: 000 Miconazole Cream USP [20.0] mg/gram Batch No:


Mg Per gram

% Exc ess

Raw Material Names

#

Sign weigh. Dept.

per [300] kg Kg

g

mg

L

mL

A

PART I - OIL PHASE 180.00 25.20 2.00 0.05 207.252

20.00 30.00 1.50 9.60 10.00


54

000

7

560 600 15


62

175

6 9

000 000

2 3

450 880 000

21

330

216

495

216

495

[Miconazole USP Micronized Peglico 5 Oleate [LABRAFIL M 1944™] Edetate Disodium USP st Heavy Mineral OIL (1 Rinsing) Heavy Mineral OIL (2nd Rinsing) Theoretical End Weight.

000





300

000

1000.0


300

000





__________ R &D

_______________ RA

Sect:11. 10

_________/________ QC / QA

Topical SEMISOLID

B


ANDA DEVELOPMENT

SECTION XI

SECTION 11

Proposed Manufacturing Instructions MANUFACTURING INSTRUCTION COMMERCIAL PRODUCTION

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

Weighing Date: Page 1 of 4 pages

Machine

MANUFACTURING INSTRUCTIONS

Sign A+B

Step 1. IDENTIFY the equipment and verify the cleanliness prior to use.

PART ONE - OIL PHASE Step 2. LOAD into kettle No [ ] fitted with [Mixer # [ ]-Type & No) the ingredients in the following order: Pegoxol 7 Stearate [Tefose 63™] Heavy Mineral OIL NF Benzoic Acid USP Butylated Hydroxyanizole and mix for [20] minutes at mixer setting speed II Step 3. HEAT while mixing to NMT [45]º C (Target: [42]º C). Time of adding [ ] min. Total Mixing Time [ ] min.

PART TWO Active OILY PHASE Step 4. LOAD into a [Small Mixer-Type & No) the ingredients in the following order: Miconazole USP - Micronized Peglico 5 Oleate - [LABRAFIL M 1944™] Edetate Disodium USP Mix for [20] minutes at mixer speed [II] until mix is fully micronized material is suspended and homogeneous. Step 5. HEAT while mixing to NMT [45]º C (Target: [42]º C). Target Temperature [ ]º C START of mixing [ ] END of mixing [ ] Total Mixing Time [ ] min Edition Number: 01 Ed. Status New




__________ R &D

_______________ RA

Sect:11. 11

_______/________ QC / QA

Topical SEMISOLID

Date


ANDA DEVELOPMENT

SECTION XI

SECTION 11

Proposed Manufacturing Instructions MANUFACTURING INSTRUCTION COMMERCIAL PRODUCTION Page 2 of 4 pages


Machine

Sign A+B

Date

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

[ ]º C). [ ] [ ] min

Step 7. Cooling the Water Phase COVER and Cool Step 6 [PURIFIED WATER USP] to a target temperature while slowly stirring - Target Temperature 280C [±20C] Target Temperature Start of Cooling Time End of Cooling Time Total of Cooling Time

NMT [ [ [ [

]º C ] ] ] min

PART FOUR - ADDITION OF OILY PHASE Step 8. Add the Active Oily Phase STEP 4 to the Bulk Oil Phase STEP 2 and mix at speed [III] until homogeneous. RINSE active material twice with heavy mineral oil. Drain container fully after each RINSE procedure. Start of Mixing [ ] End of Mixing [ ] Total of Mixing Time [ ] min Step 9. Check that the oil phase after the mixing period is a homogeneously dispersed oily suspension - if necessary mix for an additional 20 minutes Start of Mixing [ ] End of Mixing [ ] Additional Mixing Time [ ] min Edition Number: 01 Ed. Status New




__________ R &D

_______________ RA

Sect:11. 12

_________/________ QC / QA

Topical SEMISOLID


ANDA DEVELOPMENT

SECTION XI

SECTION 11



Machine

Sign A+B

Date

ADDITION OF AQUEOUS PHASE

Step 10. RECORD the Aqueous and Oil Phase temperatures. Temperature of AQUEOUS Phase NMT [30]º C (Target: 280C [±20C]) Temperature of OIL Phase NMT [30]º C (Target: 280C [±20C]) Step 11. ADD the aqueous phase to STEP 8 while continuously mixing at mixer speed III. Start of Mixing [ ] End of Mixing [ ] Total Mixing Time [ ] min Step 12. ATTACH the mixing kettle temperature graphs (Type & No) to the manufacturing instructions. Add the batch number to the temperature graph and Immediately date and sign it..

COOLING OF COMBINED PHASES Step 13. COOL Step 11 to a target temperature while slowly stirring [Set I]. Target Temperature 250C [±20C] Record Temperature ______0C Step 14. PASS the SEMISOLID through an HOMOGENIZER (Type & No) fitted with a [0.0 mm] screen into an ultra clean holding bin. Step 15. CHECK pH [25]º C of a sample of the homogenized SEMISOLID). Record pH Result: _________ [Units] DETERMINE the viscosity using (Type & No) Brookfield Viscometer; Spindle No [3] RPM [5] Temperature [25]º C Record First result: __________ [Cp] Cp Limits: [4000 to 6000] Step 16. If necessary, continue to Homogenize the bulk material (recirculate) under the same conditions as STEP 14, until the viscosity is close to the midpoint of the given range limits and check viscosity again. Record Second result: __________ [Cp] Step 17. PUMP the semisolid into (Type & No) [000] liter container. Pumping Stop Time: _________ Step 18. WEIGH the bulk material ______Kg. Step 19. Immediately ADD the batch number to the scale print-out, and attach to the manufacturing instructions, date and sign the print-out. Edition Number: 01 Ed. Status New




__________ R &D

_______________ RA

Sect:11. 13

_________/________ QC / QA

Topical SEMISOLID


ANDA DEVELOPMENT

SECTION XI

SECTION 11



Machine

Sign A+B

Date

YIELD CALCULATION Step 20. Theoretical Weight [00.0] Kg. Yield ___________ % (Yield Limits: NLT 95% of Theoretical Weight.) No of Bins ______ Step 21. COLLECT 10 samples, each equivalent to the approximate weight of 10 g in labeled sample containers. Collect samples from upper, middle and lower part of the container. Send the samples to the QC laboratory for Content Uniformity Testing. Step 22. WEIGH the final material Actual weight: [00.0] Kg. Theoretical Weight [00.0] Kg. Yield __________ % No. of containers _____ . (Yield Limits: NLT 98% of total actual weight

PART FIVE - FILLING PROCEDURE Step 23. IDENTIFY and verify the cleanliness of the filling equipment in use. FILL the material according to the written specifications into air blown tubes WITHIN 24 hours after manufacture. CAUTION: (Do not leave standing over weekends/holidays.) Check filling weight every 15 minutes. Check end-crimp every 30 minutes. Check Lot No and Expiration Date over stamping at start and end of run. Check Lot No and Expiration Date after reset or replacing type. Air Blowing machine: (Type & No). Filling machine: (Type & No). Machine Speed _______ Tubes per minute. Limit of output NLT _______ units; NMT _______ units. Step 24. COUNT the total units produced: Actual production count: [00.0] Units. Weight of Samples taken: [00.0] Units. Vacuum and rejects number: [00.0] Units. Total Units [00.0] Units Theoretical Weight [00.0] Kg. Yield _________ % (Yield Limits: NMT 3% unexplained loss compared to the final bulk weight from STEP 20. Edition Number: 01 Ed. Status: New

Effective Date DD/MM/YY



__________ R &D

_______________ RA

Sect:11. 14

_________/________ QC / QA

Topical SEMISOLID


ANDA DEVELOPMENT

SECTION XI

SECTION 11

Proposed Manufacturing Instructions MANUFACTURING INSTRUCTION COMMERCIAL PRODUCTION FLOW CHART Chart One

Water Phase Heating

Purified Water USP Water Soluble Excipients Nitrogen blanket Solvent NF Antioxidant NF Active USP

0

0

88 -92 C

MIXER Water USP Purified Water Lipophyllic Emulgent

Water Phase Cooling 600-620C

1st RINSE

2nd RINSE

Nitrogen blanket

3rd RINSE (microgram Actives )

OIL PHASE MIXER (S/S

Inlet temp. up to 62°C (target 60°C)

Mixing vessel)

Oily Solvent Lipophobic Emulgent Emulsifier (Ross

mixer)

Viscosity Agent (Specify Type) 0 at controlled temp - T C

IPQC Testing pH Viscosity Content Uniformity Microbial limits

Cool to 280C

DE-AERATOR Homogeneous Semisolid

Target Temp. 500-520C

Ultra-clean FILLING

HOLDING TANK Under Nitrogen Fill tubes according to specifications

YIELDS Overall Production Yields 24 Volume V Drug Development Series

Sect:11. 15

Topical SEMISOLID


ANDA DEVELOPMENT

SECTION XI

SECTION 11

Proposed Manufacturing Instructions MANUFACTURING INSTRUCTION COMMERCIAL PRODUCTION

ATTACHMENTS: THE FOLLOWING ATTACHMENTS ARE PLACED HERE:

Process Attachment # 1 Attachment # 2

Weight Print-Outs of the raw material / solvents. Temperature Print-Outs of manufacturing process stage .

In-process Attachment # 3

pH Print-Outs of Bulk.

Attachment # 4

Viscosity Print-Out of Bulk material.

Final Bulk

Mixing Process. Attachment # 5 Attachment # 6

Mixing time Print-Out(s) of the Final Bulk. Weight Print-Out of the Final Bulk.

Weight Control

Filling Process. Attachment # 7

In-process weight Print-Outs of the filled material

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

[ALL-FILL \ KING]


Sect:11. 16

Topical SEMISOLID


ANDA DEVELOPMENT

SECTION XI

SECTION 11

Proposed Manufacturing Instructions IN-PROCESS CONTROL SPECIFICATION BULK MATERIAL SUMMARY Product: [Generic name] SEMISOLID [USP] [000.0] mg / g Lot No: 000 Quantity 000000 Yields Bulk Yield

MNF Date:

Month DD, 1998 / 9

Limit: NLT 98.0%

Total Final Yield

Limit: NLT 98.0% (based on actual quantities processed).

Overall Production Yield

NLT 95.0%

1

Target Fill Weight Limits 5.0%

____________ g. NLT 00.000g

Target Cap Torque (jars) Cap Torque Check (jars)

- NMT 00.000g

____________ Kg ____________ Kg

¹ Recorded on Statistical Data Work Sheets.


Sect:11. 17

Topical SEMISOLID


ANDA DEVELOPMENT

SECTION XI

SECTION 11

Proposed Manufacturing Instructions IN-PROCESS CONTROL SPECIFICATIONS SUMMARY PRODUCT: [GENERIC NAME] SEMISOLID [000.0] mg. Labeled Amount: EACH gram contains [000.0] mg [Active Material] In-process Specifications Description

Opaque uniform homogeneous Semisolid with a [type] color and [type] odor.

Active Fill Weight (±5.0%)

Target 000

Limit: 000 - 000 mL

pH (±1.0 / 0.5 unit) Viscosity

Target 0.0 Target 0000

Limit: 0.0 - 0.0 Limit: 0000 - 0000 cp.

Brookfield, Spindle #[ 0] After [ 0] rpm

In-Process Semisolid Content Uniformity

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

Particle Size (microns)

Median 000µ

Limit: 000 - 000 µ

Yields Actual Bulk Weight

Limit: NLT 98.0% (based on actual quantities processed)

Calculated Filling Yield

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

Actual Filling Yield

NMT 2.0% unexplained loss from the previous final blend step

Overall Filling Yield

NLT 95.0%

Note: Exact Decimal points have been set for each specification



Sect:11. 18

Topical SEMISOLID


ANDA DEVELOPMENT

SECTION XI

SECTION 11

Proposed Manufacturing Instructions IN-PROCESS CONTROL SPECIFICATION SUMMARY Product: [Generic name] SEMISOLID [USP] [000.0] mg / g Quantity 000000

MNF Date:

Lot No: 000

Month DD, 1998 / 9

Lowest

Mean

Highest

¹Target Fill weight 000.0 (g)

000.0

000.0

000.0

¹Weight of 10 Containers #1 (g)

000.0

000.0

000.0


000.0

000.0

000.0


000.0

000.0

000.0


000.0

000.0

000.0


000.0

000.0

000.0


000.0

000.0

000.0


000.0

000.0

000.0


000.0

000.0

000.0

Weight Controls

In-Process Yields ¹Yield after filling vs. bulk material ¹Yield after filling to theoretical Semisolid Yield

00.0 % 00.0 % NMT 2.0% unexplained loss from the previous step

¹ Recorded on Statistical Data Semisolid Filling Work Sheets.


Sect:11. 19

Topical SEMISOLID


ANDA DEVELOPMENT

SECTION XI

SECTION 11

Proposed Manufacturing Instructions RELEASE SPECIFICATION FOR SEMISOLID [USP]

SUMMARY Product: [Generic name] Semisolid [000.0] mg / g Labeled Amount: Each gram contains [000.0] mg [Active Material] Description

[Opaque] uniform homogeneous Semisolid with a [type] color and [type] odor.

Identification A:

The Infra Red Absorption Spectrum conforms to the Reference Standard

Identification B:

The Chromatogram of the sample solution exhibits a peak with the same retention time as the standard solution.

Fill Volume (±5.0%)

Target 000

Limit: 000 - 000 mL

pH (±0.5 / 1.0 unit) Viscosity

Target 0.0 Target 0000

Limit: 0.0 - 0.0 Limit: 0000 - 0000 cp.


Uniformity of Dosage Units: Content Uniformity

Conforms to the current USP

Total Microbial Count Total Aerobic Count

NMT 100 NMT 100

Objectionable Organisms

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

Impurities /Degradation Products determination - Each Individual: - Any other Individual: - Total: Assay (Preservative) (Where Appropriate)

Assay (Active)


CFU / g CFU / g

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

Limit: 50.0 - 105.0% of labeled amount [00.0] - [000.0] mg / g Limit: 90.0 - 110.0% of labeled amount [00.0] - [000.0] mg / g

Sect:11. 20

Topical SEMISOLID


ANDA DEVELOPMENT

SECTION XI

SECTION 11

Proposed Manufacturing Instructions RELEASE SPECIFICATION FOR SEMISOLID [USP]

OUTLINE of IN-HOUSE ANALYTICAL SOP Content Uniformity The requirements for content Uniformity are met if the amount of the active ingredient in each of the 10 samples, as determined from the Content Uniformity Analytical Method, lies within the range of 90.0 - 110.0% of the labeled amount and the Relative Standard Deviation is less than or equal to 6.0%. If 1 sample is outside the range of 90.0 - 110.0% of labeled amount and no sample is outside the range of 80.0 - 120.0% of labeled amount, or if the Relative Standard Deviation is greater than 6.0%, or if both conditions prevail, test 20 additional samples. The requirements are met if not more than 1 sample of the 30 is outside the range of 90.0 110.0% of labeled amount and no sample is outside the range of 80.0 - 120.0% of labeled amount, the Relative Standard Deviation of the 30 samples does not exceed 7.8%.

Preservative Efficacy Preservative Efficacy Testing (USP) is omitted as a routine QC test when fully qualified with justification during the formulation development, process qualification AND pivotal batch lot testing. Preservative Efficacy Test USP are evaluated on stability testing at time of manufacture, 12; 24; and 36 months for PQ, Pivotal and validation batches only.

Preservative Efficacy / Preservative Assay Preservative Efficacy Testing (USP) and Assay is omitted as a routine QC test when fully qualified with justification during the formulation development, process qualification AND pivotal batch lot testing. Preservative Efficacy / Preservative Assay are evaluated on stability testing at time of manufacture, 12; 24; and 36 months for PQ, Pivotal and validation batches only.

Regulatory Requirements - Preservative Assay In cases of regulatory requests or insistence Preservative Assays are performed on every 5th production batch or at least once per year where only one batch is made.


