Professional Documents
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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
handbooks@locumusa.com http://www.l o c u m u s a . c o m
Generic Development
SEMISOLID
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
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 - Tablets Oral DR Vol. 13 - Analytical
(Top 50 Generic Assay Methods)
Handbook of Pharmaceutical Innovative Development Handbook of Pharmaceutical Innovative Development Handbook of Pharmaceutical Innovative Development Handbook of Pharmaceutical Drug Development (1-5)
(Master Formula & Manufacturing Instructions Parts 1 - 5)
Vol. 14 - Tablets Oral Vol. 15 - Capsules Oral Vol. 16 - Suspensions Oral Vol. 17 - MF and MMI Vol. 18 - MF and MMI Vol. 19 - SOPs/PAI-Checklist 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
Generic Development
SEMISOLID
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
(Top 50 Generic Assay Methods)
Vol. 14 - Tablets Oral DR Vol. 15 - Suspensions Oral Vol. 16 - Capsules Oral Vol. 17 - Master Formula Vol. 18 - Master processes Vol. 19 - SOPs/PAI-Checklist
Handbook of Pharmaceutical Innovative Development Handbook of Pharmaceutical Innovative Development Handbook of Pharmaceutical Innovative Development Handbook of Pharmaceutical Innovative Development
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
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Handbook of Pharmaceutical
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Generic Development
SEMISOLID
HANDBOOK OF PHARMACEUTICAL
GENERIC DEVELOPMENT
Semisolid
Part TWO
F O R M DOSAGE
Jeremy D. Block
B.Sc. MPS. D/Pharm.
handbooks@locumUSA.com / handbooks@locumEURO.com Locum Publishing House - Israel Locum Pharmaceutical Publishers - USA Locum International Publishers - Cape Town
Handbook of Pharmaceutical
handbooks@locumusa.com http://www.l o c u m u s a . c o m
Generic Development
SEMISOLID
Innovative Series
Part
Two
Semi
ANDA Development
s olids
Copyright 1994-00 - Locum Publishing
House Inc. All Rights Reserved.
L o c u m
H o u s e
P u b l i c a t i o n
Handbook of Pharmaceutical
handbooks@locumusa.com http://www.l o c u m u s a . c o m
Generic Development
SEMISOLID
HPGD Series
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
LOCUM INTERNATIONAL PUBLISHERS REGISTRATION SERVICES WARNING: THIS ISSUE A IS MULTIPLE PAGE UV CODED PUBLICATION.
PRINTED IN USA PRINTED IN ISRAEL PRINTED IN IRELAND PRINTED IN REPUBLIC OF SOUTH AFRICA
Handbook of Pharmaceutical
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Generic Development
SEMISOLID
EDITORIAL PREFACE
Handbook of Generic Drug Development - Semisolid Dosage Forms his handbook represents the third International Edition for Europe of the ongoing 24 volume series of Generic Drug Development and appears under the cumulative title of the Handbook series of Generic Drug Development. The ongoing series is updated annually at the end of each year. This is an ongoing process as new data, specifications and process techniques are added on a continual and expanding basis. This handbook is fact, never fully complete, as each new annual edition brings an enlarged and extended profile in the drug development process, as well as new agency rules, guidelines and guidance to industry which continue to be added year by year as the global product data base expands. Currently over 150 scientific publications and drug development conferences are annually referenced in the 24 volume Handbook series of Generic Drug Development. 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.
General Series ISSN 0793 7407 Electronic Series ISSN 0793 7792
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LOCUM
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Handbook of Pharmaceutical
handbooks@locumusa.com http://www.l o c u m u s a . c o m
Generic Development
SEMISOLID
Acknowledgments
I.A.G.I.M. (R&D) Foundation.
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.
L O C U M
P U B L I S H I N G
H O U S E
Handbook of Pharmaceutical
handbooks@locumusa.com http://www.l o c u m u s a . c o m
Generic Development
ANDA DEVELOPMENT
SECTION I
SECTION 1
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
Name of Applicant Title of Applicant Signature of Applicant (original ink) Proprietary name (if any) Generic name of Drug Number of volumes submitted.
Methods Validation Post Approval Commitment . Electronic Format Statement (portion or whole submission). Sterility Assurance Data Statement (Indicate that submission contains SAD) - NEW 1999/2000 Requirements
Sect: 1.1
ANDA DEVELOPMENT
ANDA DEVELOPMENT
SECTION I
SECTION 1
COVER LETTER
Date: ______________
Office of Generic Drugs CDER, Food and Drug Administration Document Control Room - No. 150 Metro Park North II 7500 Standish Place ROCKVILLE MD 20855-2773.
Letter Header
For SUPAC submissions only.
(Place on envelop as well)
Clear Brief
Introductory Statement
ANDA DEVELOPMENT
SECTION I
SECTION 1
TABLE OF CONTENTS
SECTIONS I
1.1 .2 .3 .4 Cover Letter - basis for submission of an abbreviated application. Signed Application Form (Form FDA 356h or 3439) with original ink signature. Table of Contents - to CDER Guide to Industry Format, (April 1997). Executive Summary - Introductory Outline on the organization of this ANDA1 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 .2 .3 .4 .5 Section Page (with TAG) and brief descriptor of the section. Patent Certification statement - (Paragraph I, II, III or IV) Little VIII Patent statement - i.e. no labeling claims on a new indication. Exclusivity Statement with reference to the RLD. Certification Pursuant to the Generic Drug Enforcement Act of 1992.
Sect: 1.3
ANDA DEVELOPMENT
ANDA DEVELOPMENT
SECTION I
SECTION 1
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.)
Sect: 1.4
ANDA DEVELOPMENT
ANDA DEVELOPMENT
SECTION I
SECTION 1
Sect: 1.5
ANDA DEVELOPMENT
ANDA DEVELOPMENT
SECTION I
SECTION 1
Routine Testing Protocol and Frequency of tests for Active Material Routine Testing Protocol and Frequency of tests for Inactive Material Statement that other suppliers may be used subject to meeting pharmacopoeial standards. SOP Outline of vendor qualification requirements (outlines are unsigned) SOP Outline of retesting procedures and schedule (micro. NMT 12 months) SOP Outline of RM environmental storage temperatures (15o-25 o (30o C).
Sect: 1.6
ANDA DEVELOPMENT
ANDA DEVELOPMENT
SECTION I
SECTION 1
Address of Facility for QC and Stability Testing. Brief description of facilities for MNF testing equipment and stability equipment and key personnel (no personnel CVs). Statement on the GMP Certification of Compliance for the generic mfg. site Generic Manufacturing Site - Central File No (CFN)
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
Sect: 1.8
ANDA DEVELOPMENT
ANDA DEVELOPMENT
SECTION I
SECTION 1
Distribution of Pivotal lot into various container-closures systems (Packaging) Pivotal Batch Packaging Trail - (overall disposition of UNITS i.e. net yield, QC sampling, reserve samples, stability samples, Biostudy, Packaging formats.)
SECTION XIII
Description & Characteristics of Packaging Components Packaging and labeling Procedures
13.0 .1 .2 Title Page (with TAG) and brief narrative statement of what this section contains. Outlines for Packaging and Labeling Procedures 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) - Manufacturers Container CoA .7 .8 .9 Testing Specifications / protocol and test results (CoA) of Generic packaging Lab. CoAs of Containers from Generic packaging Lab. Batch Compliance Results
Sect: 1.9
ANDA DEVELOPMENT
ANDA DEVELOPMENT
SECTION I
SECTION 1
FOAM SEALS, PRESSURE SENSITIVE, TAMPER RESISTANT, ADHESIVE, INNER SEALS: 13.20 .21 .22 .23 .24 .25 Item description and use - meets current CFR and USP requirements. LoA from manufacturer to applicant referencing their DMF # of foam seal. Foam seal Specifications or Certificate of Conformance from manufacturers Testing Specifications / protocol of Generic packaging Lab. CoA or test results of Foam seal from Generic packaging Lab. Batch Compliance Statement.
Sect: 1.10
ANDA DEVELOPMENT
ANDA DEVELOPMENT
SECTION I
SECTION 1
Stability Indicating Assay; Impurity Limit Tests; Dissolution Assay USPC Inc. Pharmacopeial Forum, FDA
Sect: 1.11
ANDA DEVELOPMENT
ANDA DEVELOPMENT
SECTION I
SECTION 1
Active material
.2 .3 Active Ingredient Test Method Active Ingredient Test Method Validation
In-process Material
.4 Final Blend Test Methods (especially Uniformity of Content)
Finished Product
.5 Finished Product Test Methods - 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 (QC Release
Sect: 1.12
ANDA DEVELOPMENT
ANDA DEVELOPMENT
SECTION I
SECTION 1
Section XVII
Reserved
17.0 17.1 Title Page (with TAG) and brief statement that section is reserved. Reserved
Section XVIII
Sect: 1.13
ANDA DEVELOPMENT
ANDA DEVELOPMENT
SECTION I
SECTION 1
Application/Table of Contents
TABLE OF CONTENTS.
Section XIX
ENVIRONMENTAL IMPACT ANALYSIS REPORTS
19.1 19.2 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.