Sect:11. 21

Topical SEMISOLID


ANDA DEVELOPMENT

SECTION XI

SECTION 11

Proposed Manufacturing Instructions COMPARISON OF EXECUTED (PIVOTAL) AND PRODUCTION FORMULAE Product: [Generic name] q [Semisolid] [000.0] mg per g. Lot: S-000

INGREDIENT

Amount per

Executed

Production

[0] mL

Batch

Batch

(mg)

0000

0000

(Kg)

(Kg)

Miconazole USP

00.00

00.00

00.00

Micronized

00.00

00.00

00.00

Pegoxol 7 Stearate [Tefose

00.00

00.00

00.00

63™]

00.00

00.00

00.00


00.00

00.00

00.00

Benzoic Acid USP

00.00

00.00

00.00


00.00

00.00

00.00

Peglico 5 Oleate

00.00

00.00

00.00


00.00

00.00

00.00

Purified Water USP

00.00

00.00

00.00

000.000

000.000

Total

000.000

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


Sect:11. 22

Topical SEMISOLID


ANDA DEVELOPMENT

SECTION XI

SECTION 11

Proposed Manufacturing Instructions COMPARISON OF EQUIPMENT AND MANUFACTURING CONDITIONS BETWEEN EXECUTED AND PRODUCTION BATCHES Product: [Generic name] q [Semisolid] [000.0] mg per g. Lot: S-000

Equipment and Manufacturing Conditions

Executed Batch 000 Kg

Production Batch 000 Kg

PROCESSING KETTLE

Production

Production

MIXER I

Production

Production

MIXER II

Production

Production

KING AIR MACHINE JD / BB

Production

Production

ZANASSI FILLING MACHINE LA-60

Production

Production

ALL FILL FILLING MACHINE SMR / 14

Production

Production

KING CAPPER C80

Production

Production

YAMATO CHECK WEIGHER

Production

Production

Equipment Variation

NONE

NONE

Manufacturing Area

Production

Production

Staff

Production

Production

SOP

Production

Production


Sect:11. 23

Topical SEMISOLID


ANDA DEVELOPMENT

SECTION XI

SECTION 11

Proposed Manufacturing Instructions PACKAGING OPERATION DESCRIPTION Product: [Generic name] q [Semisolid] [000.0] mg per g. Lot: S-000 Stage One. PACKAGING COMPONENTS: 1. Bulk Product 2. HDPE / Aluminum / Glass Containers 3. Package Outsert (Product Leaflets) 4. Container Label 5. Master Cartons 6. Carton Shipping Labels Stage Two PACKAGING PROCEDURE: HDPE Containers & Bulk Feed

Tube/Jar Cleaning Process (Air and Vacuum) Count & Fill

Capping (Tube/Jar)

Jar Closure Torque Test

Container Label and Outsert Attachment

Packed in Master Shipping Cartons


Sect:11. 24

Topical SEMISOLID


ANDA DEVELOPMENT

SECTION XI

SECTION 11

Proposed Manufacturing Instructions PACKAGING OPERATION - EQUIPMENT LISTING: Product: [Generic name] q [Semisolid] [000.0] mg per g. Lot: S-000 Machine

Operation

Manufacturer

Type

Serial #

Supplier 1

Schenck

HDPE Bottle

Schenck Process

1000-S

or Amber

GMBH Darmstadt

AccuRate

No: 543123

Output CONTAINERS per min2 50 Low 100 High

Glass Feeding 2

King

Air Cleaning

C.E. King Ltd, UK SuperKleen

3

Cream

ALLFILL KING

Filling 4

5

6.

7.

Capper

Torque

Groninger

Prestek

Capping

Torque

Outserter

KING CAPPER

(2)

CAP 80

H.G.Kalish Inc., Canada Groninger & Co

DFVK

KarlsHeim, Germany

3000

Labelling &

Prestek Ltd

Printing

Science Park

SmartDate Intelligent Thermal Transfer Printer

Nottingham UK

(1)

FILLER(1)

MK-

50 Low

2994

100 High

L-333

Count

L-334

50 50*

100 100*

2232-

50 Low

2234

100 High

2234-

50 Low

9987

100 High

5664

50 Low 100 High

53342

50 Low 100 High

Average figures for containers per minute output for Slow and High Speed. All indicated machine outputs are adjusted to the Filling rate.


Sect:11. 25

Topical SEMISOLID


ANDA DEVELOPMENT

SECTION XI

SECTION 11

Proposed Manufacturing Instructions BATCH RECORDS FOR EXECUTED BATCH TYPE OF SEMISOLID Lot No Enclosed are the batch records of the executed batch labeling).

(master, packaging and

Note: Translation Policy - (Foreign Manufacturing Plants): All documents provided are authenticated photocopies of the executed batch document. The documents are written in (local language) with parts of the data and information presented in English. Where information is provided in the (local language), a verified English translation is provided together with the original document in the local language. Where, only English is used in a document, the original copy document is provided. Executed batch of [Generic Name] SEMISOLID was manufactured on production equipment under actual production conditions.

ACTIVE MATERIAL The active material is manufactured by [BPC] Pharmaceutical and Chemical Manufacturing Company - [Address].


Sect:11. 26

Topical SEMISOLID


ANDA DEVELOPMENT

SECTION XI

SECTION 11


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 is required once the product has been marketed, the reprocessing procedure as well as the relevant supporting data will be submitted, (according to the SUPAC guideline, where appropriate), for supplementary review and approval of the Office of Generic Drugs prior to implementation.


[Name of Responsible Person] Plant Manager

--------------------------------------Date

Pharmaceutical Manufacturing Division


[Signature of Responsible Person] -----------------------------------------------[Name of Responsible Person] Director Quality Assurance Unit

---------------------------------------Date




[Name of Responsible Person] Director Pharmaceutical Research & Development Pharmaceutical Division

----------------------------------Date



Sect:11. 27

Topical SEMISOLID


ANDA DEVELOPMENT

SECTION XI

SECTION 11


REPROCESSING STATEMENT (Delete statement where appropriate)

The following manufacturing stages have been reworked during the full size process Qualification batch (essentially similar to the pivotal batch shown) and the finished product specifications were evaluated. At time of manufacture (Time zero): No detectable change was recorded for the following test studies pH Viscosity Content Uniformity At 3 months stability station (40o C / 75% RH): The above parameters showed no detectable changes. The full re-work study is presented in the “Product Development Report” and a Summary outline is given in Section XXI. Conclusion: It is concluded that an additional 20 minute mixing (last stage) may be repeated once as shown, without affecting or impacting on the products physical parameters as shown in the in-process, release or stability (check) specifications. [Signature of Responsible Person] -----------------------------------------------[Name of Responsible Person] Plant Manager

-------------------------------------Date


[Generic Company Name Inc. / Ltd.] [Signature of Responsible Person] -----------------------------------------------[Name of Responsible Person] Director Quality Assurance Unit

------------------------------------Date




Sect:11. 28

Topical SEMISOLID


ANDA DEVELOPMENT

SECTION XII

SECTION 12

Pivotal Manufacturing and Controls

TABLE OF CONTENTS. (as stated in FDA Feb. 1999 Guidance for Industry). 12.1 Copy of the executed Pivotal batch manufacturing record with - equipment used - batch reconciliation 12.2 Copy of the executed Pivotal batch packaging record with - equipment used - label reconciliation

IN-PROCESS CONTROLS 12.3.1 Sampling plans and testing procedures 12.3.2 Specifications and data

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

Section XII.. In-Process Information 1. Copy of executed batch record with equipment specified (including packaging records, and batch reconciliation) 2. In-process controls

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

4


Sect:12. 1

Topical SEMISOLID


ANDA DEVELOPMENT

SECTION XI

SECTION 12

Pivotal Manufacturing and Controls This section contains: • Outlines of Standard Operating Procedure for In-Process Controls • In-Process Control tabulation chart (Summary) • Executed Manufacturing Procedure Flow Chart • Executed Batch documents • Batch Records Packaging Records and labeling reconciliation • Summary of FILL WEIGHT Verification • Summary of CONTENT UNIFORMITY Verification • Packaging and Disbursement Summary

4


Sect:12. 2

Topical SEMISOLID


ANDA DEVELOPMENT

SECTION XII

SECTION 12

Pivotal Manufacturing and Controls OUTLINE OF STANDARD OPERATING PROCEDURES FOR:

IN-PROCESS CONTROLS 1. At all stages of processing, appropriate control procedures are employed in conformity with current good manufacturing practice. 2. Appropriate in-process controls include material testing by quality control and quality assurance personnel. These test are: ⇒ ⇒ ⇒

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

3. In-process material testing is performed by Qualified Personnel. 4. The Quality Assurance Department reviews the batch test results and evaluates the acceptance or rejection of each batch lot.

4


Sect:12. 3

Topical SEMISOLID


ANDA DEVELOPMENT

SECTION XII

SECTION 12

Pivotal Manufacturing and Controls IN-PROCESS CONTROLS DURING SEMISOLID FILLING In-process testing is conducted independently by both production and quality control trained personnel. The tests specified in the underlying tables are performed in accord with the in-process product specifications. When, a test is not required, according to the written specifications, it will not be performed. Production personnel test the physical specifications of random samples according to the individual product specifications: A minimum sampling frequency is tabulated for each eight hour (shift) period.

Production In-process Testing Schedule: Test

Sample

Frequency

Acceptance

PERFORMED

Size

per shift (1) (min)

Criteria (2)

1

At start.

Within specifications.

Fill Weight (Active)

10


Cap Torque (Jars)

6


Bulk Description

NMT 2 Containers from of the 20 tested may deviate from product spec. No deviation permitted from Double Limits(3) specification. No deviation from product specifications is permitted.

KEY: 1

The testing frequency is performed twice when the overall filling time is less than four hours.

2

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


Sect:12. 4

Topical SEMISOLID


ANDA DEVELOPMENT

SECTION XII

SECTION 12


Q

uality Control personnel test the physical specifications of samples taken at random according to the individual product specifications sheets: A minimum sampling frequency is tabulated for each eight hour (shift) period.

Quality Control In-process Testing Schedule:

TEST

Sample

Frequency

ACCEPTANCE

PERFORMED

Size

per shift (1) (min.)

CRITERIA (2)

Material Description

1 (1)

Once at start

No deviation from product specification is allowed.

Individual Fill

20 (1)

60 min

NMT 2 Containers from of the 20 tested may deviate from product spec. No deviation permitted from Double Limits(3) specification.

6 (1)

60 min

No deviation from product specification is allowed

Weight

CAP TORQUE (Jars)

KEY: 1

Samples are taken, independently by QC personnel for batch release purposes, at least once per hour throughout the FILL run, producing a total representative sample quantity of 20 - 40 Containers. This representative sampling is for the QC Unit batch release purposes 2

Deviations from specifications and acceptance criteria, that arise during the inprocess controls, determine the corrective action undertaken on the filling machinery during the line filling stage. 3

Double Limits for the Individual Fill Weight tests are defined as the double value from the minimum or maximum limit in relation to the nominal fill value (i.e. target fill weight value).


Sect:12. 5

Topical SEMISOLID


ANDA DEVELOPMENT

SECTION XII

SECTION 12

Pivotal Manufacturing and Controls OUTLINE OF STANDARD OPERATING PROCEDURES FOR: SAMPLING PLAN OF PIVOTAL LOTS FOR STABILITY AND BIOAVAILABILITY STUDIES.

S

tandard Operating Procedures are in place at the commercial manufacturing facility, that define the overall packaging procedures for the pivotal lot(s) and the representative sampling of the various pack sizes for the purpose of quality control, stability testing and bioavailability studies. These procedures are summarized below. The entire pivotal lot (i.e. 100%) is packaged in the commercial production packaging department, using routine production equipment, and operated by the standard production personnel. The smallest and largest pack size of each pack type is packaged, not less than 15 -20% of the pivotal batch is packed into each pack type. The number of each type of pack size sampled is calculated in order obtain approximately equal numbers of each presentation size. A sampling plan for each type of package, is determined on the basis of the total number of packages and the number of packages required for control, stability and topical bioavailability studies. The sampling plan is representative of the entire pivotal batch.

4


Sect:12. 6

Topical SEMISOLID


ANDA DEVELOPMENT

SECTION XII

SECTION 12

Pivotal Manufacturing and Controls EXECUTED PIVOTAL BATCH MANUFACTURING INSTRUCTIONS

Product name: Batch Number: Department: Precautions: Caution: Cat./Formula No: Based on PQ:

[Generic name] SEMISOLID [USP] [000.0] mg. 000 ______________ Batch Size: 150 Kg •‚ƒ Sub-lot No: þ1 ý2 ý3 …† Manufacture Date: Month DD, YY # F0000 SEMISOLID þ Batch # PQ000 þ PIVOTAL BATCH ý Validation Lot ý Commercial Lot

Change Control for this document:

Original - No Change þ : Change ý

Change made: - none

KEY: Precautions:

Caution:

•Wear Mask and Gloves ‚Wear disposable overalls ƒUse air stream face visor with AIR filter „Use Mask, Gloves and Safety glasses …Avoid exposure to light / Protect form light †Store in well closed containers ‡Potential danger to pregnant women ˆPregnant women prohibited in this area ‰Do not heat above 00ø øC • Room humidity below 30%


Sect:12. 7

Topical SEMISOLID


ANDA DEVELOPMENT

SECTION XII

SECTION 12

Pivotal Manufacturing and Controls EXECUTED PIVOTAL BATCH MASTER FORMULA [Generic name] SEMISOLID [USP] [000.0] mg/g Lot: 000 Miconazole Cream USP [20.0] mg/gram Batch No:


Mg Per gram

% Exc ess

Raw Material Names

#

Sign weigh. Dept.

per [150] kg Kg

g

mg

L

mL

A

PART I - OIL PHASE 180.00 25.20 2.00 0.05 207.252

20.00 30.00 1.50 9.60 10.00


27

000

3

780 300 7

500


31

087

500

3 4

000 500

1 1

225 440 500

10

665

108

247

108

247

[Miconazole USP Micronized Peglico 5 Oleate [LABRAFIL M 1944™] Edetate Disodium USP Heavy Mineral OIL (1st Rinsing) Heavy Mineral OIL (2nd Rinsing) Theoretical End Weight.



500 500



150

000

1000.0


150

000





__________ R &D

Sect:12. 8

_______________ RA

_________/________ QC / QA

Topical SEMISOLID

B


ANDA DEVELOPMENT

SECTION XII

SECTION 12

Pivotal Manufacturing and Controls EXECUTED PIVOTAL BATCH MASTER FORMULA [Generic name] SEMISOLID [USP] [000.0] mg/g Lot: 000 Batch No:

Weighing Date: Page 1 of 4 pages

Machine


Sign A+B

Step 1. IDENTIFY the equipment and verify the cleanliness prior to use.

PART ONE - OIL PHASE Step 2. LOAD into kettle No [ ] fitted with [Mixer # [ ]-Type & No) the ingredients in the following order: Pegoxol 7 Stearate [Tefose 63™] Heavy Mineral OIL NF Benzoic Acid USP Butylated Hydroxyanizole and mix for [20] minutes at mixer setting speed II Step 3. HEAT while mixing to NMT [45]º C (Target: [42]º C). Time of adding [ ] min. Total Mixing Time [ ] min.

PART TWO Active OILY PHASE Step 4. LOAD into a [Small Mixer-Type & No) the ingredients in the following order: Miconazole USP - Micronized Peglico 5 Oleate - [LABRAFIL M 1944™] Edetate Disodium USP Mix for [20] minutes at mixer speed [II] until mix is fully micronized material is suspended and homogeneous. Step 5. HEAT while mixing to NMT [45]º C (Target: [42]º C). Target Temperature [ ]º C START of mixing [ ] END of mixing [ ] Total Mixing Time [ ] min Edition Number: 01 Ed. Status New




__________ R &D

Sect:12. 9

_______________ RA

_______/________ QC / QA

Topical SEMISOLID

Date


ANDA DEVELOPMENT

SECTION XII

SECTION 12

Pivotal Manufacturing and Controls EXECUTED PIVOTAL BATCH MANUFACTURING INSTRUCTIONS Page 2 of 4 pages


Machine

Sign A+B

Date

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

[ ]º C). [ ] [ ] min

Step 7. Cooling the Water Phase COVER and Cool Step 6 [PURIFIED WATER USP] to a target temperature while slowly stirring - Target Temperature 280C [±20C] Target Temperature Start of Cooling Time End of Cooling Time Total of Cooling Time

NMT [ [ [ [

]º C ] ] ] min

PART FOUR - ADDITION OF OILY PHASE Step 8. Add the Active Oily Phase STEP 4 to the Bulk Oil Phase STEP 2 and mix at speed [III] until homogeneous. RINSE active material twice with heavy mineral oil. Drain container fully after each RINSE procedure. Start of Mixing [ ] End of Mixing [ ] Total of Mixing Time [ ] min Step 9. Check that the oil phase after the mixing period is a homogeneously dispersed oily suspension - if necessary mix for an additional 20 minutes Start of Mixing [ ] End of Mixing [ ] Additional Mixing Time [ ] min Edition Number: 01 Ed. Status New




__________ R &D

Sect:12. 10

_______________ RA

_________/________ QC / QA

Topical SEMISOLID


ANDA DEVELOPMENT

SECTION XII

SECTION 12



Machine

Sign A+B

Date

ADDITION OF AQUEOUS PHASE

Step 10. RECORD the Aqueous and Oil Phase temperatures. Temperature of AQUEOUS Phase NMT [30]º C (Target: 280C [±20C]) Temperature of OIL Phase NMT [30]º C (Target: 280C [±20C]) Step 11. ADD the aqueous phase to STEP 8 while continuously mixing at mixer speed III. Start of Mixing [ ] End of Mixing [ ] Total Mixing Time [ ] min Step 12. ATTACH the mixing kettle temperature graphs (Type & No) to the manufacturing instructions. Add the batch number to the temperature graph and Immediately date and sign it..

COOLING OF COMBINED PHASES Step 13. COOL Step 11 to a target temperature while slowly stirring [Set I]. Target Temperature 250C [±20C] Record Temperature ______0C Step 14. PASS the SEMISOLID through an HOMOGENIZER (Type & No) fitted with a [0.0 mm] screen into an ultra clean holding bin. Step 15. CHECK pH [25]º C of a sample of the homogenized SEMISOLID). Record pH Result: _________ [Units] DETERMINE the viscosity using (Type & No) Brookfield Viscometer; Spindle No [3] RPM [5] Temperature [25]º C Record First result: __________ [Cp] Cp Limits: [4000 to 6000] Step 16. If necessary, continue to Homogenize the bulk material (recirculate) under the same conditions as STEP 14, until the viscosity is close to the midpoint of the given range limits and check viscosity again. Record Second result: __________ [Cp] Step 17. PUMP the semisolid into (Type & No) [000] liter container. Pumping Stop Time: _________ Step 18. WEIGH the bulk material ______Kg. Step 19. Immediately ADD the batch number to the scale print-out, and attach to the manufacturing instructions, date and sign the print-out. Edition Number: 01 Ed. Status New




__________ R &D

Sect:12. 11

_______________ RA

_________/________ QC / QA

Topical SEMISOLID


ANDA DEVELOPMENT

SECTION XII

SECTION 12



Machine

Sign A+B

Date

YIELD CALCULATION Step 20. Theoretical Weight [00.0] Kg. Yield ___________ % (Yield Limits: NLT 95% of Theoretical Weight.) No of Bins ______ Step 21. COLLECT 10 samples, each equivalent to the approximate weight of 10 g in labeled sample containers. Collect samples from upper, middle and lower part of the container. Send the samples to the QC laboratory for Content Uniformity Testing. Step 22. WEIGH the final material Actual weight: [00.0] Kg. Theoretical Weight [00.0] Kg. Yield __________ % No. of containers _____ . (Yield Limits: NLT 98% of total actual weight

PART FIVE - FILLING PROCEDURE Step 23. IDENTIFY and verify the cleanliness of the filling equipment in use. FILL the material according to the written specifications into air blown tubes WITHIN 24 hours after manufacture. CAUTION: (Do not leave standing over weekends/holidays.) Check filling weight every 15 minutes. Check end-crimp every 30 minutes. Check Lot No and Expiration Date over stamping at start and end of run. Check Lot No and Expiration Date after reset or replacing type. Air Blowing machine: (Type & No). Filling machine: (Type & No). Machine Speed _______ Tubes per minute. Limit of output NLT _______ units; NMT _______ units. Step 24. COUNT the total units produced: Actual production count: [00.0] Units. Weight of Samples taken: [00.0] Units. Vacuum and rejects number: [00.0] Units. Total Units [00.0] Units Theoretical Weight [00.0] Kg. Yield _________ % (Yield Limits: NMT 3% unexplained loss compared to the final bulk weight from STEP 20. Edition Number: 01 Ed. Status: New

Effective Date DD/MM/YY



__________ R &D

Sect:12. 12

_______________ RA

_________/________ QC / QA

Topical SEMISOLID


ANDA DEVELOPMENT

SECTION XII

SECTION 12

Pivotal Manufacturing and Controls EXECUTED PIVOTAL BATCH MANUFACTURING INSTRUCTIONS FLOW CHART Chart One

Water Phase Heating

Purified Water USP Water Soluble Excipients Nitrogen blanket Solvent NF Antioxidant NF Active USP

0

0

88 -92 C

MIXER Water USP Purified Water Lipophyllic Emulgent

Water Phase Cooling 0 0 60 -62 C

1st RINSE

2nd RINSE

Nitrogen blanket

3rd RINSE (microgram Actives )

OIL PHASE MIXER (S/S

Inlet temp. up to 62°C (target 60°C)

Mixing vessel)

Oily Solvent Lipophobic Emulgent Emulsifier (Ross

IPQC Testing pH Viscosity Content Uniformity Microbial limits

mixer)

Viscosity Agent

0

Cool to 28 C

(Specify Type) 0 at controlled temp - T C

DE-AERATOR Homogeneous Semisolid

Target Temp. 0 0 50 -52 C HOLDING TANK Under Nitrogen Fill tubes according to specifications

Ultra-clean FILLING


Sect:12. 13

Topical SEMISOLID


ANDA DEVELOPMENT

SECTION XII

SECTION 12

Pivotal Manufacturing and Controls EXECUTED PIVOTAL BATCH MANUFACTURING INSTRUCTIONS THE FOLLOWING ATTACHMENTS ARE PLACED HERE:

Process Attachment # 1 Attachment # 2

Weight Print-Outs of the raw material / solvents. Temperature Print-Outs of manufacturing process stages .

In-process Attachment # 3

pH Print-Outs of Bulk.

Attachment # 4

Viscosity Print-Out of Bulk material.

Final Bulk

Mixing Process. Attachment # 5 Attachment # 6

Mixing time Print-Out(s) of the Final Bulk. Weight Print-Out of the Final Bulk.

Weight Control

Filling Process. Attachment # 7

In-process weight Print-Outs of the filled material

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

[ALL-FILL \ KING]


Sect:12. 14

Topical SEMISOLID


ANDA DEVELOPMENT

SECTION XII

SECTION 12

Pivotal Manufacturing and Controls IN-PROCESS CONTROL SPECIFICATION BULK MATERIAL SUMMARY PIVOTAL BATCH

Product: [Generic name] SEMISOLID [USP] [000.0] mg/g Quantity 000000 Yields Manufacturing Yield

MNF Date:

Lot No: 000

Month DD, 1998 / 9

Limit: NLT 98.0%

Total Final Bulk Yield

Limit: NLT 98.0% (based on actual quantities processed).

Overall Production Yield

NLT 95.0%

1

Target Fill Weight Limits 5.0%

____________ g

2

NLT 00.000g

Target Cap Torque Cap Torque Check Cap Torque Limits

- NMT 00.000g

____________ Kg ____________ Kg Min____ Kg Max ____ Kg



Sect:12. 15

Topical SEMISOLID


ANDA DEVELOPMENT

SECTION XII

SECTION 12

Pivotal Manufacturing and Controls IN-PROCESS CONTROL SPECIFICATIONS SUMMARY PRODUCT: [GENERIC NAME] SEMISOLID [000.0] mg /g. Labeled Amount: EACH gram contains [000.0] mg [Active Material] In-process Specifications Description


pH (±1.0 / 0.5 unit) SG Viscosity

Target 0.0 Target 0.000 Target 0000

Limit: 0.0 - 0.0 Limit: 0.000 - 0.000 g/mL Limit: 0000 - 0000 cp.


In-Process Semisolid Content Uniformity (as per attached specifications)

Limit: 94.0 - 106.0% of labeled amount RSD ≤ 6.0%

Fill Weight (±5.0%)

Target 000

Limit: 000 - 000 mL

Individual Fill Weight (±7.5%)

Target 000.0

Limit: 000.0 - 000.0 g

Yields Actual Bulk Weight

Limit: NLT 98.0% (based on actual quantities processed)

Calculated Filling Yield

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

Actual Filling Yield

NMT 2.0% unexplained loss from the previous final blend step

Overall Filling Yield

NLT 95.0%

Note: Exact Decimal points have been set for each specification



Sect:12. 16

Topical SEMISOLID


ANDA DEVELOPMENT

SECTION XII

SECTION 12

Pivotal Manufacturing and Controls IN-PROCESS CONTROL SPECIFICATION SUMMARY PIVOTAL BATCH

Product: [Generic name] SEMISOLID [USP] [000.0] mg/g. Quantity 000000

MNF Date:

Lot No: 000

Month DD, 1998 / 9

Lowest

Mean

Highest

¹Target Fill weight 000.0 (g)

000.0

000.0

000.0


000.0

000.0

000.0


000.0

000.0

000.0


000.0

000.0

000.0


000.0

000.0

000.0


000.0

000.0

000.0


000.0

000.0

000.0


000.0

000.0

000.0


000.0

000.0

000.0

Weight Controls

In-Process Yields ¹Yield after filling vs. bulk material ¹Yield after filling to theoretical Permissible Loss

00.0 % 00.0 % NMT 2.0% unexplained loss from the previous step

¹ Recorded on Statistical Data Semisolid Filling Work Sheets.


Sect:12. 17

Topical SEMISOLID


ANDA DEVELOPMENT

SECTION XII

SECTION 12

Pivotal Manufacturing and Controls RELEASE SPECIFICATION FOR SEMISOLID [USP] SUMMARY Product: [Generic name] Semisolid [000.0] mg / 5 mL Labeled Amount: Each [00.0] g contains [000.0] mg [Active Material] Description


Identification A:

The Infra Red Absorption Spectrum conforms to the Reference Standard

Identification B:

The Chromatogram of the sample solution exhibits a peak with the same retention time as the standard solution.

Fill Weight (±5.0%)

Target 000

Limit: 000 - 000 mL

pH (±o.5/1.0 unit) SG Viscosity

Target 0.0 Target 0.000 Target 0000

Limit: 0.0 - 0.0 Limit: 0.000 - 0.000 g/mL Limit: 0000 - 0000 cp.


Uniformity of Dosage Units: Content Uniformity

Conforms to the current USP

Total Microbial Count Total Aerobic Count Objectionable Organisms

NMT 100 CFU / mL NMT 100 CFU / mL Absent: S aureus; E coli; P aerugenosa; Salmonella species; Indicator orgs

Impurities /Degradation Products determination - Each Individual: - Any other Individual: - Total:

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

Assay (Preservative)

Limit: 50.0 - 110.0% of labeled amount [00.0] - [00.0] mg / g

Assay (Active)

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


Sect:12. 18

Topical SEMISOLID


ANDA DEVELOPMENT

SECTION XII

SECTION 12

Pivotal Manufacturing and Controls RELEASE SPECIFICATION FOR SEMISOLID [USP]

OUTLINE of IN-HOUSE ANALYTICAL SOP Content Uniformity The requirements for content Uniformity are met if the amount of the active ingredient in each of the 10 samples, as determined from the Content Uniformity Analytical Method, lies within the range of 90.0 - 110.0% of the labeled amount and the Relative Standard Deviation is less than or equal to 6.0%. If 1 sample is outside the range of 90.0 - 110.0% of labeled amount and no sample is outside the range of 80.0 - 120.0% of labeled amount, or if the Relative Standard Deviation is greater than 6.0%, or if both conditions prevail, test 20 additional samples. The requirements are met if not more than 1 sample of the 30 is outside the range of 90.0 110.0% of labeled amount and no sample is outside the range of 80.0 - 120.0% of labeled amount, the Relative Standard Deviation of the 30 samples does not exceed 7.8%.

Preservative Efficacy Preservative Efficacy Testing (USP) is omitted as a routine QC test when fully qualified with justification during the formulation development, process qualification AND pivotal batch lot testing. Preservative Efficacy Test USP are evaluated on stability testing at time of manufacture, 12; 24; and 36 months for PQ, Pivotal and validation batches only.

Preservative Efficacy / Preservative Assay Preservative Efficacy Testing (USP) and Assay is omitted as a routine QC test when fully qualified with justification during the formulation development, process qualification AND pivotal batch lot testing. Preservative Efficacy / Preservative Assay are evaluated on stability testing at time of manufacture, 12; 24; and 36 months for PQ, Pivotal and validation batches only.

Regulatory Requirements - Preservative Assay In cases of regulatory requests or insistence Preservative Assays are performed on every th 5 production batch or at least once per year where only one batch is made.


Sect:12. 19

Topical SEMISOLID


ANDA DEVELOPMENT

SECTION XII

SECTION 12

Pivotal Manufacturing and Controls PACKAGING OPERATION DESCRIPTION Product: [Generic name] SEMISOLID [USP] [000] mg /g - Batch No: 000 Stage One. PACKAGING COMPONENTS: 1. Bulk Product 2. HDPE / Glass Containers 3. Package Outsert (Product Leaflets) 4. Container Label 5. Master Cartons 6. Carton Shipping Labels Stage Two PACKAGING PROCEDURE: HDPE Containers & Bulk Feed

Tube/Jar Cleaning Process (Air and Vacuum) Count & Fill

Capping (Screw Cap - Jars)

Closure Torque Test

Container Label and Outsert Attachment

Packed in Master Shipping Cartons


Sect:12. 20

Topical SEMISOLID


ANDA DEVELOPMENT

SECTION XII

SECTION 12

Pivotal Manufacturing and Controls PACKAGING OPERATION - EQUIPMENT LISTING:

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

Operation

Manufacturer

Type

Serial #

Supplier 1

Schenck

HDPE Bottle

Schenck Process

1000-S

or Amber

GMBH Darmstadt

AccuRate

No:

Output CONTAINERS per min2 50 Low

543123

100 High

MK-2994

50 Low

Glass Feeding 2

King

Air Cleaning

C.E. King Ltd, UK SuperKleen

3

Cream Filling

4

5

6.

7.

Capper

Capping

Torque

Torque

checker

(Jars)

Groninger

Prestek

Outserter

ALLFILL

FILLER(1)

KING CAPPER

CAP 80

H.G.Kalish Inc., Canada Groninger & Co

DFVK

KarlsHeim, Germany

3000

Labelling &

Prestek Ltd

Printing

Science Park

SmartDate Intelligent Thermal Transfer Printer

Nottingham UK

(1)

(2)

100 High L-333

Count

L-334

50 50*

100 100*

2232-

50 Low

2234

100 High

2234-

50 Low

9987

100 High

5664

50 Low 100 High

53342

50 Low 100 High

Average figures for containers per minute output for Slow and High Speed. All indicated machine outputs are adjusted to the Fill rate.


Sect:12. 21

Topical SEMISOLID


ANDA DEVELOPMENT

SECTION XII

SECTION 12

Pivotal Manufacturing and Controls BATCH RECORDS FOR EXECUTED BATCH SEMISOLID Lot No Enclosed are the batch records of the executed batch labeling).

(master, packaging and

Note: Translation Policy - (Foreign Manufacturing Plants): All documents provided are authenticated photocopies of the executed batch document. The documents are written in (local language) with parts of the data and information presented in English. Where information is provided in the (local language), a verified English translation is provided together with the original document in the local language. Where, only English is used in a document, the original copy document is provided. Executed SEMISOLID batch was manufactured on production equipment under actual production conditions. ACTIVE MATERIAL The active material is manufactured by [BPC] Pharmaceutical and Chemical Manufacturing Company - [Address].

Label Reconciliation: A 100% Label Reconciliation is conducted for each packaging run. All damaged / rejected labels are stuck to a label card and counted & defaced at the end of the run. Reconciliation Summary: Total number of labels _________ issued [a]

Signed by

(Warehouse)

Total number of labels _________ On product [b] Total number of labels _________ On Samples [c] Total number of labels _________ Damaged [d] Total number of labels _________ Not used [e]

Signed by Signed by Signed by Signed by

(Line Checker) (QA Staff) (Line Checker) (QA Staff)

% Label Reconciliation ________ (Calculation a - [b+c+d+e] ) < 5/1000 (NMT 0.5%) Note: Where the issue of labels are calculated by weight, the issue count error permitted is NMT 0.5 %.


Sect:12. 22

Topical SEMISOLID


ANDA DEVELOPMENT

SECTION XII

SECTION 12


FILL WEIGHT RANGE VERIFICATION Product: [Generic name] SEMISOLID [USP] [000] mg /g - Batch No: 000 The following specification were given for the executed (pivotal) batch:

WEIGHT RANGE TARGET FILL RANGE

0000.0 mg

NLT 0000.0 - NMT 0000.0 mg

During the manufacture of the executed (pivotal) batch, FILL WEIGHT range verification testing was performed. The result demonstrate that FILLING of _____________SEMISOLID on production equipment at production speeds was within the proposed weight range (minimum 000, maximum 000). The uniformity of content was evaluated on at least three samples taken at each speed. Each tube sampled and tested for U of C from the top, middle and crimp positions. The weight range results demonstrate that the range limits have been suitably validated for routine commercial production batch manufacture. NOTE: Fill Weight Range verification is performed on each strength for multi-strength presentations e.g. Table 1 Table 2

-

000 mg / g 000 mg / g etc.

4


Sect:12. 23

Topical SEMISOLID


ANDA DEVELOPMENT

SECTION XII

SECTION 12


FILL WEIGHT RANGE VERIFICATION Product: [Generic name] SEMISOLID [USP] [000] mg /g - Batch No: 000 Table 1 SAMPLE

NO.