19.3
19.4
19.5
Section XX
ADDITIONAL INFORMATION
20.0 20.1 20.2 Title Page (with TAG) and brief narrative statement of what this section contains. Certification Pursuant to the Generic Drug Enforcement Act of 1992. US Agents Letter of Authorization
Section XXI
ADDITIONAL INFORMATION
21.1 21.2 21.3 21.4 21.5 21.6 21.7
1
Title Page (with TAG) and brief narrative statement of what this section contains. Reference to previously submitted Information Original Data / Literature Publication where English translation is submitted Outline of manufacturing re-work study. Table of DMF Numbers (with LOA dates). Letters of Authorization (LOA) - TWO PHOTOCOPIES1 Field Copy Certification
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
ANDA DEVELOPMENT
SECTION I
SECTION 1
(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
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 2.1.1 Basis for ANDA Submission is submitted as follows and is; 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
ANDA DEVELOPMENT
SECTION II
SECTION 2
[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 exclusivitys 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
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])
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])
----------------------------------------Date
Sect: 2.3
ANDA DEVELOPMENT
ANDA DEVELOPMENT
SECTION II
SECTION 2
----------------------------------------Date
----------------------------------------Date
INNOVATOR NAME COUNTRY US or EU USA RLD 375 / 500 mg - Application Number 000000 3 INNOVATOR
Sect: 2.4
ANDA DEVELOPMENT
ANDA DEVELOPMENT
SECTION II
SECTION 2
[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
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.
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
4
24 Volume V Drug Development Series Sect: 2.6
ANDA DEVELOPMENT
ANDA DEVELOPMENT
End of Section 2.
Sect: 2.7
ANDA DEVELOPMENT
ANDA DEVELOPMENT
SECTION III
SECTION 3
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 3.3 3.4 Little VIII Patent Statement - i.e. no labeling claims on a new indication. Exclusivity Statement with reference to the RLD. Certification Pursuant to the Generic Drug Enforcement Act of 1992.
Sect: 3.1
ANDA DEVELOPMENT
ANDA DEVELOPMENT
SECTION III
SECTION 3
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 T
e the undersigned hereby certify to the best of our knowledge and in [Generic Company Name Inc./Ltd.]s opinion patent information has not been submitted to the FDA on Patent No [00-0000-00] which claims the reference listed drug [RLD] DRUG Name [USP] [000.0] mg. NDA # 00-000
his certification is made in accordance with Section 505 (j)(2)(A)(vii)(I) of Title I the Food, Drug and Cosmetic Act, as amended September 24, 1984 and pursuant to 21 CFR 314.94 (a)(12)(i)(A)(1).
----------------------------------------Date
Sect: 3.2
ANDA DEVELOPMENT
ANDA DEVELOPMENT
SECTION III
SECTION 3
n accord with the Food, Drug and Cosmetic Act as amended September 24, 1984 and with the final regulations effective November 2 1994 Patent certification is hereby provided for our Abbreviated New Drug Application for [Generic Drug Name].
e the undersigned hereby certify that to the best of our knowledge and in [Generic Company Name Inc./Ltd.]s opinion US Patent No [00-0000-00] held by [Innovator/RLD Company Name Inc./Ltd.] which claimed the reference listed drug [RLD] DRUG Name[USP] [000.0] mg. NDA # 00-000 expired on 31 December 1999 his certification is made in accordance with Section 505 (j)(2)(A)(vii)(I) of Title I the Food, Drug and Cosmetic Act, as amended September 24, 1984 and pursuant to 21 CFR 314.94 (a)(12)(i)(A)(1). US. Patent No. 0-0000-0000 expiring Dec 31, 1999 US. Patent No. 0-0000-0000 expiring Dec 31, 1999
W T
----------------------------------------Date
Sect: 3.3
ANDA DEVELOPMENT
ANDA DEVELOPMENT
SECTION III
SECTION 3
n accord with the Food, Drug and Cosmetic Act as amended September 24, 1984 and with the final regulations effective November 2 1994 Patent certification is hereby provided for our Abbreviated New Drug Application for [Generic Drug Name]. e the undersigned hereby certify that to the best of our knowledge and in [Generic Company Name Inc./Ltd.]s opinion US Patent No [00-0000-00] held by [Innovator/RLD Company Name Inc./Ltd.] which claimed the reference listed drug [RLD] DRUG Name [USP] [000.0] mg. NDA # 00-000 will expire on [31 December 1999.] US. Patent No. 0-0000-0000 expiring MM DD, YYYY US. Patent No. 0-0000-0000 expiring MM DD, YYYY n accordance with Section 505 (j)(2)(A)(vii)(III) of the Food, Drug and Cosmetic Act, as amended [Generic Company Name Inc./Ltd.] certifies that the Company will not engage in the commercial manufacture, use or sale of the drug Product until this aforementioned patent has expired.
----------------------------------------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
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
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 .
----------------------------------------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.
Sect: 3.5
ANDA DEVELOPMENT
ANDA DEVELOPMENT
SECTION III
SECTION 3
n accord with the Food, Drug and Cosmetic Act as amended September 24, 1984 and with the final regulations effective November 2 1994 Patent certification is hereby provided for our Abbreviated New Drug Application for [Generic Drug Name]. e the undersigned hereby certify that to the best of our knowledge and in [Generic Company Name Inc./Ltd.]s opinion US Patent No [00-0000-00] issued on MM DD, YYYY and will expire on 31 December 2004 [will not be infringed] / [ is invalid] / [is unenforceable]1 by the manufacturer [Generic Company Name Inc./Ltd.] upon the manufacture use and sale by [Generic] DRUG Name [USP] [000.0]mg. for which this application is submitted NO INFRINGEMENT STATUS of the following patents. US. Patent No. 0-0000-0000 expiring MM DD, YYYY US. Patent No. 0-0000-0000 expiring MM DD, YYYY
[Signature of Responsible Person] -----------------------------------------------[Name of Responsible Person] Regulatory Affairs Director [Applicant Company Name Inc./Ltd.] ----------------------------------------Date
[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:
1Select the appropriate language that constitutes the basis of the patent challenge namely:
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
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) with mailing the notice to the [RLD Company Name Inc./Ltd.] the pertaining to the Branded Product - [RLD] DRUG Name] the [Generic Company Name Inc./Ltd.] will as required by 21 CFR 314.95(b) amend it ANDA for [Generic] DRUG Name [USP] [000.0]mg to include a certification that the notice has been provided to each person identified under CFR 314.95(a) and that the notice met the contents of CFR 314.95(c).
[Signature of Responsible Person] -----------------------------------------------[Name of Responsible Person]
Concurrently
----------------------------------------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
ANDA DEVELOPMENT
SECTION III
SECTION 3
n accord with the Food, Drug and Cosmetic Act as amended September 24, 1984 and with the final regulations effective November 2, 1994. Patent certification clarification is hereby provided for our submitted Abbreviated New Drug Application for [Generic Drug Name].
his certification is made in accordance with Section 505 (j)(2)(A)(vii)(I) of Title I the Food, Drug and Cosmetic Act, as amended, September 24, 1984 and November 2, 1994 and pursuant to 21 CFR 314.94 (a)(12)(ii).
e the undersigned hereby certify to the best of our knowledge and in [Generic Company Name Inc./Ltd.]s opinion there are no patent[s] which claim[s] the Reference Listed Drug [RLD] DRUG Name [USP] [000.0]mg. NDA #[00-000-00] referred to in this application or that claims a use of the Reference Listed Drug.
----------------------------------------Date
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
ANDA DEVELOPMENT
SECTION III
SECTION 3
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).
T
I
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] .
----------------------------------------Date
Sect: 3.9
ANDA DEVELOPMENT
ANDA DEVELOPMENT
SECTION III
SECTION 3
he undersigned hereby certifies to the best of our knowledge and in [Generic Company Name Inc./Ltd.] opinion the listed drug [RLD] DRUG Name [USP] [000.0] mg. NDA # 00-000 is not covered by any exclusivity.
OR
The following statement is made if market exclusivity exists under the Waxman-Hatch Act relative to the Reference Listed Drug - Attach the relevant page of the Orange Book
ccording to the information as published in the 'Orange Book' [Approved Drug Products with Therapeutic Equivalence Evaluations Edition #20 (2000), US Department of Health and Human Sciences], the listed drug [RLD] DRUG Name [USP] [000.0mg] is entitled to a three year period of market exclusivity under 505 (j)(4)(D) of the F.D.& C Act as a new product which does not expire until Dec 31 2002. [Generic Company Name Inc./Ltd.] does not intend to introduce its drug product subject to this ANDA, prior to the expiration of this exclusive marketing period.
[Signature of Responsible Person] -----------------------------------------------[Name of Responsible Person] ----------------------------------------Date
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
4.3
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
[RLD] SEMISOLID [RLD Company 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).
[Generic name] SEMISOLID [Generic Co. Name]. 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
Administration
Topical
000.0 mg 000.0 mg 000.0 mg 000.0 mg
Topical
000.0 mg 000.0 mg 000.0 mg 000.0 mg
Labeling: The labeling proposed for the [Generic Company Name Inc. / Ltd.] drug product is the same as the labeling for the listed drug product except for: 1) Changes required because the drugs are produced and distributed by different manufacturers and distributors. 2) Product are packed in different size containers.
Sect: 4.2
Topical SEMISOLID
ANDA DEVELOPMENT
SECTION IV
SECTION 4
Rx / OTC Statement
[Generic name] SEMISOLID [USP] [All strengths]
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.
----------------------------------------Date
Sect: 4.3
Topical SEMISOLID
ANDA DEVELOPMENT
NOTES
Sect: 4.4
Topical SEMISOLID
ANDA DEVELOPMENT
SECTION V
SECTION 5
Labeling
TABLE OF CONTENTS
(Overall ANDA Guideline Requirements for this Section).
1. Section Page and cover statement 2. Proposed Generic container panel labeling for each strength & pack size. 3. Proposed Generic Insert / Outsert 4. Innovators Insert / Outsert - (obtain latest insert from FDA FOI). 5. Innovators container panel labeling for each strength & pack size 6. Side-by-side comparison of package leaflet (insert or Outsert.) 7. Side-by-side comparison of label for each strength & pack size 8. Certification that proposed labeling is the same as listed drug (RLD).