LOW SPEED Fill Weight (g)

Uniformity of Content (check 3:20)

Machine Type 1 2 3 4 5 6 7 8 9 10 11 12 13 14 14 16 17 18 19 20

00.000 00.000 00.000 00.000 00.000 00.000 00.000 00.000 00.000 00.000 00.000 00.000 00.000 00.000 00.000 00.000 00.000 00.000 00.000 00.000

HIGH SPEED Fill Weight (g)

Machine No: 00.000 00.000 00.000 -

00.000 00.000 00.000 00.000 00.000 00.000 00.000 00.000 00.000 00.000 00.000 00.000 00.000 00.000 00.000 00.000 00.000 00.000 00.000 00.000

Uniformity of Content (check 3:20) Lot No 00.000 00.000 00.000 -

TARGET SPEED Fill Weight (g)

Uniformity of Content (check 3:20)

Date 00.000 00.000 00.000 00.000 00.000 00.000 00.000 00.000 00.000 00.000 00.000 00.000 00.000 00.000 00.000 00.000 00.000 00.000 00.000 00.000

00.000 00.000 00.000

AVG. RSD % USL LSL


Sect:12. 24

Topical SEMISOLID


ANDA DEVELOPMENT

SECTION XII

SECTION 12


PACKAGING TRAIL PACKAGING AND DISBURSEMENTS

Product: [Generic name] SEMISOLID [000]mg /g - Batch No: 000 The disposition and distribution of the [000] mg strength are shown as actual numerical example. The packaging trail should show the packed units used in the pivotal lot for:•

Quality Control Testing (Physical, Chemical & Microbial) • •

QA Reserve Samples for Annual Evaluation •

•

Stability testing

Topical Bioequivalency testing

Topical Bioequivalency Retention Samples.

Bulk Material: [150] Kg packed in : [Two] bulk containers x 75 Kg Packaging date: Month DD, 1999

[75 Kg] bulk containers

[75 Kg] bulk containers

Release Bio & Stability Testing

Release Bio & Stability Testing

Month DD, 1999

Month DD, 1999

(US)

(EU)


Sect:12. 25

Topical SEMISOLID


SECTION

ANDA DEVELOPMENT

XII

SECTION 12

Pivotal Manufacturing and Controls Product: [Generic name] SEMISOLID [000]mg /g - Batch No: 000

000g HDPE Container (Jar) with Screw cap [00 mm] 300 units x 100 g Packaging date: Month DD, 1999

Nov.28, 1996

5 unit

15 units

280 units



Balance stored in

Month DD, 1999

Month DD, 1999

Pivotal Warehouse

000g HDPE CONTAINER (Jar) with Screw cap [00 mm]

198 units x 500 g Packaging date: Month DD, 1999

5 unit

25 units

168 units



Balance stored in

Month DD, 1999

Month DD, 1999

Pivotal Warehouse


Sect:12. 26

Topical SEMISOLID


ANDA DEVELOPMENT

SECTION XII

SECTION 12

Pivotal Manufacturing and Controls PACKAGING AND DISBURSEMENT Product: [Generic name] SEMISOLID [USP] [000]mg /g - Batch No: 000


Nov.28, 1996

55 units x 60 g Release & Stability Testing

5 units x 60 g QC Testing

Month DD, 1999

Month DD, 1999

80 units 60 g Balance stored in

BIOSTUDY

Pivotal Warehouse 60 units 60 g Biostudy (European Market)

Month DD, 1999


Nov.28, 1996

10 units x 30 g

25 units x 30 g



Month DD, 1999

Month DD, 1999

200 units x 30 g

BIOSTUDY

Balance stored in Pivotal Warehouse

65 units x 30 g Biostudy & Retained Samples

Month DD, 1999

Topical Biostudy Disbursements (See Semisolid Trail) Section 6


Sect:12. 27

Topical SEMISOLID


ANDA DEVELOPMENT

NOTES


Sect:12. 28

Topical SEMISOLID


ANDA DEVELOPMENT

SECTION XIII

SECTION 13

Packaging and Labeling Procedures


This Section contains information on the container-closure systems, including type III DMF authorization letters from the component manufacturers, as well as the applicant's component specifications and component test data.

The

container closure system for the drug product are described in detail in the specifications and drawings included in this section. 13.1

Outlines for Packaging and Labeling Procedures

13.2

Blank Packaging Forms and Packaging reconciliation . A relatively standardized ANDA section that emphasizes the intended commercial production packaging procedures and reconciliation controls in force.

The limit for unexplained loss of 20 per 1000 i.e. 2% of the amount received is a common upper limit industry standard. Unexplained material losses of 0.5 - 1% are generally target levels.

NOTE: STANDARD OPERATION PROCEDURES - OUTLINES.

Actual

Standard Operation Procedures should not generally be included in an ANDA submission. For various reasons new editions or amendments to SOPs are continually being development or new SOP procedure are introduced from time to time.

The

period between submission and pre-approval inspection or first commercial production 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 Controls 1. Summary of packaging system 2. Components specification and test data (Type III DMF references) 3. Packaging configuration and sizes 4. Container/closure testing (include ingress testing in Section XXII, as appropriate for sterile processes only) 5. Vendor qualification specifications 6. Applicants acceptance criteria 7. Retest schedule


Sect: 13.1

ANDA DEVELOPMENT


SECTION XIII

ANDA DEVELOPMENT

SECTION 13

Packaging and Labeling Procedures OUTLINE OF STANDARD OPERATING PROCEDURES FOR: PACKAGING AND LABELING PROCEDURES Applicants Acceptance Criteria The Acceptance criteria for new packaging

components are detailed in the firms appropriate SOPs required according to cGMP (21 CFR 211). Actual acceptance activities 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 work station and equipment cleanliness. The packaging station must be free of all previous leftover work materials and the packaging line must be completely clear. 2. The product and packaging materials are identified according to the Standard Packaging Sheets printed with the required packaging specifications. 3. In-Process Control of the packaging procedure is carried out at the start of packaging procedure, and then at approximately every hour during the packaging process. When packaging machines are temporary stopped, the work station is re-inspected and full In-Process Control checks are carried out prior to restarting the cleared line. 4. At the end of packaging procedure, a material balance and a packaging reconciliation is performed on the packed product and the unused printed packaging 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 an unexplained loss. The limit for the unexplained loss may not exceed 2% of the amount received. 6. A Packaging Department supervisor / representative and a QA representative checks and approves that the entire packaging procedure was performed according to required specifications, and signs the Packaging Work Sheet. NOTE: BLANK PACKAGING FORMS Examples of Blank Packaging Forms are not given in this example. The critical checks to proper packaging control forms are; • Identify and quantify - all incoming printed packaging material (including primary and secondary packaging materials) • Identify and quantify - all incoming containers, closures and containers inserts (including applicators, special nozzles etc.) • Perform a material balance check on all Packed Goods and a Packaging Reconciliation on all printed materials and containers.


Sect: 13.2

ANDA DEVELOPMENT


ANDA DEVELOPMENT

SECTION XIII

SECTION 13

Packaging and Labeling Procedures Packaging Material Balance and Reconciliation Product & Strength: _______________________ Packaging Size

Batch No:

________________

1. PACKAGING SUMMARY Date

Package Material Description

Total Packages Received

Total Units Packaged

Total Units Rejected

Total Units Sampled

Non packaged Quarantine Units

Initial

2. PACKAGING Reconciliation 2.1

TOTAL Units

Department Material Balance:

packed 2.2

2.3

TOTAL Packs

100 x [Total no. of units] = _______%

rejected

Theoretical no. of units

TOTAL Packs

Compare to last production stage

sampled

(≤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 Theoretical no. of units Signature:

=

%

_______________________ Quality Assurance Unit


Sect: 13.3

(Limits: 95.0% - 103.0%) Date: _______________

ANDA DEVELOPMENT


ANDA DEVELOPMENT

TABLE OF CONTENTS (Overall ANDA Guideline Requirements for this Section). Glass Thermoplastic Containers Solid oral dosage forms.

Vendor qualification Specifications Appropriate documentation from the packaging component manufacturer as highlighted below is obtained for each component according to in-house SOPs, including but not limited to, DMF reference authorization letters, cGMP compliance certifications, manufacturers specifications and test results. Furthermore samples of all materials with corresponding manufacturers Certificate of Analysis are evaluated for QC and functionality testing as well as any compatibility testing with the intended product.

FROM THE GENERIC FIRM'S QC LAB 1. 2. 3. 4. 5.

General description (summary) of Container-closure-liner-seal-cotton system used for each dosage strength Description of Packaging Components of pack sizes used for each strength Testing Specifications or protocol and test results (CoA) of Generic packaging Lab. CoAs of Containers from the QC Packaging Lab. Batch Compliance Statement of applicants acceptance tests

FROM THE CONTAINER MANUFACTURER:6

7 8

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) Brief description of manufacturing process (as appropriate) Letters of Authorization - (LoA) 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 10

LoA from resin manufacturer referencing their resin DMF # as used in the manufacture of the container Obtain separate letters for each resin type used in different plastic containers


Sect: 13.4

ANDA DEVELOPMENT


SECTION XIII

ANDA DEVELOPMENT

SECTION 13

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

Metal Caps or Thermoplastic Closures Solid oral dosage forms.

FROM THE GENERIC FIRM'S QC LAB:11 12 13

Testing Specifications or protocol and test results (CoA) of Generic packaging Lab CoA of closures from the QC Packaging Lab Batch Compliance Statement of applicants acceptance tests

FROM THE CLOSURE MANUFACTURERS :14 15 16 17 18 19 20 21

Closure Specifications (including) - drawings / diagrams with annotated dimensions - Tests performed on closure system to include USP <661> and <671> 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 closure only) Letters of Authorization i. LoA from manufacturer referencing their facility DMF #. 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 23

i. LoA from (cap) resin manufacturer referring thermoplastic resin DMF # and Statement of GMP compliance of manufacturer Obtain separate letters for each resin type used in thermoplastic closures

Note: Child Resistant Closures (CRCs) may consists of two parts made with different HDPP/HDPE resins. Both inner (HDPP) and outer part (HDPE) resins need to be treated separately in the documentation requirements.


Sect: 13.5

ANDA DEVELOPMENT


SECTION XIII

ANDA DEVELOPMENT

SECTION 13

Packaging Components Description


Inner closure liner Solid oral dosage forms.


Testing Specifications or protocol and test results (CoA) of Generic packaging Lab CoA of liner from the QC Packaging Lab Batch Compliance Statement of applicants acceptance tests

FROM THE LINER MANUFACTURER:27 28 29 30 31

Liner Specifications (including); - drawings / diagrams with annotated dimensions - Tests performed on liner - Certificate of Conformance meeting all current USP requirements and complies to 21 CFR requirements - Certificate of Analysis

LETTERS OF AUTHORIZATION:32 33

i. LoA from manufacturer referencing their facility DMF #. ii. LoA from liner manufacturer referencing DMF # of liner

STATEMENTS OF COMPLIANCE 34 35

Statement of GMP compliance of liner manufacturer 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 existing compendial interchangeability protocol for equivalent HDPE resins.


Sect: 13.6

ANDA DEVELOPMENT


SECTION XIII

ANDA DEVELOPMENT

SECTION 13



Foam Seals Pressure sensitive, tamper resistant, adhesive seals (data required for each container seal) Solid oral dosage forms.


Testing Specifications or protocol and test results (CoA) of Generic packaging Lab. CoA of adhesive seal from the QC Packaging Lab. Batch Compliance Statement of applicants acceptance tests

FROM THE ADHESIVE SEAL MANUFACTURERS :39 40 41 42 43

Adhesive seal Specifications (including) - Drawings / diagrams with annotated dimensions - Tests performed on adhesive seal - Complies to 21 CFR requirements - Certificate of Analysis

LETTERS OF AUTHORIZATION - (LOA) 44 45

LoA from seal manufacturer referencing their facility DMF #. LoA from manufacturer referencing their seal DMF #.

STATEMENTS OF COMPLIANCE 46 47

Statement of GMP compliance of seal manufacturer 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


Sect: 13.7

ANDA DEVELOPMENT


ANDA DEVELOPMENT

SECTION XIII

SECTION 13

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

Nozzles / Applicators (required for Applicator/Nozzle ) Topical Dosage Forms.

FROM THE GENERIC FIRM: 48 49 50

Testing Specifications or protocol and test results (CoA) of Generic packaging Lab. CoA from the QC Packaging Lab Batch Compliance Statement of applicants acceptance tests

FROM THE APPLICATOR MANUFACTURERS :51 52 53 54 55

Applicator/Nozzle Specifications (including) - Tests performed on Applicator/Nozzle - Compliance to USP requirements - Complies to 21 CFR requirements - Certificate of Analysis (include resin ID)

LETTERS OF AUTHORIZATION - (LOA) 56 57 58

LoA from Applicator/Nozzle manufacturer referencing their facility DMF #. LoA from manufacturer referencing their Applicator/Nozzle DMF #. STATEMENTS OF COMPLIANCE Applicator/Nozzle manufacturer's: Statement of GMP Compliance Statements of Compliance with Applicable Sections of the Indirect Food Additive Regulations (21 CFR).


Sect: 13.8

ANDA DEVELOPMENT


ANDA DEVELOPMENT

SECTION XIII

SECTION 13


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

This Section Contains: ◊

Package Characteristics for container-liner-closure systems

◊

Package Description concerning container-liner-closure systems

◊

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

Ü

Certificates of Analysis outlining the components used for packages containing;

Ü

00 / 000 cc Flexible Tube

(HDPE nozzle)

Ü

00 / 000 cc HDPE (Bulk) Jar

(HDPE cap with liner).

Ü

Technical Specifications (Diagrams &Drawings) of each component.

Ü

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

Ü

DMF Referral Letters

◊ Statements of Compliance with applicable sections of the Indirect Food Additive Regulations (21 CFR).

◊ USP XXIII Testing Results of the closure system.

4


Sect: 13.9

ANDA DEVELOPMENT


ANDA DEVELOPMENT

SECTION XIII

SECTION 13

Packaging Components Description PACKAGE CHARACTERISTICS Lot: 000

[Generic name] SEMISOLID [USP] [000.0] mg /g.

Pivotal Lot ITEM

TYPE 1

TYPE 2

TYPE 3

TYPE 4

Container manufacturer Container size

Drug Plastics & Glass Co. Inc.




00 / 000cc round, HDPE JAR


00 / 000cc HDPE/

00 / 000cc HDPE/

COLLAPSIBLE TUBE

COLLAPSIBLE TUBE

(coated metal)

(coated metal)

Resin Type Cap Manufacturer 11087 PE White Master batch Cap / Nozzle Type Cap Size Closure Liner Foam seal Mfg Inner liner composition CONTAINER CONTAINER CAP Nozzle / Applicator LINER SEAL

HDPE Quantum LR-734043 U.S. CAN (Penn-Wheeling Closure Corp.) White Ampacet 11078 Polyethylene




HDPE LDPE

HDPE LDPE

HDPE LDPE

HDPE LDPE

00 / 00 mm

00 / 00 mm

00 / 00 mm

00 / 00 mm

Tekni-Plex Inc. Foamseal PS 22


-

-

TEKNISEAL RVT + LF

TEKNISEAL X-14 (polyethylene/Kraft Paper laminate) Lot #00000 CoA #0000 Lot #00000 CoA #0000 Lot #00000 CoA #0000 Lot #00000 CoA #0000 Lot #00000 CoA #0000 Lot #00000

-

-

Lot #00000 CoA #0000 Lot #00000 CoA #0000 Lot #00000 CoA #0000 Lot #00000 CoA #0000 -


CoA #00000

CoA #00000

Lot #00000 CoA #0000 Lot #00000 CoA #0000 Lot #00000 CoA #0000 Lot #00000 CoA #0000 Lot #00000 CoA #0000 Lot #00000

CoA = Certificate of Analysis/Compliance


Sect: 13.10

ANDA DEVELOPMENT


SECTION XIII

ANDA DEVELOPMENT

SECTION 13

Packaging Components Description PACKAGING COMPONENT DESCRIPTION FOR THERMOPLASTIC CONTAINERS CONTAINING: All container and closure systems are certified to comply with the indirect food additive regulations (Parts 170-199) or are otherwise certified safe for use in contact with a drug product - generally accepted as safe (Appear in the 21 CFR GRAS List) 30 and 60 & 1000 Units

HDPE: Description

White, Round HDPE Bottle with 29/33/53 mm/400 Neck Finish

CODE & Size

Code 000

Manufacturer

Drug Plastics & Glass Company, Inc., DMF # 1933

Resin used

QUANTUM

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 as per table 14-A are performed by either the vendor or applicant and supported in the documentation attached.

Stability Testing

Where product stability testing is conducted referencing this specific item's code then all above specifications shall apply to the container-closure item.

-

Size: 30, 50, 750 cc

DMF # 885


Sect: 13.11

ANDA DEVELOPMENT


SECTION XIII

ANDA DEVELOPMENT

SECTION 13

Packaging Components Description PACKAGING COMPONENT DESCRIPTION FOR CLOSURES OF CONTAINERS CONTAINING: BULK Units

CLOSURES Description

HDPE cap, 38 mm / 400 White, Unlined Polypropylene Cap with Pressure Sensitive Inner Seal

CODE & Size

Code 000

Fits Container Size

000 & 000 cc

Manufacturer

Owens Brockway

Inner Liner

None

Foam Seal

-

29/33 mm diameter

Foamseal PS 22 - Pressure Sensitive, adhesive

DMF (MFG)

DMF [0000]

DMF (Item)

DMF DMF # 2229

LoA

Month DD, YYYY

21 CFR


Documentation




Stability Testing



Sect: 13.12

ANDA DEVELOPMENT


SECTION XIII

ANDA DEVELOPMENT

SECTION 13

Packaging Components Description PACKAGING COMPONENT DESCRIPTION FOR CLOSURES OF CONTAINERS CONTAINING: Bulk Containers

METAL SCREW CAP Description

38/53 mm 400 White, Tin Plated Metal Screw Cap with Pressure Sensitive Inner Seal

CODE & Size

Code 000

Fits Container Size

000 & 000 mL

Manufacturer:

U.S. CAN [Full address]

DMF (MFG)

DMF #4162

DMF (Item)

DMF #4162

LoA

Month DD, YYYY

21 CFR


Documentation




Stability Testing


-

Size: [38/53] mm diameter

4


Sect: 13.13

ANDA DEVELOPMENT


SECTION XIII

ANDA DEVELOPMENT

SECTION 13

Packaging Components Description PACKAGING COMPONENT DESCRIPTION FOR CLOSURES OF CONTAINERS CONTAINING: Bulk Containers

INNER CAP LINER Inner Liner

Tekniseal X-14(Polyethylene)

CODE & Size

Code 000

Manufacturer

Tekni-Plex Inc.

DMF (MFG)

DMF # 1378

DMF (Item)

DMF # 1378

LoA

Month DD, YYYY

21 CFR


-

Size: [00] mm diameter

CONTAINER FOAM SEAL Foam 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

21 CFR





Sect: 13.14

ANDA DEVELOPMENT


SECTION XIII

ANDA DEVELOPMENT

SECTION 13

Packaging Components Description PACKAGING COMPONENT DESCRIPTION FOR CLOSURES OF CONTAINERS CONTAINING:

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

Collapsible Tubes Description

:

[000] cc lined collapsible LD Tube with HDPE nozzle

Inner Coating

:

Epoxy Coat [0.0] mm thick

Length

:

[00] mm

Size

:

000 & 000 g

Manufacturer

:

[Name].

Seal

:

Heat sealed or breaking inner seal

DMF of MNF

:

DMF [0000]

Product DMF

:

DMF [0000]

LoA

:

Month DD, YY

Extended Nozzle Description:

:

[000] White, HDPE Nozzle

Size

:

[00] mm (length)

Fits Sizes

:

000 & 000 mL

Manufacturer:

:

[Name]

DMF of MNF

:

DMF [0000]

Product DMF

:

DMF [0000]


Sect: 13.15

ANDA DEVELOPMENT


ANDA DEVELOPMENT

SECTION XIII

SECTION 13

Packaging Components Description U.S. Pharmacopoeia / National Formulary General Tests and Assays - Table 1 SUBTITLE General Tests and Assays

Ref. No

USP

TITLE

1.

<1>

Injections

2.

<87>

In vitro

Biological Reactivity Tests

3.

<88>

In vivo

Biological Reactivity Tests

4.

<161>

Transfusion

5.

<381>

Transfusion and Infusion Assemblies

Elastomeric closures for injections

6.

n

Biological Test Procedures

7.

n

Physiochemical Test Procedures

8.

<601>

Aerosols

9.

<661>

Containers

10.

n

Light transmission

11.

n

Chemical resistance - Glass Containers

12.

n

Biological Tests - Plastic and others

13.

n

Polymer

14.

n

Physiochemical Test - Plastics

15.

n

Polyethylene Containers

16.

n

Polyethylene Terephthalate / Terephthalate G Bottles

17.

n

Single Unit Containers & Unit Dose (Containers for Non-sterile solid & liquids dosage forms )

18.

n

Customized Patient Medication Packages

19.

<671>

20.

Containers

Permeation - n Multiple unit containers for capsules and tablets

n

Permeation - n Single unit containers and Unit dose for capsules and tablets

21.

<691>

Cotton

22.

<771>

Ophthalmic

23.

<1151>

Cotton or Purified Rayon Monograph (with exclusions) Ointments

Pharmaceutical Dosage Forms


Sect: 13.16

ANDA DEVELOPMENT


ANDA DEVELOPMENT

Above - Table 1 contains all USP testing procedures described in the pharmacopoeia that impact on aspects of container closure systems. All components comply with the appropriate tests.


Sect: 13.17

ANDA DEVELOPMENT


SECTION XIV

ANDA DEVELOPMENT

SECTION 14

Finished Dosage Form Controls


14.1

Section Page and Title State if drug product is: q Compendial and test methods¡ used are USP XXIII q Non-Compendial and test methods¡ are validated in-house methods. q Non-Compendial and test methods¡ based on published analytical methods² and validated.

14.2

Certificate of Analysis of Pivotal Batch(es), including:q HPLC, TLC, GC, UV chromatograms and spectra for all pivotal strengths q CoA for each strength of SEMISOLID [USP] + HPLC chromatograms

¡

Stability Indicating Assay Impurity Limit Tests USP Monograph tests

²

USPC Inc. Pharmacopeial Forum Published Reference Works


Sect: 14.1

Topical SEMISOLID


SECTION XIV

ANDA DEVELOPMENT

SECTION 14

Finished Dosage Form Controls This section contains: THE DRUG PRODUCT IS NON-COMPENDIAL. Certificates of Analysis for the finished drug product [Generic name] SEMISOLID [000.0] mg/g (all strengths). Copies of the test methods and method validations are enclosed in Sections XVI, for “Analytical Methods”. These methods are used for release and stability purposes, assuring identity, strength, quality and purity of the finished drug product. Note: Additionally, separately bound copies of all non-compendial methods have been provided in accordance with 21 CFR 314.50(e)(2)(i). or THE DRUG PRODUCT IS COMPENDIAL. Certificates of Analysis for the finished drug product [Generic name] SEMISOLID [000.0] mg/g (all strengths). The drug product is compendial. Copies of the stability indicating test methods and method validations are enclosed in Sections XVI, under “Analytical Methods”. Compendial methods are used for release, assuring identity, strength, quality and purity of the finished drug product on batch release. Stability indicating test methods are used for stability, assuring identity, strength, and purity of the finished drug product during the entire shelf life period of the drug.

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


Sect: 14.2

Topical SEMISOLID


SECTION XIV

ANDA DEVELOPMENT

SECTION 14

Finished Dosage Form Controls SUMMARY OF CERTIFICATE OF ANALYSES

AND ANALYTICAL SPECTRA : Pivotal Batch

Executed Lot Pivotal Lot No: [000-01]

C of A No.

[000.0] mg per g

GC Pivotal Lot No: [000-01]

SPECTRA [000.0] mg per g

UV Pivotal Lot No: [000-01]

C 000-01

C 000-01

SPECTRA [000.0] mg per g

HPLC

C 000-01

SPECTRA

Pivotal Lot No: [000-01]

[000.0] mg per g

C 000-01

TLC Pivotal Lot No: [000-01]

[000.0] mg per g

C 000-01

(Labeled Photocopies of TLC plates provided)

NOTE: Attach summary and spectra for each of the pivotal lots and strengths manufactured. Above table represents one pivotal lot of each dosage strength.


Sect: 14.3

Topical SEMISOLID


ANDA DEVELOPMENT

SECTION XIV

SECTION 14

Finished Dosage Form Controls SUMMARY OF ANALYTICAL METHODS AND METHOD NUMBERS: Table details the analytical Control Methods used :

Analytical Method

Active Ingredient

Stability PURPOSES

QC Release PURPOSES

Method Validation

Not Applicable

QC-021-00

SI -V -021-00

Finished Product Physical TESTS

SI-A22-00

Finished Product Assay / Impurities

SI-A23-00

Finished Product Microbial testing

SI-D24-00

QC-025-00

SI -V -A23-00 SI -V -D24-00

-

-

KEY QC = A Quality Control Method that has been validated and based on the R&D validated method. SI = A Stability Indicating Method that has been fully validated A = An Assay Method V = The full validation procedure and test results of a corresponding stability indicting method (Note: the same method number is used) 00 = The last two zeros (-00) indicated the editions number of the procedure - i.e. edition number three is written as '-03.' Test methods for release and for stability purposes. The R&D analytical methods are used for product stability purposes. The QC. testing methods which are based on the R&D methods are used for the release 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.


Sect: 14.4

Topical SEMISOLID


ANDA DEVELOPMENT

SECTION XV

SECTION 15

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

Included

in his section are the analytical methods, method validations and test specifications and data for the drug substance [Generic name] and the drug product [Generic name] tablets [000]mg manufactured by the applicant. The methodology includes validated stability indicating analytical assay methods

State if drug substance and drug product is: q q q

- Compendial and test methods used are USP XXIV - Non-Compendial and test methods in-house and validated. - US Non-Compendial test methods based on published reference works and validated (e.g. Ph Eur / BP / Japan Pharm / DAB.) Active material 15.1 Active Ingredient Test Method (QC Release method) 15.2 Active Ingredient Test Method Validation (Stability Check method) In-process Material 15.3 Final Blend Test Methods Finished Product 15.4 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.

FDA's Published January 1999 ANDA Guideline Requirements: (actual excerpt as published in agency guideline)

Section XV. Analytical Methods (two additional separately bound copies if the drug substance and/or drug product are not USP articles) 1. Methods for drug substance a. Method validation b. Test specifications and data (derived from bioequivalent batch lot) 2. Methods for drug product a. Method validation b. Test specifications and data (derived from bioequivalent batch lot) Edition Number: 01 Ed. Status : New



24 VOLUME DRUG DEVELOPMENT SERIES:

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Sect: 15.1

_________/________ QC / QA

ANDA Development


ANDA DEVELOPMENT

SECTION XV

SECTION 15

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 US Pharmacopoeia. The active material is of compendial status in the BP and Ph. Eur. ý - US Pharmacopoeia ý - US Pharmacopoeial Forum þ - BP Pharmacopoeia þ - Ph. Eur. Pharmacopoeia þ - In-house Stability Indicting methods (based on BP Pharmacopoeia)

Drug Product analytical methods and stability indicating methodology are in-house based on the current BP ; Ph. Eur. or US Pharmacopoeial Forum and have been fully validated in-house. ý - US Pharmacopoeia ý - US Pharmacopoeial Forum þ - BP Pharmacopoeia þ - Ph. Eur. Pharmacopoeia þ - 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


•

Finished Product Test Methods (Release)


•

Finished Product Test Methods (Stability)

•

⇒

Assay/Impurities

⇒

Degradation Products Determination

⇒

Dissolution Test

⇒

Test of Appearance

Finished Product Analytical Method Validation



Note: Additional separately bound copies are provided in accordance with 21 CFR 314.50(e)(2)(i).

Edition Number: 01 Ed. Status : New




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ANDA Development


ANDA DEVELOPMENT

SECTION XV

SECTION 15

Analytical Methods SUMMARY OF ANALYTICAL METHODS AND METHOD NUMBERS:

Analytical Method

Method No.

Active Material Stability Indicating Assay

SI-1000-01

Impurity Limit tests

SI-1000-01

Validation of Stability Indicating Assay

SI-1000-01

In-process Material Content Uniformity (on bulk material)

SI-2000-01

Microbial Limit test (on bulk material)

Finished Product Release

SI-4000-01

QC Release Assay

SI-4000-01


SI-4000-01

Content Uniformity (on bulk material)

SI-4000-01

Microbial Limit test (on bulk material)

Finished Product Stability Methods Stability Indicating Assay

SI-5000-01


SI-5000-01

Validation of Stability Indicating Assay

SI-5000-01

Microbial Limit test

SI-5000-01

Preservative Efficacy test

SI-5000-01

(All Analytical Methods Placed Here) Edition Number: 01 Ed. Status : New




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ANDA Development


ANDA DEVELOPMENT

SECTION XV

SECTION 15

Analytical Methods (TYPICAL ANALYTICAL METHOD VALIDATION) 1. PURPOSE The purpose of this Standard Analytical Procedure is to demonstrate the procedure required to validate in-house HPLC analytical methods and to show that the methods are stability-indicating. Methods based on the USP but modified for stability indicating test purposes require full in-house validation. This procedure ensures that the Product Development Process and Process Qualification Batch analysis is based on a foundation of Good Laboratory Practice using validated test procedures. 2. RESPONSIBILITY The Head of Analytical Development in coordination with the managers of QC and Regulatory Affairs at the proposed manufacturing site. 3. FREQUENCY For 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 validation procedure. 4. PROCEDURE [a]. Method Validation Non-compendial methods validation will follow the USP direction for parameters needed for the validation of test methods. Typical parameters for validating assays and other non-compendial analytical methods 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.





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ANDA DEVELOPMENT

[c]. The stability of the Standard solution is assessed by re-injection of the standard solution after 24 x n hours (where n = number of days the Standard will be used). Standard Preparation for Assay Comparison of standard solutions for Assay of Active material, injected after one month and freshly prepared demonstrate that the standard solutions are stable and does not lose its quality after one month if refrigerated. Standard Preparation for Impurity Comparison of standard solutions of Guanine, injected after one month and freshly prepared demonstrate that the standard solutions are stable and does not lose its quality after 1 month if refrigerated. Name of standards

Storage conditions

Difference. relative to freshly prepared standard

[Active] 100%

4°C

<2%

[Impurity] 100%

4°C

<2%

Standard Solutions are stored at controlled temperatures and light conditions as per labeling. [d]. Stability Indicating Procedures. For the Stability Indicating Method, the product sample shall include forced degradation by stressed analysis. Conditions of concentration and reaction time may vary depending on the active drug substance and drug product e.g. : • • • • •

Oxidation Base Hydrolysis Acid Hydrolysis Sun light Heat

-

(H2O2 plus standing time). (NaOH x N plus standing time). (HCl conc. plus standing time). (24 hours standing time). (x degrees C).

Summary of Stability Indicating Results Stressed Conditions

Solution heating

Temp.

Time

(°°C)

(hr)

Raw Material; Remaining Substance. (%)

Tablets Remaining Substance

Peak Purity, (Figure)

(%)

Peak Purity, (Figure)

90

12

100.2

pure

98

pure

160

2

101.3

pure

92

pure

Sunlight 765 w/m

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

Solid heating 2





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_________/________ QC / QA

ANDA Development


ANDA DEVELOPMENT

[e]Specificity and Suitability (Resolution and Tailing Factors). When a satisfactory separations of all the degradation peaks have been achieved through the forced degradation reactions, a Resolution Factor (according to the USP requirements) between the main active peak and the nearest degradant peak is calculated using the USP formula. A Tailing Factor (according to the USP formula) is calculated for the main active peak. [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 Method SI-1000 was prepared and injected into the HPLC system. For chromatogram obtained the following values were calculated (according to USP): 1. Relative Retention Time for [Impurity] peak RRT = RT [Impurity] RT [Active]

=

2.65 = 0.31 8.45

2. Tailing factor for [Active] peak Tf =

W0.05 9 = = 1.1 2f 4.2

The values depict the specificity of the method for resolution between the main peak and impurity peak. (values shown for demonstrations purposes).

Peak Purity The photo diode-array is used for the evaluation of the stability indicating nature of the assay method number SI-1000 for [000]mg and [000]mg tablets using a Waters 996™ 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. the weighed average of all Spectral Contrast Angles calculated by comparing all spectra in the integrated peak against the peak apex spectrum. Purity Threshold is the sum of Noise Angle and Solvent Angle. It is the limit of detection of shape differences between two spectra. Match Angle is a comparison of the spectrum at the peak apex against a library spectrum. 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.





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ANDA Development


Peak Purity

ANDA DEVELOPMENT

(Cont.)

Solvent Angle is a measure of spectral non-homogeneity caused by solvent composition. It the purity angle is smaller than the purity threshold and the match angle is smaller than the match threshold, this indicates that no significant differences between spectra are detected. There is no spectroscopic evidence for co-elution and the peak is considered pure.