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]
000 mg per g
_________________________ Contains: [Active Material] 000 mg per g Caution: Federal law prohibits dispensing without prescription
KEEP THIS AND ALL MEDICATIONS OUT OF REACH OF CHILDREN 6/YY. MANUFACTURED BY [Generic 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]
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 INNOVATIVE PACKAGE INSERT - use line side bars where differences appear.
Use point size 7 and highlight the differences in the GENERIC PACKAGE INSERT - use line side bars where differences appear as shown:
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
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 INNOVATIVE CONTAINER LABEL - use line side bars where differences appear.
Use point size 12 and highlight the differences in the GENERIC PACKAGE CONTAINER LABEL - use line side bars where differences appear as shown:
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
NDC [0000-0000-00]
[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.
Sect: 5.6
Topical SEMISOLID
ANDA DEVELOPMENT
SECTION V
SECTION 5
Labeling
INNOVATIVE CONTAINER ADHESIVE LABELING
NDC [0000-0000-00]
Keep tightly closed. Store at controlled room temperature 15 - 30 C (59 - 86 F). Protest from exposure to temperatures above 40 C (104 F) and moisture. KEEP THIS MEDICATION OUT OF REACH OF CHILDREN.
NOTE: Examine innovators labeling carefully and reproduce meeting all regulatory requirements
Sect: 5.7
Topical SEMISOLID
ANDA DEVELOPMENT
SECTION V
SECTION 5
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 Innovators 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.
Sect: 6.1
Topical SEMISOLID
ANDA DEVELOPMENT
SECTION VI
SECTION 6
Bioavailability / Bioequivalence
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:
Sect: 6.2
Topical SEMISOLID
ANDA DEVELOPMENT
SECTION VI
SECTION 6
Bioavailability / Bioequivalence
Products used in Topical Biostudy:
PRODUCT REFERENCE GENERIC
Table 1 Strength
[RLD] Semisolid [USP] [000.0] mg/g [Generic name] Semisolid [000.0] mg/g
Batch No:
Lot: AA000
C o A No:
R000
Lot: OO0
G000
Batch No:
Lot: AA000
C o A No:
R001
Lot: BB000
R002
GENERIC GENERIC
[Generic name] Semisolid [000.0] mg/g [Generic name] Semisolid [000.0] mg/g
Lot: OO0
G001
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.
FORMULA INGREDIENTS
Miconazole USP Micronized Pegoxol 7 Stearate [Tefose 63] Heavy Mineral OIL NF Benzoic Acid USP Butylated Hydroxyanizole Peglico 5 Oleate
[LABRAFIL M 1944]
The weight of the ACTIVE may alter according to the potency of active raw material
Sect: 6.4
Topical SEMISOLID
ANDA DEVELOPMENT
SECTION VI
SECTION 6
Bioavailability / Bioequivalence
QUALITATIVE COMPARATIVE
INGREDIENTS LIST
Table 4.
[Generic name] Form [USP]
[Active Material] [Generic Company Name Inc. / Ltd.]
Miconazole USP Micronized Pegoxol 7 Stearate [Tefose 63] Heavy Mineral OIL NF Benzoic Acid USP Butylated Hydroxyanizole Peglico 5 Oleate
[LABRAFIL M 1944]
Miconazole USP Pegoxol 7 Stearate [Tefose 63] Heavy Mineral OIL NF Benzoic Acid USP Butylated Hydroxyanizole Peglico 5 Oleate Edetate Disodium 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
Bioavailability / Bioequivalence
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
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:
In vitro release testing is a useful test to assess product sameness under certain scale-up and post-approval changes for semisolid products. 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. bioequivalence.
In vitro release testing, alone, is not a surrogate test for in vivo bioavailability or 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
8
BC No: 1 2 3 4 No:
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
11
BC No:
File 15 Calc-Method: AREA RT AREA HEIGHT 3.63 445 56 7.62 5553456 588456 14.63 445 66 15.93 445 96
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 [Generic Product] Semisolid 000 mg/g [Generic Product] Semisolid 000 mg/g - Waiver hereby being requested. - Waiver hereby being requested. - Waiver hereby being requested.
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).
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
Nov.28, 1996
5 units x 60 g QC Testing
BIOSTUDY
Nov.28, 1996
200 units x 30 g
BIOSTUDY
Refer to Section 12 for complete Packaging and Disbursement summary of Pivotal Lot: 000
Sect: 6.9
Topical SEMISOLID
ANDA DEVELOPMENT
SECTION VI
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).
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] [CRO Company Name Inc. / Ltd.] [Address] [CRO Testing Lab Name Inc. / Ltd.] [Address]
INVESTIGATION SITE
ANALYTICAL CENTER(S)
BIOMETRICAL CENTER
PRINCIPAL INVESTIGATOR CLINICAL STUDY DATES Start Date Completion date DATE OF COMPLETION OF FINAL REPORT Report Code No
S00000
Sect: 6.11
Topical SEMISOLID
ANDA DEVELOPMENT
SECTION VI
SECTION 6
Bioavailability/ Bioequivalence
TABLE OF CONTENTS
VOLUME ONE
1. 2. 3. 4. Section Section Section 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
Bioavailability/ Bioequivalence
----------------------------------------Date
Sect: 6.13
Topical SEMISOLID
ANDA DEVELOPMENT
SECTION VI
SECTION 6
--------------------------------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].
----------------------------------------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 2. Section 3. Section 4. Section 5. Section 6. Section 7. Section 8. Section 9. Section 10. Section 11. Section 12. Section : Project Summary : Rationale for [topical] study according to FDA Guidelines. : 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 the [Active Material] : Analytical Method Report for [Active Material] : Analytical Method Validation for the [Active Material] : Test Results of [Active Material] : Analytical Chromatograms of the [Active Material] : Statistical Data of Standards and Quality Control Samples for the [Active Material]
Sect: 6.17
Topical SEMISOLID
ANDA DEVELOPMENT
SECTION VI
SECTION 6
Bioavailability/ Bioequivalence
TITLE
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
Bioavailability/ Bioequivalence
TITLE
BIOEQUIVALENCE Evaluation of two TOPICAL [Active Material] Preparations in [00] Healthy Volunteers
Volume Three
Case Records Forms
(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
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:
Analytical Method:
The assay methodology selected should ensure the following Specificity Accuracy Inter-day precision (ruggedness) Intra-day precision (ruggedness) Linearity of standard curves Adequate sensitivity Recovery 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
Bioavailability/ Bioequivalence
NOTES
Sect: 6
Topical SEMISOLID
ANDA DEVELOPMENT
SECTION VII
SECTION 7
Sect: 7.1
Topical SEMISOLID
ANDA DEVELOPMENT
SECTION VII
SECTION 7
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
Sect: 7.2
Topical SEMISOLID
ANDA DEVELOPMENT
SECTION VII
SECTION 7
Miconazole USP Micronized Pegoxol 7 Stearate [Tefose 63] Heavy Mineral OIL NF Benzoic Acid USP Butylated Hydroxyanizole Peglico 5 Oleate
[LABRAFIL M 1944]
* The weight of the ACTIVE may alter according to the potency of active raw material
Sect: 7.3
Topical SEMISOLID
ANDA DEVELOPMENT
SECTION VII
SECTION 7
Formula Ingredients 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
Amount in % per gram 2.000 18.000 4.480 0.200 0.005 3.000 0.150 72.165 100.000 %
TOTAL
Sect: 7.4
Topical SEMISOLID
ANDA DEVELOPMENT
SECTION VIII
SECTION 8
8.12 8.13
Sect: 8.1
Topical SEMISOLID
ANDA DEVELOPMENT
SECTION VIII
SECTION 8
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
Sect: 8.2
Topical SEMISOLID
ANDA DEVELOPMENT
SECTION VIII
SECTION 8
Sect: 8.3
Topical SEMISOLID
ANDA DEVELOPMENT
SECTION VIII
SECTION 8
Sect: 8.4
Topical SEMISOLID
ANDA DEVELOPMENT
SECTION VIII
SECTION 8
Representative Certificate of Analysis(a) CoA # CoA # CoA # CoA # CoA # CoA # CoA # CoA #
Miconazole USP [micronized Lot # material] Pegoxol 7 Stearate [Tefose 63] Butylated Hydroxyanizole Benzoic Acid USP Peglico 5 Oleate [LABRAFIL M 1944] Heavy Mineral OIL NF Edetate Disodium USP Purified Water USP
(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
Sect: 8.6
Topical SEMISOLID
ANDA DEVELOPMENT
SECTION VIII
SECTION 8
[ACTIVE MATERIAL]
SPECIFICATIONS TEST RESULTS Complies Complies TEST METHOD
Bulk Density Suppliers CoA - C0000 Particle Size Suppliers CoA - C0000 Bulk Density In-house CoA - C0000 Particle Size In-house CoA - C0000
SI-A076-01 SI-A076-02
Complies Complies
SI-A076-01 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
Remarks In-house CoA Suppliers CoA In-house Ref. Material In-house I R Suppliers I R In-house Ref. material In-house HPLC Suppliers HPLC In-house HPLC
[Active Material]
CoA
[Active Material]
CoA
[Active Material]
CoA
[Active Material]
I R Spectra (or UV)
Approved Supplier Approved Supplier Approved Supplier Approved Supplier Approved Supplier
[Active Material]
I R Spectra (or UV)
[Active Material]
I R Spectra (or UV)
[Active Material]
Typical HPLC Spectra
[Active Material]
Typical HPLC Spectra
[Active Material]
Typical HPLC Spectra
[Active Material]
Typical TLC Photocopy
[Active Material]
Typical TLC Photocopy
[Active Material]
Typical TLC Photocopy
Sect: 8.8
Topical SEMISOLID
ANDA DEVELOPMENT
SECTION VIII
SECTION 8
Attachments.
Page No. ___ to Page No: ___ . Active Ingredients:
- as per table.
-
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
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] -----------------------------------------------[Name of Responsible Person] ----------------------------------------Date
Plant General Manager Pharmaceutical Manufacturing Division [Active Material Company Name Inc. / Ltd.]
[Signature of Responsible Person] -----------------------------------------------[Name 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
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 COMPANYS
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.
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
Representative C of As
[CA388-98] [CA237-98] [CA0637-98] [CA0224-98] [CA0572-98] [CA0637-98]
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 - all Representative Certificates of Analysis in date -
Yes q No. all Routine Certificates of Analysis precede pivotal MNF date Yes q No.
Note : Approved NON ACTIVE Suppliers are not an FDA OGD requirements at the time of publishing (December 1999), but is strongly recommended. NON ACTIVE SUPPLIERS List non-active suppliers only
Sect: 8.12
Topical SEMISOLID
ANDA DEVELOPMENT
SECTION VIII
SECTION 8
Page References:
CoAs Testing Monographs Routine Testing Protocols
Page No. ___ to Page No: ___ . Page No. ___ to Page No: ___ . Page No. ___ to Page No: ___ .
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
PEGOXOL 7 STEARATE
(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
(Trade Name)
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 Where absent from USP / NF add BP or Pharm Eur. Tests
Description Identification Test PURIFIED WATER USP Per week - Microbial Testing Per month - Full USP Monograph
Sect: 8.14
Topical SEMISOLID
ANDA DEVELOPMENT
SECTION IX
SECTION 9
TABLE OF CONTENTS
(Overall ANDA Guideline Requirements for this Section).
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)
Statement of commercial site address of Manufacture(s) Statement of commercial packaging & Labeling site address Statement of commercial site of Distribution site address Address of Facility for QC and Stability Testing
9.5 Brief description of facilities for MNF, testing and stability (no personnel CVs). 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)
4
24 Volume V Drug Development Series Sect: 9.1
ANDA DEVELOPMENT
ANDA DEVELOPMENT
SECTION IX
SECTION 9
Sect: 9.2
ANDA DEVELOPMENT
ANDA DEVELOPMENT
SECTION IX
SECTION 9
Sect: 9.3
ANDA DEVELOPMENT
ANDA DEVELOPMENT
SECTION IX
SECTION 9
10. Housekeeping
Scale-up Department Validation Unit Stability Unit Packaging Materials Lab. Physical Lab. Microbiology Lab. QC Lab. / QA Lab. Development (R&D) Lab. Warehousing
11. Weighing Center 12. Granulation Department 13. Drying Department 14. Milling Department 15. Sieving Department 16. Blending Department 17. Slugging Department 18. Compression 19. Coating Department 20. Packaging Department
10. Housekeeping
Sect: 9.4
ANDA DEVELOPMENT
ANDA DEVELOPMENT
SECTION IX
SECTION 9
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.)
Sect: 9.5
ANDA DEVELOPMENT
ANDA DEVELOPMENT
SECTION IX
SECTION 9
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] -----------------------------------------------[Name of Responsible Person] ----------------------------------------Date
Plant General Manager Pharmaceutical Manufacturing Division [Generic Company Name Inc. / Ltd.]
[Signature of Responsible Person] -----------------------------------------------[Name 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.)
Sect: 9.6
ANDA DEVELOPMENT
ANDA DEVELOPMENT
SECTION X
SECTION 10
TABLE OF CONTENTS
(Overall ANDA Guideline Requirements for this Section).
10.1 10.2 10.3 10.4 10.5 10.6 Title Page and statement Name and Site Address of all Contract Laboratories Registration No. of each Contract Laboratory List of Test(s) or functions to be Performed by Contract Laboratory Certification letter of GMP/GLP Compliance of Contract Laboratory 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
Sect: 10.1
ANDA DEVELOPMENT
ANDA DEVELOPMENT
SECTION X
SECTION 10
(and / or)
----------------------------------------Date
----------------------------------------Date
4
24 Volume V Drug Development Series Sect: 10.2
ANDA DEVELOPMENT
ANDA DEVELOPMENT
SECTION X
SECTION 10
----------------------------------------Date
QA Manager
Pharmaceutical Manufacturing Division [Generic Company Name Inc./Ltd.]
----------------------------------------Date
Production Manager
Pharmaceutical Manufacturing Division [Generic Company Name Inc./Ltd.]
Sect: 10.3
ANDA DEVELOPMENT
ANDA DEVELOPMENT
SECTION X
SECTION 10
(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
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
STATEMENT
Where Company has NO previous convictions AND does not use a debarred person in connection with the ANDA
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] ------------------------------------------------[Name of Responsible Person] --------------------------------------Date
______________________
Date
Sect: 10.6
ANDA DEVELOPMENT
ANDA DEVELOPMENT
STATEMENT
Where Company has a previous conviction but does not use a debarred person in connection with the ANDA
n behalf of [3rd Party Company Name Inc. / Ltd.], we hereby certify, 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] ------------------------------------------------[Name 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
----------------------------------------Date
Production Manager
Pharmaceutical Manufacturing Division
Sect: 10.8
ANDA DEVELOPMENT
ANDA DEVELOPMENT
SECTION XI
SECTION 11
TABLE OF CONTENTS
(Current ANDA Guideline Requirements for this Section.)
Description of Manufacturing Process Manufacturing Procedure Flow Chart Blank Master Production Batch Records (largest intended commercial production lots.) Blank Packaging Records (largest intended commercial production lots.) Formula comparison (compares pivotal batch parameters with intended commercial production) Equipment Comparison (compares pivotal batch parameters with intended commercial production) Description of Intended Commercial Packaging Operation
Reprocessing Statement (if reprocessing step is undertaken full data, process validation rework specifications and stability must be shown in Section 21)
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.
Sect:11. 1
Topical SEMISOLID
ANDA DEVELOPMENT
SECTION XI
SECTION 11
Sect:11. 2
Topical SEMISOLID
ANDA DEVELOPMENT
SECTION XI
SECTION 11
1. 2. 3.
4.
5.
6.
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
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:
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.
Sect:11. 4
Topical SEMISOLID
ANDA DEVELOPMENT
SECTION XI
SECTION 11
Production In-process
Testing Schedule:
TEST PERFORMED
Bulk Description
Sample Size
At start.
10
Cap Torque
The testing frequency is performed twice when the overall filling time is less than four hours.
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
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 PERFORMED
Material Description
Sample Size
1 (1)
20 (1)
60 min
CAP TORQUE
6 (1)
60 min
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
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.
Sect:11. 7
Topical SEMISOLID
ANDA DEVELOPMENT
SECTION XI
SECTION 11
Product name: Batch Number: Department: Precautions: Caution: Cat./Formula No: Based on PQ:
000
______________
# F0000 Batch # PQ-000
Batch Size: 0000 Kg/units Sub-lot No: 1 2 3 Manufacture Date: Month DD, YY SEMISOLID PIVOTAL BATCH Validation Lot Commercial Lot Original - No Change : Change
KEY: Precautions:
Wear Mask and Gloves Wear disposable overalls Use 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 Pregnant women prohibited in this area Do not heat above 00C
Room humidity below 30%
Caution:
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
Weighing Date :
Page 1 of 2 pages
per [150] kg
Kg g
000 780 300 7 087 000 500 225 440 500
665
mg
mL
Pegoxol 7 Stearate [Tefose 63] Heavy Mineral OIL NF Benzoic Acid USP Butylated Hydroxyanizole
27 3
500 500
31 3 4
1 1
10
108 108
247 247
500 500
150 150
000 000
APPROVED
_____________ Department __________ R &D _______________ RA _________/________ QC / QA
Sect:11. 9
Topical SEMISOLID
ANDA DEVELOPMENT
SECTION XI
SECTION 11
Weighing Date :
Page 2 of 2 pages
per [300] kg
Kg g
000 560 600 15 175 000 000 450 880 000
330
mg
mL
Pegoxol 7 Stearate [Tefose 63] Heavy Mineral OIL NF Benzoic Acid USP Butylated Hydroxyanizole
54 7
000
62 6 9
2 3
21
216 216
495 495
300 300
000 000
APPROVED
_____________ Department __________ R &D _______________ RA _________/________ QC / QA
Sect:11. 10
Topical SEMISOLID
ANDA DEVELOPMENT
SECTION XI
SECTION 11
MANUFACTURING INSTRUCTIONS
Step 1. IDENTIFY the equipment and verify the cleanliness prior to use.
Machine
Sign A+B
Date
APPROVED
_____________ Department __________ R &D _______________ RA _______/________ QC / QA
Sect:11. 11
Topical SEMISOLID
ANDA DEVELOPMENT
SECTION XI
SECTION 11
MANUFACTURING INSTRUCTIONS
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] C (Target: [95] C). (iii) Hold the heated Water at the target temperature for NLT60 minutes Target Temperature Time of Heating Total Process Time [ ] C). [ ] [ ] min
Machine
Sign A+B
Date
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 [ [ [ [ ] C ] ] ] min
APPROVED
_____________ Department __________ R &D _______________ RA _________/________ QC / QA
Sect:11. 12
Topical SEMISOLID
ANDA DEVELOPMENT
SECTION XI
SECTION 11
MANUFACTURING INSTRUCTIONS
ADDITION OF AQUEOUS PHASE
Step 10. RECORD the Aqueous and Oil Phase temperatures. Temperature of AQUEOUS Phase NMT [30] C (Target: 280C [20C]) Temperature of OIL Phase NMT [30] 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..