[f] Relative Retention Time of Main and Additional peaks. Each stressed analysis shall indicate the percentage by which the Main peak is decreased as well as the RRT for any other Additional peaks. If the RRT of an Additional peak corresponds to a known degradant/impurity etc. it shall be stated. The peak purity of the main peak shall be given for each stressed analysis (where possible).

[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 of analyte in a sample which can be detested but not necessary quantitated as an exact value. Quantitation Limit (QL) The Quantitation limit of an individual analytical procedure is the lowest amount of analyte in a sample which can be quantitatively determined with suitable precision and accuracy. Used in the determination of impurities and or degradation products. [h]. Contents of a typical HPLC Analytical Validation Protocol refer Method No. A-0340-01-1299





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ANDA Development


ANDA DEVELOPMENT

Validation of HPLC Analytical Method Method 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 - Precision Ten replicate (single) injections of the standard solution at the nominal concentration described in the method is performed and the RSD calculated. The Results (sample # and peak areas) are tabulated. The Average Peak Area, SD and RSD 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 Area Standard Deviation Relative Standard Deviation



= = =

0.5 - 1.0



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ANDA Development


ANDA DEVELOPMENT

[3] Method Reproducibility - Precision The full analytical method # is carried out and repeated Ten times on the finished product (batch #) and the RSD is calculated. Two HPLC injections are performed per method assay and the peak areas are averaged. The Results (assay %) are tabulated. The Average Assay %, SD and RSD are calculated and shown in the tabulations. Target values for RSD = 1.5 to 3.0.

METHOD REPRODUCIBILITY SAMPLE No

ASSAY %

Batch No: 1 2 3 4 5 6 7 8 9 10

Average Assay % Standard Deviation Relative Standard Deviation.

= = = 1.5 - 3.0

[4] Accuracy The Accuracy of an analytical procedure expresses the closeness of agreement between the true value and the value found. Ten replicate (single) injections of the standard solution at the nominal concentration of x mg/100 mL as described in the Analytical Method / Ed # [00] is made and the percent deviation from the true values as determined from the linear regression line is calculated. The Results (Peak areas and % accuracy) are tabulated. The Mean, SD and C.of.V are shown in the tabulations





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ANDA Development


ANDA DEVELOPMENT

[4] Accuracy (continued).

ACCURACY INJECTION No

PEAK AREA

CALCULATED CONC.

% ACCURACY

1 2 3 4 5 6 7 8 9 10

Mean (% Accuracy) = Standard Deviation = % Coef. of Variation =

[5] Recovery

(Extraction time)

The extraction efficiency is demonstrated by varying the extraction time of prepared sample solutions as described in the analytical method #. Two HPLC injections are performed per method assay and the peak areas are averaged. The extraction time suitable 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).





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Sect: 15.10

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ANDA Development


[5] Recovery

ANDA DEVELOPMENT

(Extraction time - tabulations continued).

The Results (Extraction time and Assay %) are tabulated as shown.

RECOVERY - EXTRACTION TIME IN MINUTES Batch No:

% ASSAY

0.5 T T 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 the assay procedure is prepared and analyzed to show the percentage active recovery. Two HPLC injections are performed per method assay and the peak areas are averaged. The Results (Theoretical conc. Actual conc. and % recovery ) are tabulated. The Average Recovery, SD and the % Coefficient of Variation are given.





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ANDA Development


ANDA DEVELOPMENT

[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.

RECOVERY Standard solution mg/100mL Peak Area = CONC. Theoretical (mg/100ml)

PEAK AREA FOUND

CONC. FOUND (mg/100ml)

PERCENTAGE RECOVERY

50 75 100 125 150

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 of Additional Peaks

[7] Linearity and range.

The linearity on an analytical procedure is its ability (within a given range) to obtain test results which are directly proportional to the concentration (amount) of the analyte in the test sample.

Five Standard solutions in a concentration range of (about) 50 % to 150 % of the stated concentration required by the assay procedure are prepared and analyzed by the stated method. Two HPLC injections are performed per method assay and the peak areas are averaged.





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ANDA DEVELOPMENT

[7] Linearity and range - (continued).

The Area count and concentration range is plotted. Linear regression analysis will demonstrate the acceptability of the method for quantitative analysis over the full spectrum of the concentration range. Detector linearity is demonstrated. The Results (Range conc. and peak areas ) are tabulated.

LINEARITY AND R A N G E CONC. Batch No:

PEAK AREAS

50 % 75 % 100 % 125 % 150 %

Linear Regression Y-Intercept Slope

= = =

The results are shown graphically (peak area Vs range conc. (mg/100 mL). GRAPH OF LINEARITY 120000 P e 100000 a 80000 k 60000 A 40000 r e 20000 a 0 0

25

50

75

100 125

150

Conc. mg/100mL





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ANDA DEVELOPMENT

[8] RUGGEDNESS & Robustness. Ruggedness measures the lack of external influence on the test results whereas robustness measures the lack of internal influences on the test results. The Robustness of an analytical procedure is a measure of its capacity to remain unaffected by small but deliberate variations in method parameters and thus providing 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.

Robustness Robustness determinations are essential when transferring analytical methods from the 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 critical parameters of the method such as column, flow rate and concentration of [organic acid] in the mobile phase. Using the System Suitability solution and LOQ solution as the 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) CONDITION Condition Column No.

Flow Rate mL/min

RESULTS Buffer Conc. (%)

RRT

Tf

RSD RSD bet. LOQ of bet. LOQ of [Active] [Impurity]

1 2 3 4

1 1 1 1

2.5 2.2 2.8 2.5

0.1 0.1 0.1 0.15

0.3 0.3 0.3 0.3

1.1 1.1 1.1 1.1

<10 <10 <10 <10

<10 <10 <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; with different equipment; or different analysts is known as - intermediate precision. REPRODUCIBILITY (INTRA-LAB) This intra-laboratory precision or the precision between laboratories is known as reproducibility or more specifically - intra-laboratory reproducibility. Both the above are ruggedness - and a USP requirement.





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ANDA DEVELOPMENT

[8] RUGGEDNESS & Robustness - (Tabulations - continued). The Results (Average assay % for Analyst 1 and 2 ) are tabulated.

RUGGEDNESS ANALYST No 1

% ASSAY Column I

ANALYST No 2

% ASSAY Column 2

1 2 3 4 5 6 7 8 9 10

Mean (% Accuracy) = Standard Deviation = % Coef of Variation =

Robustness. The evaluation of robustness should be finalized at the end of the development phase - around the time of the process qualification lot manufacture. The robustness evaluation should be developed with the commercial laboratory equipment in mind. It should show the reliability of an analysis with respect to deliberate variations in the method parameters A consequence of robustness evaluation is that a series of system suitability parameters are established to ensure that the validity of the analytical procedure is maintained whenever used. Robustness is defined by both the USP and the ICH Tripartite guidelines as "a measure of its capacity to remain unaffected by small but deliberate variations in method parameters and provides an indication of its reliability during normal use " Robustness is defined both in the USP and ICH, but is not required.





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ANDA DEVELOPMENT

[9] Stability of Standard solutions Re-chromatography of ten replicate single injections of the same standard solution (which have been allowed to stand for x hours ) against freshly prepared Standards showed no significant differences from the original results.

STABILITY OF STANDARD SOLUTIONS mg/100mL Initial Analysis (Date)

mg/100mL Repeat Analysis 2nd (Date)

1 injection 2 injection 3 injection 4 injection 5 injection 6 injection 7 injection 8 injection 9 injection 10 injection

1 injection 2 injection 3 injection 4 injection 5 injection 6 injection 7 injection 8 injection 9 injection 10 injection

Mean Standard Deviation Relative Standard Dev.

= = = NMT 2.0 %

[10] Typical Chromatograms. Representative chromatograms of the following traces are routinely provided:-

♦

System Suitability

♦

Standard Solution

♦

Drug Product

♦

placebo





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ANDA DEVELOPMENT

Typical Chromatograms When Representative Chromatograms are displayed - all peaks are LABELED with the peak name and RRT.

Representative chromatogram Drug Product

Label the peak clearly Name and Retention time (8.78 min)

[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 for carrying out assay analysis as part of the Assay and Stability Studies for the Drug Product conforming to the formula as shown in Appendix 1”

[12] References and Appendixes.

Acknowledgment

to references as well as attachments such as the drug product formula are attached at the end of the validation protocol.

It is important to emphasize that analytical

validation applies to a drug formula and a set manufacturing procedure. Extraneous peaks and processing stresses are specific to a manufacturing procedure, equipment used and the nature of the excipients.

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.





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_________/________ QC / QA

ANDA Development


ANDA DEVELOPMENT

NOTES





__________ R &D

_______________ RA

Sect: 15.18

_________/________ QC / QA

ANDA Development


ANDA DEVELOPMENT

SECTION XVI

SECTION 16

Stability of Finished Dosage Form

TABLE OF CONTENTS (Overall ANDA Guideline Requirements for this Section). 16.1

Section Page and Title.

16.2

Stability Protocol for Post Approval Production Batches (ANDA commitment)

16.3

Expiration Dating Period Statement

16.4

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

16.5

Stability Protocol used for Pivotal lot

16.6

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

16.7

Stability Data Summary Report (plus 0 and 12 week graphs).


Section XVI - Section 16. Stability of Finished Dosage Form 1. Protocol 2. Post-approval commitments 3. Expiration dating period 4. Stability data submitted 5. Stability-indicating test data of samples under various stress conditions

4


Sect: 16.1

ANDA Development


ANDA DEVELOPMENT

SECTION XVI

SECTION 16

Stability of Finished Dosage Form This stability section contains: ♦ Stability protocol for post-approval production batches ♦ Proposed expiration date and stability commitment - a signed commitment to conduct long term stability studies as described in our stability protocol (ref. page [00 - 00]) ♦ Summary of Stability summary - that addresses the details of our stability program for the finished project. This protocol includes container-closure system, storage conditions, methods and specifications , report format , batch size, dates of analysis and room temperature intervals. (ref. page [00 - 00]) ♦ Stability reports containing data from 3 month accelerated and 6 months controlled room temperature studies. (ref. page [00 - 00]) ♦ Package Characteristic of pivotal batch. (ref. page [00 - 00])

OVERVIEW

Stability testing is performed on the largest and smallest container-closure systems proposed for marketing; i.e. in each material type, namely plastic (HDPE/HDPP), glass, or push-through blister packs. When more than one closure for the same container material type (e.g. glass bottle) is used in the proposed marketing containers, the largest and smallest containerclosure configuration is tested, - for both accelerated and long term studies. In cases where plastic bottles of the same size range and shape are manufactured from different thermoplastic resins, they exhibition different storage characteristics and thus are considered as completely separate container-closure systems. The expiration dating process starts between 21 to 30 days from the completion of the manufacturing of the pivotal batch and release by quality control. This 21 to 30 day period is in keeping with the 1987 informal guidance document which stipulates that stability testing should initiate at the time of release which should not itself exceed 30 days from the date of manufacture.

The example below for the following packaging configuration highlights the number of stability tests needed. Tests may be reduced using a matrix stability protocol. 1. 2. 3.

HDPP (smallest) container with plastic HDPE cap / nozzle HDPP (smallest) container with plastic HDPE cap / nozzle HDPP (largest) container with plastic HDPE cap / nozzle

When tested on ONE strength with 4 container-closure configuration at accelerated and long term testing (2) will produce 8 separate stability protocols Calculation. (4 container/sizes x [1 Strength] x 1 closures x [25ÐC+40ÐC] = 8 studies).

4 24 VOLUME DRUG DEVELOPMENT SERIES:

Sect: 16.2

ANDA Development


ANDA DEVELOPMENT

SECTION XVI

SECTION 16

Stability of Finished Dosage Form Proposed Expiration Date and Stability Commitment

A

ll stability data support the proposed expiration period of 24 months when the product is stored at room temperatures. This conditional dating will be verified by 24 month room temperature studies which will be filed annual as the data becomes available, as per our commitment.

Stability commitment

Long

term commercial stability studied in accordance with the approved stability protocol shall be carried out by [Generic Company Name Inc./Ltd.] The stability results of these studies shall be submitted in the routine annual ANDA Reports filed on the anniversary date of the submitted product or as specified by the FDA. Extensions to the expiration date will be made via the annual ANDA Reports as acceptable long term stability data becomes available. The extension will be files in the annual reports in accordance with 21 CFR 314.70 (d)(5)

Stability

data will be submitted in the annual reports in accordance with 21 CFR 314.70 (d)(6) or in a prior approval supplement in accordance with 21 CFR 314.70 (b)(2), whichever is appropriate at the time of submission.

Rework

procedures may be submitted for batches that fail to meet established specifications. Prior to implementation, these procedures will be submitted in a supplement in accord with: 21 CFR 314.70 (b)(2)(x) on a lot by lot basis. [Generic Company Name Inc./Ltd.] commits to remove any batch promptly from the market place any material falling outside the products check specifications. BATCH ANALYSIS COMMITMENT Where future batch analysis of 3 consecutive finished product lots indicate that the specifications limits of the impurities/degradation products present in future commercial production need to be tightened then the stability specifications in the finished product stability protocols will be amended appropriately. The stability data of future batches will comply with the new specifications where appropriate.. [Signature of Responsible Person] ------------------------------------------------

-----------------------------------------


Date


4


Sect: 16.3

ANDA Development


ANDA DEVELOPMENT

SECTION XVI

SECTION 16

Stability of Finished Dosage Form Stability Protocol for Post-approval Production Batches [Generic name] SEMISOLID [USP] [000.0] mg per g.

[Batch No: 00]

FINISHED PRODUCT STABILITY PROTOCOL Package sizes: Smallest and largest containers Storage Conditions: Controlled Room Temperature: 25-30°C. Test Intervals: 0,3,6,9,12,18,24 and 36 months. Samples: First three marketable production batches and annual batch thereafter. Storage Conditions Accelerated 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. Test parameters will include: TEST PROCEDURE 1

Appearance

TEST METHOD & ED. NUMBER SI-5-000-01

2

pH

SI-5-000-01

NLT 0.0 NMT 0.0

3

Assay (Preservative) [Only where necessary] Assay Active material

SI-5-000-01

50.0 - 105.0% of labeled amount To (annually) and End of Study 90.0 - 110.0% of labeled amount

4

SPECIFICATION

SI-5-000-01

Conforms

IMPURITIES / DEGRADATION PRODUCTS

6

- Each Individual - Any other Individual - Total: Microbial Limit Test

SI-5-000-01 SI-5-000-01 SI-5-000-01 SI-5-000-01

NMT 0.5% of the labeled amount NMT 0.5% of the labeled amount NMT 2.0% of the labeled amount Meets USP Specifications o T (annually) and End of Study

7

Preservative Efficacy

SI-5-000-01

Meets USP Specifications o T (annually) and End of Study

5

Report Format Results will be tabulated in the format of the Stability Report Form: 1) Product Name, and Strength 2) Batch Number and Batch size 3) Storage Conditions and Intervals 4) Container/Closure Systems - Description 5) Inventory Control Number of (4) 6) Fill Size and No of units on stability 7) Batch Manufacturing Date 8) Batch Packaging Date


9) 10) 11) 12) 13) 14) 15) 16)

Stability Start Date Manufacturing Site Manufacturer of Bulk Drug Inventory Control Number of (11) Manufacturer of Container/Closure Formulation Data profile Methodology and Specifications

Sect: 16.4

ANDA Development


ANDA DEVELOPMENT

SECTION XVI

SECTION 16

Stability of Finished Dosage Form SUMMARY OF STABILITY STUDIES Stability Data Overview The 3 months accelerated (40° ±2°C / 75 RH ±5% ) and 6 months room temperature (25° ±2°C / 60 RH ±5%) stability data in all container-closure systems were examined for Lots #[000] and Lots #[000] of [Generic Drug name] [USP] [00.0] mg. Labeled chromatograms for the end 12 week period are included. (ref. page [00 00]) The data indicate that the formulation is stable, with no observed degradation peaks, under test conditions. Samples were stored for testing in their proposed market container/closure systems. The stability results indicate that the formulation is stable, with no observed degradation, under the tested conditions. No significant change in either chemical or physical attributes was noted in any sample under any of the storage conditions. This stability data supports the proposed expiry period of the product of 2 years at room temperature as there was no significant changes in either the physical chemical, or microbiological specifications in any samples evaluated after the exposed storage test conditions. The attached tables and graphs are summaries of the results for the parameters used to establish the stability profile of [Generic Drug name] [USP] [00.0] mg. (ref. page [00 - 00]) The attached tables and graphs are summaries of the results for the parameters used to establish the stability profile of [Generic Drug name] [USP] [00.0] mg. Included, are assay chromatogram spectra of the stability tests for zero time (T0) and the three (3) months accelerated test conditions. [Generic Drug name] [USP] [00.0]mg were stored at accelerated conditions (40° ±2°C / 75% RH ± 5%) and at room temperature (25° ±2°C/ 60% RH ±5%) in the proposed market container/closure system. Where PRODUCTS fail the accelerated testing, Intermediate testing is performed according to the following specification. Intermediate testing 0,1,2,3,6,9 and 30±2°C/60±5%RH 12 months This stability data supports the proposed expiry period of the product of 2 years at room temperature as there was no significant changes in either the physical chemical, or microbiological specifications in any samples evaluated after the exposed storage test conditions. Thus stability data generated support the proposed expiration period of 2 years when the product is stored at the defined room temperatures.