Machine
Sign A+B
Date
APPROVED
_____________ Department __________ R &D _______________ RA _________/________ QC / QA
Sect:11. 13
Topical SEMISOLID
ANDA DEVELOPMENT
SECTION XI
SECTION 11
MANUFACTURING INSTRUCTIONS
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
Machine
Sign A+B
Date
APPROVED
_____________ Department __________ R &D _______________ RA _________/________ QC / QA
Sect:11. 14
Topical SEMISOLID
ANDA DEVELOPMENT
SECTION XI
SECTION 11
Purified Water USP Water Soluble Excipients Nitrogen blanket Solvent NF Antioxidant NF Active USP MIXER
Water USP Purified Water Lipophyllic Emulgent
88 -92 C
1st RINSE
Nitrogen blanket
OIL PHASE MIXER (S/S
Mixing vessel)
Viscosity Agent
(Specify Type) 0 at controlled temp - T C
Cool to 280C
Ultra-clean FILLING
ANDA DEVELOPMENT
SECTION XI
SECTION 11
Process
Attachment # 1 Attachment # 2 In-process Attachment # 3 Attachment # 4 Final Bulk pH Print-Outs of Bulk. Viscosity Print-Out of Bulk material. Weight Print-Outs of the raw material / solvents. Temperature Print-Outs of manufacturing process stage .
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
Limit: NLT 98.0% Limit: NLT 98.0% (based on actual quantities processed). NLT 95.0%
____________ Kg ____________ Kg
Sect:11. 17
Topical SEMISOLID
ANDA DEVELOPMENT
SECTION XI
SECTION 11
Limit: 000 - 000 mL Limit: 0.0 - 0.0 Limit: 0000 - 0000 cp.
In-Process Semisolid Content Uniformity Particle Size (microns) Yields Actual Bulk Weight Calculated Filling Yield Actual Filling Yield Overall Filling Yield
Limit: 94.0 - 106.0% of labeled amount RSD 6.0% (as per attached specifications) Median 000 Limit: 000 - 000
Limit: NLT 98.0% (based on actual quantities processed) Limit: NLT 100.0% (based on bulk weight/ target fill weight). NMT 2.0% unexplained loss from the previous final blend step NLT 95.0%
Note: Exact Decimal points have been set for each specification
Sect:11. 18
Topical SEMISOLID
ANDA DEVELOPMENT
SECTION XI
SECTION 11
00.0 % 00.0 % NMT 2.0% unexplained loss from the previous step
Sect:11. 19
Topical SEMISOLID
ANDA DEVELOPMENT
SECTION XI
SECTION 11
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. The Infra Red Absorption Spectrum conforms to the Reference Standard The Chromatogram of the sample solution exhibits a peak with the same retention time as the standard solution.
Identification A: Identification B:
Target 000
Target 0.0 Target 0000
Uniformity of Dosage Units: Content Uniformity Total Microbial Count Total Aerobic Count
Objectionable Organisms
Conforms to the current USP NMT 100 NMT 100 CFU / g CFU / g
Impurities /Degradation Products determination - Each Individual: - Any other Individual: - Total: Assay (Preservative)
(Where Appropriate)
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
Assay (Active)
Sect:11. 20
Topical SEMISOLID
ANDA DEVELOPMENT
SECTION XI
SECTION 11
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.
Sect:11. 21
Topical SEMISOLID
ANDA DEVELOPMENT
SECTION XI
SECTION 11
INGREDIENT
Miconazole USP Micronized Pegoxol 7 Stearate [Tefose 63] Heavy Mineral OIL NF Benzoic Acid USP Butylated Hydroxyanizole Peglico 5 Oleate Edetate Disodium USP Purified Water USP
Total
00.00 00.00 00.00 00.00 00.00 00.00 00.00 00.00 00.00 00.00 000.000
00.00 00.00 00.00 00.00 00.00 00.00 00.00 00.00 00.00 00.00 000.000
00.00 00.00 00.00 00.00 00.00 00.00 00.00 00.00 00.00 00.00 000.000
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
PROCESSING KETTLE MIXER I MIXER II KING AIR MACHINE JD / BB ZANASSI FILLING MACHINE LA-60 ALL FILL FILLING MACHINE SMR / 14 KING CAPPER C80 YAMATO CHECK WEIGHER Equipment Variation Manufacturing Area Staff SOP
Production Production Production Production Production Production Production Production NONE Production Production Production
Production Production Production Production Production Production Production Production NONE Production Production Production
Sect:11. 23
Topical SEMISOLID
ANDA DEVELOPMENT
SECTION XI
SECTION 11
Capping (Tube/Jar)
Container Label
and Outsert Attachment
Sect:11. 24
Topical SEMISOLID
ANDA DEVELOPMENT
SECTION XI
SECTION 11
Type
Serial #
Schenck
1000-S AccuRate
No: 543123
King
Air Cleaning
Cream Filling
ALLFILL KING
Capper
Capping
KING CAPPER
CAP 80
22322234
Torque
Torque
22349987 5664
6.
Groninger
Outserter
7.
Prestek
53342
(1)
Average figures for containers per minute output for Slow and High Speed. All indicated machine outputs are adjusted to the Filling rate.
(2)
Sect:11. 25
Topical SEMISOLID
ANDA DEVELOPMENT
SECTION XI
SECTION 11
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.
--------------------------------------Date
[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
------------------------------------Date
Sect:11. 28
Topical SEMISOLID
ANDA DEVELOPMENT
SECTION XII
SECTION 12
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
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.
Sect:12. 1
Topical SEMISOLID
ANDA DEVELOPMENT
SECTION XI
SECTION 12
Sect:12. 2
Topical SEMISOLID
ANDA DEVELOPMENT
SECTION XII
SECTION 12
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.
Sect:12. 3
Topical SEMISOLID
ANDA DEVELOPMENT
SECTION XII
SECTION 12
Bulk Description
Within 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.
10
The testing frequency is performed twice when the overall filling time is less than four hours.
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
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SECTION 12
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 PERFORMED
Material Description Individual Fill Weight
Sample Size
1 (1) 20 (1)
6 (1)
60 min
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
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.
Sect:12. 6
Topical SEMISOLID
ANDA DEVELOPMENT
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SECTION 12
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 Sub-lot No: 1 2 3 Manufacture Date: Month DD, YY # F0000 SEMISOLID Batch # PQ000 PIVOTAL BATCH Validation Lot Commercial Lot
Original - No Change : Change
KEY: Precautions:
Wear Mask and Gloves Wear disposable overalls Use 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 Pregnant women prohibited in this area Do not heat above 00C
Room humidity below 30%
Caution:
Sect:12. 7
Topical SEMISOLID
ANDA DEVELOPMENT
SECTION XII
SECTION 12
Weighing Date :
Page 1 of 1 pages
per [150] kg
Kg g
000 780 300 7 087 000 500 225 440 500
665
mg
mL
Pegoxol 7 Stearate [Tefose 63] Heavy Mineral OIL NF Benzoic Acid USP Butylated Hydroxyanizole
27 3
500 500
31 3 4
1 1
10
108 108
247 247
500 500
150 150
000 000
APPROVED
_____________ Department __________ R &D _______________ RA _________/________ QC / QA
Sect:12. 8
Topical SEMISOLID
ANDA DEVELOPMENT
SECTION XII
SECTION 12
MANUFACTURING INSTRUCTIONS
Step 1. IDENTIFY the equipment and verify the cleanliness prior to use.
Machine
Sign A+B
Date
APPROVED
_____________ Department __________ R &D _______________ RA _______/________ QC / QA
Sect:12. 9
Topical SEMISOLID
ANDA DEVELOPMENT
SECTION XII
SECTION 12
MANUFACTURING INSTRUCTIONS
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] C (Target: [95] C). (iii) Hold the heated Water at the target temperature for NLT60 minutes Target Temperature Time of Heating Total Process Time [ ] C). [ ] [ ] min
Machine
Sign A+B
Date
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 [ [ [ [ ] C ] ] ] min
APPROVED
_____________ Department __________ R &D _______________ RA _________/________ QC / QA
Sect:12. 10
Topical SEMISOLID
ANDA DEVELOPMENT
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SECTION 12
MANUFACTURING INSTRUCTIONS
ADDITION OF AQUEOUS PHASE
Step 10. RECORD the Aqueous and Oil Phase temperatures. Temperature of AQUEOUS Phase NMT [30] C (Target: 280C [20C]) Temperature of OIL Phase NMT [30] 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..
Machine
Sign A+B
Date
APPROVED
_____________ Department __________ R &D _______________ RA _________/________ QC / QA
Sect:12. 11
Topical SEMISOLID
ANDA DEVELOPMENT
SECTION XII
SECTION 12
MANUFACTURING INSTRUCTIONS
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
Machine
Sign A+B
Date
APPROVED
_____________ Department __________ R &D _______________ RA _________/________ QC / QA
Sect:12. 12
Topical SEMISOLID
ANDA DEVELOPMENT
SECTION XII
SECTION 12
Purified Water USP Water Soluble Excipients Nitrogen blanket Solvent NF Antioxidant NF Active USP MIXER
Water USP Purified Water Lipophyllic Emulgent
88 -92 C
1st RINSE
Nitrogen blanket
OIL PHASE MIXER (S/S
Mixing vessel)
Viscosity Agent
(Specify Type) 0 at controlled temp - T C
Cool to 28 C
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
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SECTION 12
Process
Attachment # 1 Attachment # 2 In-process Attachment # 3 Attachment # 4 Final Bulk pH Print-Outs of Bulk. Viscosity Print-Out of Bulk material. Weight Print-Outs of the raw material / solvents. Temperature Print-Outs of manufacturing process stages .
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
Product: [Generic name] SEMISOLID [USP] [000.0] mg/g Quantity 000000 Yields Manufacturing Yield Total Final Bulk Yield MNF Date:
Limit: NLT 98.0% Limit: NLT 98.0% (based on actual quantities processed).