Sect: 16.5

ANDA Development


ANDA DEVELOPMENT

SECTION XVI

SECTION 16

Stability of Finished Dosage Form SUMMARY OF STABILITY STUDY RESULTS. HDPE Container Closure liner system Container Size (cc) Ü

25°C 60%RH

40°C 75%RH

Smallest

Largest

Smallest

Largest

000 mL

HDPE Tube with (HDPP Cap)

þ

þ

þ

þ

000 mL

HDPE Container with (HDPP Cap)

þ

þ

þ

þ

Glass Container Closure liner system

ý

ý

ý

ý

ý

ý

ý

ý

ý

ý

Bulk Packaging

Number of Temperature/RH Levels

2

Number of Dosage Strengths

1

Number of Container Closure Sizes

4

Number of Resins present in Containers

1

Number of Closures

1

Number of Resins present in Closures

1

Number of Stability Studies Performed

8

Number of resins used in the HDPE containers = one resin from same supplier.


Sect: 16.6

ANDA Development


ANDA DEVELOPMENT

SECTION XVI

SECTION 16

Stability of Finished Dosage Form STABILITY REPORT 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19

Product name, dosage form and strength. Fill size Site of Manufacture Batch or lot number Batch size (type) Batch manufacturing Date and Packaging Date Manufacturer of Active Material (approved supplier) Date placed on stability Batch number or receiving number of Active Material Full details of container/closure system (type, material, resin)

[Generic name] [000.0] mg./g 00 cc SEMISOLID [USP] NJ MNF SITE 002 000 Kg Month DD, YY / Month DD YY LEK Chemical Co. dd Month DD, YY LK 2323 80cc HDPE (LR-7340-43) HDPP white cap (resin LR-7340-43) Goods Receiving number of container-liner GRN 96-2-02234 (body) Goods Receiving number of closure GRN 96-2-02237 (cap) Manufacturer of container/closure Wheeler Cap Co PA USA. Objective of the stability program þ Pivotal Batch Site where stability test conducted US PA MAN Site Number of units to be sent for testing in each time interval 2 x 80cc Analytical method number and Edition Number for each stability indicating testS-I 555-03 / S-I 1234 Ed . 03 Stability specifications indicating names of test required. Tabulated Number of packages placed on stability 70 Testing intervals required 0, 1, 2, 3 months

40 degrees C / 75% RH

20 Stability storage conditions

Stability Parameters

Storage Period

SPECIFICATIONS

Months

Date of Analysis

Method #

Contents Appearance

ASSAY Percentage


Microbial Limits Test

Description COLOR

90.0 % 110.0%


Microbial Limits Test

S-I 552 -02

pH

S-I 555 -03

0

6/6/97

conforms

100.8

Meets Specification

Conforms

Conforms

1

5/7/97

conforms

101.4

-

Conforms

Conforms

2

7/8/97

conforms

100.3

-

Conforms

Conforms

3

6/9/97

conforms

100.9

Meets Specification

Conforms

Conforms

21. Product Formula On Stability (Formula No: S000). 1. 2. 3. 4. 5. 6. 7. 8.

Miconazole USP Micronized Pegoxol 7 Stearate [Tefose 63™] Heavy Mineral OIL NF Benzoic Acid USP Butylated Hydroxyanizole Peglico 5 Oleate [LABRAFIL M 1944™] Edetate Disodium USP Purified Water USP


Sect: 16.7

ANDA Development


ANDA DEVELOPMENT

SECTION XVI

SECTION 16

Stability of Finished Dosage Form STABILITY REPORT 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19

Product name, dosage form and strength. Fill size Site of Manufacture Batch or lot number Batch size (type) Batch manufacturing Date and Packaging Date Manufacturer of Active Material (approved supplier) Date placed on stability Batch number or receiving number of Active Material Full details of container/closure system (type, material, resin)

[Generic name] [000.0] mg/g. 00 cc SEMISOLID [USP] NJ MNF SITE P-5432 000 Kg May 22, 1996 / May 28, 1996 LEK Chemical Co. dd June 15, 1996 LK 2323 80cc HDPE (LR-7340-43) HDPP white cap (resin LR-7340-43) Goods Receiving number of container-liner GRN 96-2-02234 (body) Goods Receiving number of closure GRN 96-2-02237 (cap) Manufacturer of container/closure Wheeler Cap Co PA USA. Objective of the stability program þ Pivotal Batch Site where stability test conducted US PA MNF Site Number of units to be sent for testing in each time interval 2 x 80cc Analytical method number and Edition Number for each stability indicating testS-I 555-03 / S-I 1234 Ed . 03 Stability specifications indicating names of test required. Tabulated Number of packages placed on stability 70 Testing intervals required 0; 3; 6; 12; 18; 24; 36; months

25 degrees C / 60% RH

20 Stability storage conditions

Stability Parameters

Storage Period

SPECIFICATIONS

Months

Date of Analysis

Method #

Contents Appearance

ASSAY Percentage

Description COLOR

90.0 % 110.0%

S-I 000-02

S-I 000 -03

-

Preservative Efficacy Test

Microbial Limits

pH

S-I 000 -03

S-I 000 -03

S-I 000 -03

Meets Specification

Conforms

Conforms

0

4/6/97

conforms

101.3

3

5/9/97

conforms

99.9

-

-

Conforms

6

6/12/97

conforms

101.3

-

-

Conforms

9

15/3/98

conforms

101.2

-

-

Conforms

12

5/6/98

conforms

100.6

18

5/9/98

conforms

102.2

24

7/3/99

conforms

100.4

36

6/3/00

Meets Specification Meets Specification

Conforms Conforms

Conforms Conforms Conforms

21. Product Formula On Stability (Formula No: S000). 1. 2. 3. 4. 5. 6. 7. 8.

Miconazole USP Micronized Pegoxol 7 Stearate [Tefose 63™] Heavy Mineral OIL NF Benzoic Acid USP Butylated Hydroxyanizole Peglico 5 Oleate [LABRAFIL M 1944™] Edetate Disodium USP Purified Water USP


Sect: 16.8

ANDA Development


ANDA DEVELOPMENT

SECTION XVI

SECTION 16

Stability of Finished Dosage Form PACKAGE CHARACTERISTICS [Generic name] SEMISOLID [USP] [000.0] mg per g. [Batch No: 00]

Pivotal Lot Packaging Material Characteristics ITEM

TYPE 1

TYPE 2

TYPE 3

TYPE 4

Container manufacturer Container size







00 / 000cc HDPE/

00 / 000cc HDPE/

COLLAPSIBLE TUBE

COLLAPSIBLE TUBE

(coated metal)

(coated metal)

Resin Type Cap Manufacturer 11087 PE White Master batch Cap / Nozzle Type Cap Size Closure Liner Foam seal Mfg Inner liner composition CONTAINER CONTAINER CAP Nozzle / Applicator LINER SEAL





HDPE LDPE

HDPE LDPE

HDPE LDPE

HDPE LDPE

00 / 00 mm

00 / 00 mm

00 / 00 mm

00 / 00 mm



-

-

TEKNISEAL RVT + LF

TEKNISEAL X-14 (polyethylene/Kraft Paper laminate) Lot #00000 CoA #0000 Lot #00000 CoA #0000 Lot #00000 CoA #0000 Lot #00000 CoA #0000 Lot #00000 CoA #0000 Lot #00000

-

-



CoA #00000

CoA #00000

Lot #00000 CoA #0000 Lot #00000 CoA #0000 Lot #00000 CoA #0000 Lot #00000 CoA #0000 Lot #00000 CoA #0000 Lot #00000

CoA = Certificate of Analysis/Compliance


Sect: 16.9

ANDA Development


ANDA DEVELOPMENT

NOTES


Sect: 16.10

ANDA Development


ANDA DEVELOPMENT

SECTION XVII

SECTION 17

Reserved

TABLE OF CONTENTS (Overall ANDA Guideline Requirements for this Section). 17.1

RESERVED

This section is reserved: ELECTRONIC FORMATTED ANDAs Proposed use is anticipated for electronic formatted ANDAs

4


Sect: 17.1

ANDA Development


ANDA DEVELOPMENT

SECTION XVII

SECTION 17

RESERVED THIS SECTION HAS BEEN RESERVED FOR FUTURE USE.

ELECTRONIC FORMATTED ANDAs Proposed use is anticipated for electronic formatted ANDAs

4


Sect: 17.2

ANDA Development


ANDA DEVELOPMENT

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)). 1. Drug substance 2. Finished dosage form

Sample availability and identification of:


Sect: 18.1

ANDA Development


ANDA DEVELOPMENT

SECTION XVIII

SECTION 18

Samples of Drug/Article Components

SAMPLES OF THE

DRUG AND ARTICLES USED AS COMPONENTS 21 CFR Section 314.50 (e) (1).

[Generic Company Name Inc./Ltd.] shall submit samples of the drug substance or the finished drug product or otherwise make such samples FDA, in accordance with their instructions and requirements pertaining to 21 CFR Section: 314.50 (e) (1). Furthermore the [Generic Company Name Inc./Ltd.] shall submit appropriate REFERENCE STANDARDS with appropriate identification, graphs and spectra as required.


___________________


Date

Director Quality Assurance Unit Pharmaceutical Manufacturing Division [Generic Company Name Inc. Ltd.]

4


Sect: 18.2

ANDA Development


ANDA DEVELOPMENT

SECTION XIX

SECTION 19

Environmental Impact Analysis Reports


20.1

Section Page and Title

20.2

Environmental Exclusion Assessment - Development Site - Manufacturing Site

20.3

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

20.4

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

20.5

Statement on Environmental Compliance - Development Site - Manufacturing Site - Contract Manufacturers

20.6

Commercial Plant Manager and QA Director Signatures.

FDA's Published January 1999 ANDA Guideline requirements:1. 2.

Environmental Consideration: Environmental Assessment (EA) or Claim of Categorical Exclusion (§ 3l4.94(a)(9))

4


Sect: 19.1

ANDA Development


ANDA DEVELOPMENT

SECTION XIX

SECTION 19

Environmental Impact Analysis Reports This section contains: ♦

Requests for Categorical Exclusion

♦

Environmental Regulations Compliance Certification

♦

Environmental Regulations Compliance Certification (Foreign Firms)

♦ Site Environmental Certification (USA)

OVERVIEW This section is used for clarifying the various ENVIRONMENTAL PROTECTION REQUIREMENTS that apply to the development and the manufacturing environment. Note:Where the development and/or the manufacturing of the drug product is performed in a foreign country, the applicable National Environmental laws of the country need to be closely observed. Statements of Environmental Compliance with respect to:-

1. 2. 3.

Toxic waste Waste disposal Environmental Compliance Laws

need to be addressed with appropriate signed certification by senior responsible personnel. The FDA needs to see that there was no infringement of the local countries Environment and Waste Management laws in BOTH the development and manufacture of the drug product or the drug's Active Ingredient.

4


Sect: 19.2

ANDA Development


ANDA DEVELOPMENT

SECTION XIX

SECTION 19

Environmental Impact Analysis Reports 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 [in

accord with 21 CFR 25.23(c) and 21 CFR 25.24(c)(1)] from the requirement of an 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 Drug Application 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 of exposure, 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 required with this application and, therefore requests that it be categorically excluded from the requirements to submit an Environmental Impact Analysis.

[Signature of Responsible Person]

___________________________________

_________________

[Name of Responsible Person] Director Pharmaceutical Research & Development Pharmaceutical Division

Date



Sect: 19.3

ANDA Development


ANDA DEVELOPMENT

SECTION XIX

SECTION 19


STATEMENT OF ENVIRONMENTAL COMPLIANCE The undersigned hereby certifies that [Generic Company Name Inc./Ltd.] operates its [Address] manufacturing facility in compliance with all local and national environmental laws and with the emission requirements set forth in all permits. The undersigned further certifies that the approval and subsequent increase in production at the facility is not expected to affect compliance with current emission requirements or compliance with environmental laws. [Signature of Responsible Person]

__________________________

___________________


Date

Plant Manager Pharmaceutical Manufacturing Division [Generic Company Name Inc. Ltd.]

[Signature of Responsible Person]

__________________________

___________________


Date



Sect: 19.4

ANDA Development


ANDA DEVELOPMENT

SECTION XIX

SECTION 19


STATEMENT OF ENVIRONMENTAL COMPLIANCE

FOREIGN SITE Development and manufacturing The undersigned hereby certifies that [Generic Company Name Inc./Ltd.] operates a certified waste disposal program its [Address] manufacturing facility which is in full compliance with all Local, State and National environmental laws and with the emission requirements set forth in all required permits. The undersigned further certifies that the approval and subsequent increase in production at the facility is not expected to affect compliance with current emission requirements or compliance with environmental laws. [Signature of Responsible Person] __________________________

___________________


Date



___________________


Date

Director Quality Assurance Unit Pharmaceutical Manufacturing Division [Generic Company Name Inc. Ltd. ]


Sect: 19.5

ANDA Development


ANDA DEVELOPMENT

SECTION XIX

SECTION 19


Site Environmental Certification The undersigned hereby certifies that [Generic Company Name Inc. / Ltd.]. maintains compliance with all appropriate Federal, Sate and Local environmental laws and regulations in the distribution of [Generic name] Tablets [USP] [000.0] mg.


___________________


Date



___________________


Date


333


Sect: 19.6

ANDA Development


ANDA DEVELOPMENT

SECTION XX

SECTION 20

Generic Drug Enforcement Act


19.1

Section Page and Title and Color Tag

19.2

Generic Drug Enforcement Act

19.3

U.S. Agent Letter of Authorization


1. Generic Drug Enforcement Act 2. U.S. Agent - Letter of Authorization

4


Sect: 20.1

ANDA Development


ANDA DEVELOPMENT

SECTION XX

SECTION 20


Applicant or Agent Letterhead

STATEMENT Where Company has NO previous convictions AND does not use a debarred person in connection with the ANDA


O

n behalf of [Generic Company Name's Inc. / Ltd.], the applicant, I hereby certify, 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 in any capacity 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.

Applicant further certifies that there have been no conviction of applicant for any of the types of crimes set forth in Section 2(a) and Section 2(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, nor has any person affiliated with the applicant, who is responsible in whole or in part, for the development or the submission of this application been convicted of any crime of the type listed in Section 2(a) and Section 2(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] -------------------------------------------------

---------------------------------------


Date


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

__________________________

______________________


Date

Director Quality Assurance Unit Pharmaceutical Manufacturing Division [Generic Company Name Inc. Ltd. ]


Sect: 20.2

ANDA Development


ANDA DEVELOPMENT

SECTION XX

SECTION 20


Applicant or Agent Letterhead

STATEMENT Where Company has a previous conviction but does not use a debarred person in connection with the ANDA.


O

n behalf of [Generic Company Name's Inc. / Ltd.], the applicant, I hereby certify, 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 in any capacity 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.

Applicant further certifies that during the previous five years it has sustained the following conviction for the types of offenses as set forth in Section 2(a) and Section 2(b) of the Generic Drug Enforcement Act of 1992, 21 USC 335a (a) and/or (b), Date of Conviction Nature of Conviction

MM/DD/YY Conviction on six counts of fraudulent documentation pertaining to stability reports.

To the best of [Generic Company Name's Inc. / Ltd.] knowledge no person affiliated with the applicant, who is responsible in whole or in part, for the development or the submission of this application has been convicted of any offence of the type listed in Section 2(a) and Section 2(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] -------------------------------------------------

---------------------------------------


Date




Sect: 20.3

ANDA Development



ANDA DEVELOPMENT

Sect: 20.4

ANDA Development


ANDA DEVELOPMENT

SECTION XX

SECTION 20

Letter of Authorization - US Agent

[PRINTED ON US APPOINTED AGENTS LETTERHEAD]

n behalf of [Generic Company Name's Inc. / Ltd.], I, [US APPOINTED Applicant's Name] hereby certify, that [Applicant Company Name Inc. / Ltd.] has been duly appointed as representative applicant for the submission of the this ANDA and that the said applicant shall be the responsible person for all future communications with the relevant agencies in connection with matters pertaining to this application.