NLT 95.0%
1 2
Sect:12. 15
Topical SEMISOLID
ANDA DEVELOPMENT
SECTION XII
SECTION 12
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) Fill Weight (5.0%) Individual Fill Weight (7.5%) Yields Actual Bulk Weight Calculated Filling Yield Actual Filling Yield Overall Filling Yield
Limit: 94.0 - 106.0% of labeled amount RSD 6.0% Target 000 Target 000.0 Limit: 000 - 000 mL Limit: 000.0 - 000.0 g
Limit: NLT 98.0% (based on actual quantities processed) Limit: NLT 100.0% (based on bulk weight / target fill weight). NMT 2.0% unexplained loss from the previous final blend step NLT 95.0%
Note: Exact Decimal points have been set for each specification
Sect:12. 16
Topical SEMISOLID
ANDA DEVELOPMENT
SECTION XII
SECTION 12
Product: [Generic name] SEMISOLID [USP] [000.0] mg/g. Quantity 000000 Weight Controls Target Fill weight 000.0 (g) Weight of 10 Containers #1 (g) Weight of 10 Containers #2 (g) Weight of 10 Containers #3 (g) Weight of 10 Containers #4 (g) Weight of 10 Containers #5 (g) Weight of 10 Containers #6 (g) Weight of 10 Containers #7 (g) Weight of 10 Containers #8 (g) 000.0 000.0 000.0 000.0 000.0 000.0 000.0 000.0 000.0 MNF Date: Lowest
Lot No: 000 Mean 000.0 000.0 000.0 000.0 000.0 000.0 000.0 000.0 000.0 Highest 000.0 000.0 000.0 000.0 000.0 000.0 000.0 000.0 000.0
In-Process Yields Yield after filling vs. bulk material Yield after filling to theoretical Permissible Loss
00.0 % 00.0 % NMT 2.0% unexplained loss from the previous step
Sect:12. 17
Topical SEMISOLID
ANDA DEVELOPMENT
SECTION XII
SECTION 12
Target 000
Target 0.0 Target 0.000 Target 0000
Uniformity of Dosage Units: Content Uniformity Total Microbial Count Total Aerobic Count Objectionable Organisms Impurities /Degradation Products determination - Each Individual: - Any other Individual: - Total: Assay (Preservative)
Conforms to the current USP NMT 100 CFU / mL NMT 100 CFU / mL Absent: S aureus; E coli; P aerugenosa; Salmonella species; Indicator orgs
NMT 0.5% of the labeled amount NMT 0.5% of the labeled amount NMT 2.0% of the labeled amount
Limit: 50.0 - 110.0% of labeled amount [00.0] - [00.0] mg / g Limit: 90.0 - 110.0% of labeled amount [00.0] - [00.0] mg / g
Assay (Active)
Sect:12. 18
Topical SEMISOLID
ANDA DEVELOPMENT
SECTION XII
SECTION 12
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.
Sect:12. 19
Topical SEMISOLID
ANDA DEVELOPMENT
SECTION XII
SECTION 12
Container Label
and Outsert Attachment
Sect:12. 20
Topical SEMISOLID
ANDA DEVELOPMENT
SECTION XII
SECTION 12
Type
Serial #
Schenck
1000-S AccuRate
No: 543123
King
Air Cleaning
MK-2994
Cream Filling
ALLFILL KING CAPPER FILLER(1) CAP 80
L-333 L-334
Count
50 50* 100 100*
Capper
Capping
22322234
Torque checker
22349987 5664
6.
Groninger
7.
Prestek
53342
(1)
Average figures for containers per minute output for Slow and High Speed. All indicated machine outputs are adjusted to the Fill rate.
(2)
Sect:12. 21
Topical SEMISOLID
ANDA DEVELOPMENT
SECTION XII
SECTION 12
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] 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 Signed by (Warehouse) (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
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.
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
LOW SPEED
Fill Weight
(g)
HIGH SPEED
Fill Weight
(g)
TARGET SPEED
Fill Weight
(g)
NO.
Machine Type 1 2 3 4 5 6 7 8 9 10 11 12 13 14 14 16 17 18 19 20 AVG. RSD % USL LSL 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 -
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
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
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) Stability testing
Bulk Material:
[150] Kg packed in : [Two] bulk containers x 75 Kg Packaging date: M onth DD, 1999
(US)
(EU)
Sect:12. 25
Topical SEMISOLID
ANDA DEVELOPMENT
SECTION
XII
SECTION 12
Nov.28, 1996
Sect:12. 26
Topical SEMISOLID
ANDA DEVELOPMENT
SECTION XII
SECTION 12
Nov.28, 1996
5 units x 60 g QC Testing
BIOSTUDY
Nov.28, 1996
200 units x 30 g
BIOSTUDY
Sect:12. 27
Topical SEMISOLID
ANDA DEVELOPMENT
NOTES
Sect:12. 28
Topical SEMISOLID
ANDA DEVELOPMENT
SECTION XIII
SECTION 13
TABLE OF CONTENTS
(Overall ANDA Guideline Requirements for this Section).
The
container closure system for the drug product are described in detail in the specifications and drawings included in this section. 13.1 13.2 Outlines for Packaging and Labeling Procedures 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.
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
4
24 Volume V Drug Development Series Sect: 13.1
ANDA DEVELOPMENT
ANDA DEVELOPMENT
SECTION XIII
SECTION 13
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.
333
24 Volume V Drug Development Series Sect: 13.2
ANDA DEVELOPMENT
ANDA DEVELOPMENT
SECTION XIII
SECTION 13
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 packed 2.2 TOTAL Packs rejected 2.3 TOTAL Packs sampled 100 x [Total no. of units] = _______% Theoretical no. of units Compare to last production stage (2%) Signature _______ Date ________ 2.4 TOTAL PACKS Department Material Balance:
3. TOTAL BATCH RECONCILIATION (OF OVERALL PACKAGING PROCESS) 3.1 3.2 Material Rejected
______________________ units
Samples Taken
______________________ units
Sect: 13.3
ANDA DEVELOPMENT
ANDA DEVELOPMENT
TABLE OF CONTENTS
(Overall ANDA Guideline Requirements for this Section). Glass Thermoplastic Containers
Solid oral dosage forms.
FROM THE CONTAINER MANUFACTURER:6 Container Specifications:-name, product code and manufacturer (including) - drawings / diagrams with annotated dimensions - Tests performed on closure to include USP <661> and <671> n Light transmission and n moisture vapor permeation - Certificate of Conformance meeting all USP XXIII - Complies to 21 CFR requirements / Food Additives Regulations Certificate of Analysis DSC thermal analysis (for thermoplastic containers only) 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
7 8
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
4
24 Volume V Drug Development Series Sect: 13.4
ANDA DEVELOPMENT
ANDA DEVELOPMENT
SECTION XIII
SECTION 13
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.
4
24 Volume V Drug Development Series Sect: 13.5
ANDA DEVELOPMENT
ANDA DEVELOPMENT
SECTION XIII
SECTION 13
TABLE OF CONTENTS
(Overall ANDA Guideline Requirements for this Section).
FROM THE GENERIC FIRM'S QC LAB:24 25 26 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 34 35 i. LoA from manufacturer referencing their facility DMF #. ii. LoA from liner manufacturer referencing DMF # of liner
STATEMENTS OF COMPLIANCE
Statement of GMP compliance of liner manufacturer Statements of Compliance with Applicable Sections of the Indirect Food Additive Regulations (21 CFR).
Note: A change from one type of resin to another type - requires prior approval. A change from one type of resin to the same type - prior approval not required. Changing resins requires an equivalency protocol which demonstrates sameness. For solid dosage forms only, The USP section <661> is in fact an existing compendial interchangeability protocol for equivalent HDPE resins.
4
24 Volume V Drug Development Series Sect: 13.6
ANDA DEVELOPMENT
ANDA DEVELOPMENT
SECTION XIII
SECTION 13
TABLE OF CONTENTS
(Overall ANDA Guideline Requirements for this Section).
Foam Seals
Pressure sensitive, tamper resistant, adhesive seals
(data required for each container seal) Solid oral dosage forms.
FROM THE GENERIC FIRM'S QC LAB:36 37 38 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
STATEMENTS OF COMPLIANCE
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.
Sect: 13.7
ANDA DEVELOPMENT
ANDA DEVELOPMENT
SECTION XIII
SECTION 13
Nozzles / Applicators
(required for Applicator/Nozzle ) Topical Dosage Forms.
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)
Sect: 13.8
ANDA DEVELOPMENT
ANDA DEVELOPMENT
SECTION XIII
SECTION 13
TABLE OF CONTENTS
(Overall ANDA Guideline Requirements for this Section)
Certificates of Analysis outlining the components used for packages containing; 00 / 000 cc Flexible Tube 00 / 000 cc HDPE (Bulk) Jar (HDPE nozzle) (HDPE cap with liner).
Technical Specifications (Diagrams &Drawings) of each component. Certificates of Analysis of [Generic Company Name Inc./Ltd.] packages. DMF Referral Letters
Sect: 13.9
ANDA DEVELOPMENT
ANDA DEVELOPMENT
SECTION XIII
SECTION 13
Pivotal Lot
ITEM
TYPE 1
Drug Plastics & Glass Co. Inc. 00 / 000cc round, HDPE JAR HDPE Quantum LR-734043 U.S. CAN (Penn-Wheeling Closure Corp.) White Ampacet 11078 Polyethylene HDPE LDPE 00 / 00 mm Tekni-Plex Inc. Foamseal PS 22 TEKNISEAL RVT + LF Lot #00000 CoA #0000 Lot #00000 CoA #0000 Lot #00000 CoA #0000 Lot #00000 CoA #0000 Lot #00000 CoA #0000 Lot #00000
TYPE 2
Drug Plastics & Glass Co. Inc. 00 / 000cc round, HDPE JAR HDPE Quantum LR-734043 U.S. CAN (Penn-Wheeling Closure Corp.) White Ampacet 11078 Polyethylene HDPE LDPE 00 / 00 mm Tekni-Plex Inc. Foamseal PS 22 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
TYPE 3
Drug Plastics & Glass Co. Inc. 00 / 000cc HDPE/
COLLAPSIBLE TUBE
TYPE 4
Drug Plastics & Glass Co. Inc. 00 / 000cc HDPE/
COLLAPSIBLE TUBE
Container manufacturer Container size 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
(coated metal)
HDPE Quantum LR-734043 U.S. CAN (Penn-Wheeling Closure Corp.) White Ampacet 11078 Polyethylene HDPE LDPE 00 / 00 mm -
(coated metal)
HDPE Quantum LR-734043 U.S. CAN (Penn-Wheeling Closure Corp.) White Ampacet 11078 Polyethylene HDPE LDPE 00 / 00 mm -
Lot #00000 CoA #0000 Lot #00000 CoA #0000 Lot #00000 CoA #0000 Lot #00000 CoA #0000 CoA #00000
Lot #00000 CoA #0000 Lot #00000 CoA #0000 Lot #00000 CoA #0000 Lot #00000 CoA #0000 CoA #00000
Sect: 13.10
ANDA DEVELOPMENT
ANDA DEVELOPMENT
SECTION XIII
SECTION 13
HDPE:
Description White, Round HDPE Bottle with 29/33/53 mm/400 Neck Finish Code 000 Size: 30, 50, 750 cc
QUANTUM
DMF # 885
AMPACET 11078 PE, DMF # 8354 DMF [0000] DMF [0000] Month DD, YYYY
Complies with Food Additives Regulations Part 170 -199 Relevant data copies of the manufacturers current DMF # [0000] (Type II) are attached for ease and simplicity of review. 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. Where product stability testing is conducted referencing this specific item's code then all above specifications shall apply to the container-closure item.
Stability Testing
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24 Volume V Drug Development Series Sect: 13.11
ANDA DEVELOPMENT
ANDA DEVELOPMENT
SECTION XIII
SECTION 13
CLOSURES
Description CODE & Size
Fits Container Size HDPE cap, 38 mm / 400 White, Unlined Polypropylene Cap with Pressure Sensitive Inner Seal Code 000 000 & 000 cc 29/33 mm diameter
Complies with Food Additives Regulations Part 170 -199 Relevant data copies of the manufacturers current DMF # [0000] (Type II) are attached for ease and simplicity of review. 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. Where product stability testing is conducted referencing this specific item's code then all above specifications shall apply to the container-closure item.
Stability Testing
Sect: 13.12
ANDA DEVELOPMENT
ANDA DEVELOPMENT
SECTION XIII
SECTION 13
Manufacturer:
DMF (MFG) DMF (Item) LoA
21 CFR Documentation
Complies with Food Additives Regulations Part 170 -199 Relevant data copies of the manufacturers current DMF # [0000] (Type II) are attached for ease and simplicity of review. 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. Where product stability testing is conducted referencing this specific item's code then all above specifications shall apply to the container-closure item.
Stability Testing
Sect: 13.13
ANDA DEVELOPMENT
ANDA DEVELOPMENT
SECTION XIII
SECTION 13
Tekniseal X-14(Polyethylene)
Code 000 Size: [00] mm diameter
21 CFR
[00] mm diameter
DMF # 1378 DMF # 1378 Month DD, YYYY
Complies with Food Additives Regulations Part 170 -199 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.
Sect: 13.14
ANDA DEVELOPMENT
ANDA DEVELOPMENT
SECTION XIII
SECTION 13
Collapsible Tubes
Description Inner Coating Length Size Manufacturer Seal DMF of MNF Product DMF LoA : : : : : : : : :
[000] cc lined collapsible LD Tube with HDPE nozzle Epoxy Coat [0.0] mm thick [00] mm
Heat sealed or breaking inner seal DMF [0000] DMF [0000] Month DD, YY
Extended Nozzle
Description: Size Fits Sizes Manufacturer: DMF of MNF Product DMF : : : : : :
[000] White, HDPE Nozzle [00] mm (length)
Sect: 13.15
ANDA DEVELOPMENT
ANDA DEVELOPMENT
SECTION XIII
SECTION 13
Elastomeric closures for injections n n Aerosols Containers n n n n n n n n n Containers n Cotton Light transmission Chemical resistance - Glass Containers Biological Tests - Plastic and others Polymer Physiochemical Test - Plastics Polyethylene Containers Polyethylene Terephthalate / Terephthalate G Bottles Single Unit Containers & Unit Dose (Containers for Non-sterile solid & liquids dosage forms ) Customized Patient Medication Packages Permeation - n Multiple unit containers for capsules and tablets Permeation - n Single unit containers and Unit dose for capsules and tablets Cotton or Purified Rayon Monograph (with exclusions) Ointments Biological Test Procedures Physiochemical Test Procedures
22. 23.
<771> <1151>
Ophthalmic
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
ANDA DEVELOPMENT
SECTION XIV
SECTION 14
TABLE OF CONTENTS
(Overall ANDA Guideline Requirements for this Section). 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 methods 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 USPC Inc. Pharmacopeial Forum Published Reference Works
Sect: 14.1
Topical SEMISOLID
ANDA DEVELOPMENT
SECTION XIV
SECTION 14
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
ANDA DEVELOPMENT
SECTION XIV
SECTION 14
C of A No.
C 000-01
[000.0] mg per g
SPECTRA
C 000-01
SPECTRA
C 000-01
SPECTRA
C 000-01
[000.0] mg per g
C 000-01
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
Analytical Method
Stability PURPOSES
Not Applicable
QC Release PURPOSES
QC-021-00
Method Validation
SI -V -021-00
Active Ingredient Finished Product Physical TESTS Finished Product Assay / Impurities Finished Product Microbial testing
SI-A22-00
SI-A23-00 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
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 Effective Date: DD/MM/YY
APPROVED
_____________ Department __________ R &D _______________ RA _________/________ QC / QA
Sect: 15.1
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. - US Pharmacopoeia - US Pharmacopoeial Forum - BP Pharmacopoeia - Ph. Eur. Pharmacopoeia - 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. - US Pharmacopoeia - US Pharmacopoeial Forum - BP Pharmacopoeia - Ph. Eur. Pharmacopoeia - In-house Stability Indicting methods (based on BP Pharmacopoeia). This analytical section contains: Active Ingredient Test Methods Final Blend Test Methods Finished Product Test Methods (Release) Finished Product Test Methods (Stability) Note: Additional separately bound copies are provided in accordance with 21 CFR 314.50(e)(2)(i). Assay/Impurities Degradation Products Determination Dissolution Test Test of Appearance (ref. pages [00] to [00]) (ref. pages [00] to [00]) (ref. pages [00] to [00]) (ref. pages [00] to [00]) (ref. pages [00] to [00])
APPROVED
_____________ Department __________ R &D _______________ RA _________/________ QC / QA
Sect: 15.2
ANDA Development
ANDA DEVELOPMENT
SECTION XV
SECTION 15
Analytical Methods
SUMMARY OF ANALYTICAL METHODS AND METHOD NUMBERS:
Analytical Method
Active Material Stability Indicating Assay Impurity Limit tests Validation of Stability Indicating Assay
Method No.
SI-1000-01 SI-1000-01 SI-1000-01
In-process Material Content Uniformity (on bulk material) Microbial Limit test (on bulk material) SI-2000-01
Finished Product Release QC Release Assay Impurity Limit tests Content Uniformity (on bulk material) Microbial Limit test (on bulk material)
Finished Product Stability Methods Stability Indicating Assay Impurity Limit tests Validation of Stability Indicating Assay Microbial Limit test Preservative Efficacy test SI-5000-01 SI-5000-01 SI-5000-01 SI-5000-01 SI-5000-01
APPROVED
_____________ Department __________ R &D _______________ RA _________/________ QC / QA
Sect: 15.3
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.
APPROVED
_____________ Department __________ R &D _______________ RA _________/________ QC / QA
Sect: 15.4
ANDA Development
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 <2% <2%
4C 4C
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).
Time
(hr)
Raw Material;
Remaining Substance. (%) 100.2 101.3 101.1 99.8 77.5 79.7 Peak Purity, (Figure) pure pure pure pure pure pure
Tablets
Remaining Substance
90 160 40 70 37 Room
12 2 14 10 3 20
APPROVED
_____________ Department __________ R &D _______________ RA _________/________ QC / QA
Sect: 15.5
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. 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.
APPROVED
_____________ Department __________ R &D _______________ RA _________/________ QC / QA
Sect: 15.6
ANDA Development
ANDA DEVELOPMENT
Peak Purity
(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.
[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
APPROVED
_____________ Department __________ R &D _______________ RA _________/________ QC / QA
Sect: 15.7
ANDA Development
ANDA DEVELOPMENT
SYSTEM REPRODUCIBILITY
SAMPLE No. PEAK AREAS
1. 2. 3. 4. 5. 6. 7. 8. 9. 10.
= = =
0.5 - 1.0
APPROVED
_____________ Department __________ R &D _______________ RA _________/________ QC / QA
Sect: 15.8
ANDA Development
ANDA DEVELOPMENT
METHOD REPRODUCIBILITY
SAMPLE No
Batch No: 1 2 3 4 5 6 7 8 9 10
ASSAY %
= = = 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
APPROVED
_____________ Department __________ R &D _______________ RA _________/________ QC / QA
Sect: 15.9
ANDA Development
ANDA DEVELOPMENT
ACCURACY
INJECTION No PEAK AREA CALCULATED CONC. % ACCURACY
1 2 3 4 5 6 7 8 9 10
[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).