O

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

---------------------------------------


Date

US APPOINTED APPLICANT


[Applicant Company Site Address]

Full Site Address

[Applicant Company Contact Numbers] Contact Person. Responsibility. Director of Registration Quality Assurance Director

Tel.

Fax.


Sect: 20.5

ANDA Development


ANDA DEVELOPMENT

SECTION XXI

SECTION 21

Additional Information OVERVIEW

T

his section is used for clarifying the various ADDITIONAL DATA REQUIREMENTS that may apply to the development and the manufacturing procedures of this application.

Note:Where the manufacturing of the drug product may require a rework procedure the data validating the process step is summarized in this section. All necessary data is presented that indicates no significant change in the overall drug specifications both at product release and during the overall shelf life period claimed for the drug.

Steps that do not require support data are minor process procedures; such as fluid bed drying operations that may require additional drying to reach the required target moisture content (LOD %) of the granule or additional bulk mixing or homogenization in liquids and semisolids. These conditional procedures are highlighted as standard instructions in the manufacturing method or manufacturing instructions.

This

section is also useful to tabulate Drug Master File (DMF) numbers and list Letters of Access (LOA) to various DMFs as referenced in the Application. LOA letters should be clear copies and display recent dates with correct vendor names and addresses - especially if there has been a name or site change in the vendor's organization.

(Cut and paste where required)


Sect: 21. 1

Topical SEMISOLID.


ANDA DEVELOPMENT

SECTION XXI

SECTION 21

Additional Information TABLE OF CONTENTS (Overall ANDA Guideline Requirements for this Section). 21.1 21.2

Outline of manufacturing re-work study Table of DMF Numbers (with LOA dates)

Special Note: DMF numbers are required for active / excipient materials such as. • Active material • Specific Excipients • Capsules (Hard Gelatin) • Film coating color premixes. Colors/dyes (require US Certification.) DMF numbers are required for container/closure materials. Primary Material in direct contact with the drug product e.g. • Plastic containers • Plastic / Metal caps • Plastic / Metal closures • Plastic liners / laminates • Plastic seals (Foam seals / tamper evident seals) • Plastic application nozzles / integral measuring cups (Glass bottles are exempt from a DMF number) Product DMF numbers are required for container closure material that is a; Secondary Material in indirect contact or during use of the drug product e.g. • Inner Liners • Closure seals • Epoxy Coated Liners (tubes) • Foam Seals • Cotton Wool (solid dosage forms only.) • Silica gel drying agent in plastic containers (solid dosage forms only.) • Measuring caps as an integral part of closure system. MNF DMFs Manufacturing DMF numbers are required for the manufacturing facility supplying the raw material. LOAs Letters of Access (recent date and two copies is essential) are required for all referenced DMF numbers.


Sect: 21. 2

Topical SEMISOLID.


ANDA DEVELOPMENT

SECTION XXI

SECTION 21

Additional Information SUMMARY OF DMF NUMBERS USED IN THIS APPLICATION:

RAW MATERIAL / COMPONENT

DMF NO.

ACTIVE MATERIAL(S) Active material used for Biostudy and Pivotal

DMF

Alternative Supplier

DMF

Alternative Supplier

DMF

NON ACTIVE MATERIALS Non-compendial Excipient I

DMF

Non-compendial Excipient II

DMF

Color / Pigment (US Certification)

Cert.

Color / Pigment (US Certification)

Cert.

Special Ingredients

DMF

Special Ingredients

DMF

CONTAINER-CLOSURES HDPE / LDPE Container (rigid / collapsible)

DMF

HDPE / LDPE Container (rigid / collapsible)

DMF

HDPE Cap

DMF

ROPP Cap

DMF

Metal Cap

DMF

Cap liner

DMF

Adhesive Tamper evident inner-seal Special delivery nozzles or applicators / droppers

DMF DMF

THERMOPLASTIC RESINS AND MASTER BATCH DYES Resin No [001]

DMF

Resin No [002]

DMF

Resin No [003]

DMF

Master Batch White

DMF

Master Batch color

DMF


Sect: 21. 3

Topical SEMISOLID.


ANDA DEVELOPMENT

SECTION XXI

SECTION 21

Additional Information SUMMARY OF LOA LETTERS BY DATE AS USED IN THIS APPLICATION:

RAW MATERIAL / COMPONENT

LOA DATE.

ACTIVE MATERIAL(S) Active material used for Biostudy and Pivotal Alternative Supplier

LOA LOA

NON ACTIVE MATERIALS Color / Pigment (US Certification) Color / Pigment (US Certification) Special Ingredients

Cert. Cert. LOA

CONTAINER-CLOSURES HDPE / LDPE Container (rigid / collapsible) HDPE / LDPE Container (rigid / collapsible) HDPE Cap ROPP Cap Metal Cap Cap liner Adhesive Tamper evident inner-seal / Foam seals Special delivery nozzles or applicators / droppers

LOA LOA LOA LOA LOA LOA LOA LOA

THERMOPLASTIC RESINS AND MASTER BATCH DYES Resin No [123456] of THERMOPLASTIC container

DMF

LOA

Resin No [12345] of Cap

DMF

LOA

DMF

LOA

Resin No [123] of CRC INNER component

DMF

LOA

Master Batch White Master Batch color Resin No [001]

LOA LOA LOA

Resin No [002]

LOA

Resin No [003]

LOA

Master Batch White Master Batch color

LOA LOA

1

Resin No [1234] of CRC OUTER component 1

No LOA date greater than two years. Change in Ownership show new DMF Holder. 1 Note: Child Resistant Closures consist of both an inner and outer component.


Sect: 21. 4

Topical SEMISOLID.


ANDA DEVELOPMENT

SECTION XXII

SECTION 22

Sterilization Assurance


This section applies to sterile processes: Sterile Manufacturing Processes Only Copies of the original batch manufacturing instructions in the language of origin q Chinese q Dutch q French q Hebrew q Italian q Polish q Portuguese q Spanish q _________ FDA's Published January 1999 ANDA Guideline Requirements: (actual excerpt as published in agency guideline)

Section XXII.

Sterilization Assurance Information and Data Note: This section can be provided as a separate volume for ease of review. If the microbiology section is in a separate volume, please provide copies of the indicated information that may be in other sections of the application instead of page references. 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 composition statement (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 for Sterilization Process Validation in Applications for Human and Veterinary Drug Products that apply to the process in the application.

4


Sect: 22.1

ANDA Development


ANDA DEVELOPMENT

Do's and Don'ts 13 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 '.

24 VOLUME DRUG DEVELOPMENT SERIES

ANDA DEVELOPMENT


ANDA DEVELOPMENT

International Association

Drug20×Ø00Manufacturers High Quality Low Cost Drug Development & Manufacturing Excellence World Wide

Innovative & Generic

HANDBOOK OF DRUG DEVELOPMENT Series Part I - Drug Development Part II - US Type CMCs & EC DOSSIERS

US CHEMISTRY MANUFACTURING CONTROL Know How Technology & EU DOSSIERS Know How Technology


ANDA DEVELOPMENT


I n t e r n a t i o n a l

ANDA DEVELOPMENT

A s s o c i a t i o n

Drug20×Ø00Manufacturers High Quality Cost Effective Drug Development & M anufacturing 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 Development Part II - US Type CMCs or EC DOSSIERS Generic Development ISSN Series number 0793 7407 Generic Development ISSN Series number 0793 7792 - Electronic Issue (Disk/CD ROM)

The follow HBGD HANDBOOKS KNOW-HOW SERIES are available in the most common dosage forms namely solid, semisolid and liquid dosage forms. The presentation of the actual data is based on manufactured production batches and the format of all sections is similar to the data in the standard ANDA.

Drug Development Series Alendronate Sodium Alendronate Sodium

Amitriphyline HCl Azithromycin Azithromycin Azithromycin Atenolol EU Atenolol US Amoxicillin Bromhexine Hydrochloride Bromhexine Hydrochloride Bromocriptine Mesylate Bupropion Buspirone HCl Carbamazepine (EU + US) Carbamazepine (Chewable) Carbamazepine (Extented Release) ≡ Geigy TEGRATOL XR™ Carbidopa/Levodopa Carbidopa/Levodopa Carbidopa/Levodopa Carbidopa/Levodopa ER Cefaclor Oral Suspension USP Cefaclor Oral Suspension USP Cefaclor Oral Suspension EU Cefaclor Cefuroxime Sodium USP Clonazepam Tablets USP

Form Tablets Tablets Tablets Suspension Capsules Tablets Tablets Tablets Capsules Tablets Syrup Tablets Tablets Tablets Tablets Chewable Tab Coated Tab Tablets Tablets Tablets Tablets Suspension Suspension Suspension Capsules Vials Tablets USP

Strength 5 - 10 mg

40 mg 10 mg 200 mg 250 /600 mg 600 mg 50 /100 mg 50 /100 mg 250/500mg 8mg 8mg 2.5mg 75.0/100 mg 5 mg /10 mg 200mg 100 mg 400 mg 10/100 mg 25/100 mg 25/250mg 50/200mg 125 /187 mg/5mL

250/375 mg/5mL 250 mg/5mL 250/500mg 750-1500mg 0.5/1.0/ 2.0mg

Volume

Part

Volume II Volume II Volume II Volume II Volume II Volume II Volume II Volume II Volume II Volume II Volume II Volume II Volume II Volume II Volume II Volume II Volume II

1&2 1&2 1&2 1&2 1&2 1&2 1&2 1&2 1&2 1&2 1&2 1&2 1&2 1&2 1&2 1&2 1&2

Volume II Volume II Volume II Volume II Volume II Volume II Volume II Volume II Volume II Volume II

1&2 1&2 1&2 1&2 1&2 1&2 1&2 1&2 1&2 1&2

Latest Lists are viewable on web http://locumusa.com/2go


ANDA DEVELOPMENT


ANDA DEVELOPMENT

HANDBOOK of DRUG DEVELOPMENT +120 Series Generic Development ISSN Series number 0793 7407 Generic Development ISSN Series number 0793 7792 - Electronic Issue (Disk/CD ROM)

Clomiphene Citrate Clomipramine HCl Clomipramine HCl Diclofenac Potassium Diclofenac Sodium Diclofenac Sodium Diclofenac Sodium Dorzolamide HCL Ophthalmic Etodolac Etodolac ≡ Wyeth Lodine™ Etodolac ≡ Wyeth Lodine™ Enalapril Maleate Etidronate Disodium Famotidine Famotidine Famotidine Felodipine Felodipine Felodipine Extended Release Felodipine Extended Release Felodipine Extended Release Flunisolide Hemihydrate solution Flunitazapam Fluoxetine Fusemide Gabapentin (=Neurontin-Park Davis) Gabapentin (=Neurontin-Park Davis) Gemfibrosil Gemfibrosil Extended Release Glibenclamide Glipizide Extended Release Ibuprofen Isosorbide Mononitrate Ketorolac Tromethamine Levodopa/ Benserazide HCl Labetalol HCL Labetalol HCL Loperimide Mesalamine (Enteric Coated) Metformin HCl (Coated) Metformin HCl (Coated) Miconazole/Hydrocortazone Miconazole Nitrate Nabumatone Nabumatone

Tablets USP Capsules Capsules Tablets Tablets Tablets Clear Gel Solution Capsules Tablets Tablets Tablets Tablets Tablets Tablets Tablets Tablets Tablets Tablets Tablets Tablets Nasal solution Tablets Capsules Capsules Capsules Capsules Tablets Tablets Tablets Tablets Tablets Tablets Tablets Tablets Tablets Tablets Tablets Tablets Tablets Tablets Cream Cream Tablets Tablets

50mg 25/50 mg 75 mg 50 mg 50 / 75 mg 100 mg 10 mg/g 2% 200/300mg 400 mg 500 mg 40 mg 0 mg 10 mg 20 mg 40 mg 5 mg 10 mg 2.5 mg 5 mg 10 mg 1mg/5mL 2 mg 10 / 20 mg 40 mg 100/200 mg 300 /400 mg 450 mg 600 mg 5 mg 2.5 mg 200-800mg 20 mg 10 mg 200/50 mg 100 +200mg 300mg 400mg 500 mg 850 mg 2% + 1% 2% 500 mg 750mg

Volume II Volume II Volume II Volume II Volume II Volume II Volume II Volume II Volume II Volume II Volume II Volume II Volume II Volume II Volume II Volume II Volume II Volume II Volume II Volume II Volume II Volume II Volume II Volume II Volume II Volume II Volume II Volume II Volume II Volume II Volume II Volume II Volume II Volume II Volume II Volume II Volume II Volume II Volume II Volume II Volume II Volume II Volume II Volume II

1&2 1&2 1&2 1&2 1&2 1&2 1&2 1&2 1&2 1&2 1&2 1&2 1&2 1&2 1&2 1&2 1&2 1&2 1&2 1&2 1&2 1&2 1&2 1&2 1&2 1&2 1&2 1&2 1&2 1&2 1&2 1&2 1&2 1&2 1&2 1&2 1&2 1&2 1&2 1&2 1&2 1&2 1&2 1&2 1&2

Copyright © 1995-9 by Locum Publishing House Inc. All Rights Reserved. Neither this book nor any part may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, microfilming and recording, or by any information storage and retrieval system, without the permission of the publishers



ANDA DEVELOPMENT


ANDA DEVELOPMENT

HANDBOOK of DRUG DEVELOPMENT

+120 Series Generic Development ISSN Series number 0793 7407 Generic Development ISSN Series number 0793 7792 - Electronic Issue (Disk/CD ROM)

Naproxen (Enteric Coated) Naproxen DR Naproxen Sodium Naproxen Sodium Norfloxacin USP Ofloxacin

Tablets 250mg Volume II Tablets 375/500mg Volume II Tablets 220 mg Volume II Tablets 275/550 mg Volume II Tablets 400 mg Volume II Tablets 400 mg Volume II 100/200/ Oxolamine Syrup 10 mg/mL Volume II Paracetamol - sugar/dye-free Syrup 125 mg Volume II Paracetamol Chewable Fruit Flavors Tablets 160 mg Volume II Pentoxifylline ER Tablets 400 mg Volume II Penfluridol Capsules 10 mg Volume II Piroxicam Capsules 20 mg Volume II Quinidine Bisulphate Tetrahydrate Tablets 250 mg Volume II Ranitidine HCl Tablets 150 mg Volume II Ranitidine HCl Tablets 300 mg Volume II Simvastatin Tablets 5/10mg 20 / 40 mg Volume II Scopolamine Butylbromide Tablets 10 mg Volume II Selegiline Tablets 5 /10 mg Volume II Sotalol (=Betapace/Berlex) Tablets 80 /120mg Volume II Sotalol (=Betapace/Berlex) Tablets 160 /240mg Volume II Silver Sulphadiazine Cream 1% Volume II Tamoxifen EU Tablets 10 / 20 mg Volume II Tamoxifen EU Tablets 30 / 40mg Volume II Tamoxifen US Tablets 10/20/40mg Volume II Terbutaline Sulfate Syrup 0.3 mg/mL Volume II Terazosin Tablets 1mg / 2mg Volume II Terazosin Tablets 5mg / 10mg Volume II Terfenadine Tablets 60 mg Volume II Tetrahydrozoline HCl USP Eye Drops 2,5mg/5mL Volume II Ticlopidine Tablets 250 mg Volume II Timolol maleate Drops USP Eye Drops 0.25 / 0.5% Volume II Tolmetin Sod. Capsules 400 mg Volume II Tolmetin Sod. Tablets 600 mg Volume II Trazodone Tablets 50/100 mg Volume II Trazodone Tablets 150 mg Volume II Tretinoin Cream USP 0.025% Volume II Sulfamethoxazole Trimethoprim Tablets USP 80/400mg Volume II Sulfamethoxazole Trimethoprim Tablets USP 160/800mg Volume II Sulfamethoxazole Trimethoprim Suspension 80/400mg Volume II Sodium Valproate Syrup 200mg/5mL Volume II Verapamil Hydrochloride Tablets 40 mg Volume II AN ONGOING SERIES - NEW ADDITIONS ADDED TO SERIES

1&2 1&2 1&2 1&2 1&2 1&2 1&2 1&2 1&2 1&2 1&2 1&2 1&2 1&2 1&2 1&2 1&2 1&2 1&2 1&2 1&2 1&2 1&2 1&2 1&2 1&2 1&2 1&2 1&2 1&2 1&2 1&2 1&2 1&2 1&2 1&2 1&2 1&2 1&2 1&2 1&2

Generic Development ISSN Series number 0793 7407 Generic Development ISSN Series number 0793 7792 - Electronic Issue (Disk/CD ROM) Second International Edition - 02 (First to Fourth Print). Fourth printing published and distributed in UK, US, EU, Israel, Asia, and Japan in January 1998 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



ANDA DEVELOPMENT

136188075 Handbook of Pharmaceutical Generic Development Vol 12 Part 2

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