APPROVED
_____________ Department __________ R &D _______________ RA _________/________ QC / QA
Sect: 15.10
ANDA Development
ANDA DEVELOPMENT
[5] Recovery
RECOVERY - EXTRACTION
TIME IN MINUTES Batch No: % ASSAY
0.5 T T 1.5 T
APPROVED
_____________ Department __________ R &D _______________ RA _________/________ QC / QA
Sect: 15.11
ANDA Development
ANDA DEVELOPMENT
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
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
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.
APPROVED
_____________ Department __________ R &D _______________ RA _________/________ QC / QA
Sect: 15.12
ANDA Development
ANDA DEVELOPMENT
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
= = =
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
APPROVED
_____________ Department __________ R &D _______________ RA _________/________ QC / QA
Sect: 15.13
ANDA Development
ANDA DEVELOPMENT
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 10, C-18, 300 x 3.9mm (OOH-2117-CD) Column 2: Waters -Bondapak 10, C-18, 300 x 3.9mm (27324) CONDITION
Condition Column No. 1 2 3 4 5 1 1 1 1 2 Flow Rate mL/min 2.5 2.2 2.8 2.5 2.5 Buffer Conc. (%) 0.1 0.1 0.1 0.15 0.1 RRT
RESULTS
Tf RSD RSD bet. LOQ of bet. LOQ of [Active] [Impurity] <10 <10 <10 <10 <10 <10 <10 <10 <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.
APPROVED
_____________ Department __________ R &D _______________ RA _________/________ QC / QA
Sect: 15.14
ANDA Development
ANDA DEVELOPMENT
RUGGEDNESS
ANALYST No 1 1 2 3 4 5 6 7 8 9 10 % ASSAY Column I ANALYST No 2 % ASSAY Column 2
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.
APPROVED
_____________ Department __________ R &D _______________ RA _________/________ QC / QA
Sect: 15.15
ANDA Development
ANDA DEVELOPMENT
[10] Typical Chromatograms. Representative chromatograms of the following traces are routinely provided:-
APPROVED
_____________ Department __________ R &D _______________ RA _________/________ QC / QA
Sect: 15.16
ANDA Development
ANDA DEVELOPMENT
Typical Chromatograms
When Representative Chromatograms are displayed - all peaks are LABELED with the peak name and RRT.
Label the peak clearly Name and Retention time (8.78 min)
[11] Conclusion.
Acknowledgment
to references as well as attachments such as the drug product formula are attached at the end of the validation protocol.
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.
APPROVED
_____________ Department __________ R &D _______________ RA _________/________ QC / QA
Sect: 15.17
ANDA Development
ANDA DEVELOPMENT
NOTES
APPROVED
_____________ Department __________ R &D _______________ RA _________/________ QC / QA
Sect: 15.18
ANDA Development
ANDA DEVELOPMENT
SECTION XVI
SECTION 16
TABLE OF CONTENTS
(Overall ANDA Guideline Requirements for this Section).
16.1 16.2 16.3 16.4 Section Page and Title. Stability Protocol for Post Approval Production Batches (ANDA commitment) Expiration Dating Period Statement Package Configuration and sizes (largest and smallest) used in stability studies. Stability Protocol used for Pivotal lot Stability Reports indicating results of Pivotal lot from 3 months accelerated and controlled room temperature studies Stability Data Summary Report (plus 0 and 12 week graphs).
16.5 16.6
16.7
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
Sect: 16.1
ANDA Development
ANDA DEVELOPMENT
SECTION XVI
SECTION 16
OVERVIEW
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
4
24 VOLUME DRUG DEVELOPMENT SERIES:
Sect: 16.2
ANDA Development
ANDA DEVELOPMENT
SECTION XVI
SECTION 16
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) 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. 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] -----------------------------------------------[Name of Responsible Person] ----------------------------------------Date
Stability
Rework
Sect: 16.3
ANDA Development
ANDA DEVELOPMENT
SECTION XVI
SECTION 16
IMPURITIES / DEGRADATION PRODUCTS 5 - 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 Meets USP Specifications o T (annually) and End of Study
Preservative Efficacy
SI-5-000-01
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
4
24 VOLUME DRUG DEVELOPMENT SERIES:
Sect: 16.5
ANDA Development
ANDA DEVELOPMENT
SECTION XVI
SECTION 16
Bulk Packaging
2 1 4 1 1 1 8
Number of Temperature/RH Levels Number of Dosage Strengths Number of Container Closure Sizes Number of Resins present in Containers Number of Closures Number of Resins present in Closures Number of Stability Studies Performed
Number of resins used in the HDPE containers = one resin from same supplier.
Sect: 16.6
ANDA Development
ANDA DEVELOPMENT
SECTION XVI
SECTION 16
40 degrees C / 75% RH
Contents Appearance ASSAY Percentage Preservative Efficacy Microbial Limits Test pH
Stability Parameters
Storage Period
Date of Analysis
SPECIFICATIONS
Months
Preservative Efficacy
Method #
0 1 2 3
Sect: 16.7
ANDA Development
ANDA DEVELOPMENT
SECTION XVI
SECTION 16
25 degrees C / 60% RH
Contents Appearance ASSAY Percentage
Stability Parameters
Storage Period
Date of Analysis
SPECIFICATIONS
Months
Microbial Limits
pH
Method #
0 3 6 9 12 18 24 36
Sect: 16.8
ANDA Development
ANDA DEVELOPMENT
SECTION XVI
SECTION 16
TYPE 1
Drug Plastics & Glass Co. Inc. 00 / 000cc round, HDPE JAR HDPE Quantum LR-734043 U.S. CAN (Penn-Wheeling Closure Corp.) White Ampacet 11078 Polyethylene HDPE LDPE 00 / 00 mm Tekni-Plex Inc. Foamseal PS 22 TEKNISEAL RVT + LF Lot #00000 CoA #0000 Lot #00000 CoA #0000 Lot #00000 CoA #0000 Lot #00000 CoA #0000 Lot #00000 CoA #0000 Lot #00000
TYPE 2
Drug Plastics & Glass Co. Inc. 00 / 000cc round, HDPE JAR HDPE Quantum LR-734043 U.S. CAN (Penn-Wheeling Closure Corp.) White Ampacet 11078 Polyethylene HDPE LDPE 00 / 00 mm Tekni-Plex Inc. Foamseal PS 22 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
TYPE 3
Drug Plastics & Glass Co. Inc. 00 / 000cc HDPE/
COLLAPSIBLE TUBE
TYPE 4
Drug Plastics & Glass Co. Inc. 00 / 000cc HDPE/
COLLAPSIBLE TUBE
Container manufacturer Container size 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
(coated metal)
HDPE Quantum LR-734043 U.S. CAN (Penn-Wheeling Closure Corp.) White Ampacet 11078 Polyethylene HDPE LDPE 00 / 00 mm -
(coated metal)
HDPE Quantum LR-734043 U.S. CAN (Penn-Wheeling Closure Corp.) White Ampacet 11078 Polyethylene HDPE LDPE 00 / 00 mm -
Lot #00000 CoA #0000 Lot #00000 CoA #0000 Lot #00000 CoA #0000 Lot #00000 CoA #0000 CoA #00000
Lot #00000 CoA #0000 Lot #00000 CoA #0000 Lot #00000 CoA #0000 Lot #00000 CoA #0000 CoA #00000
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
Sect: 17.1
ANDA Development
ANDA DEVELOPMENT
SECTION XVII
SECTION 17
RESERVED
THIS SECTION HAS BEEN RESERVED FOR FUTURE USE.
Sect: 17.2
ANDA Development
ANDA DEVELOPMENT
SECTION XVIII
SECTION 18
TABLE OF CONTENTS
(Overall ANDA Guideline Requirements for this Section).
Section Page and Title Statement on Sample Submission Procedures to FDA on request Drug substance Finished drug product 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:
4
24 VOLUME DRUG DEVELOPMENT SERIES:
Sect: 18.1
ANDA Development
ANDA DEVELOPMENT
SECTION XVIII
SECTION 18
SAMPLES OF THE
[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.]
Sect: 18.2
ANDA Development
ANDA DEVELOPMENT
SECTION XIX
SECTION 19
TABLE OF CONTENTS
(Overall ANDA Guideline Requirements for this Section).
20.1 20.2
Section Page and Title Environmental Exclusion Assessment - Development Site - Manufacturing Site
20.3
Applicable Environmental Laws (National / State / Local /Foreign) - Development Site - Manufacturing Site - Contract Manufacturers
20.4
20.5
20.6
FDA's Published January 1999 ANDA Guideline requirements:1. 2. Environmental Consideration: Environmental Assessment (EA) or Claim of Categorical Exclusion ( 3l4.94(a)(9))
Sect: 19.1
ANDA Development
ANDA DEVELOPMENT
SECTION XIX
SECTION 19
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.
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.
Sect: 19.2
ANDA Development
ANDA DEVELOPMENT
SECTION XIX
SECTION 19
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.
___________________________________
[Name of Responsible Person] Director Pharmaceutical Research & Development Pharmaceutical Division
_________________
Date
Sect: 19.3
ANDA Development
ANDA DEVELOPMENT
SECTION XIX
SECTION 19
__________________________
[Name of Responsible Person]
___________________
Date
Plant Manager Pharmaceutical Manufacturing Division [Generic Company Name Inc. Ltd.]
__________________________
[Name of Responsible Person]
___________________
Date
Director Quality Assurance Unit Pharmaceutical Manufacturing Division [Generic Company Name Inc. Ltd.]
Sect: 19.4
ANDA Development
ANDA DEVELOPMENT
SECTION XIX
SECTION 19
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]
__________________________
[Name of Responsible Person]
___________________
Date
Plant Manager Pharmaceutical Manufacturing Division [Generic Company Name Inc. Ltd.]
___________________
Date
Director Quality Assurance Unit Pharmaceutical Manufacturing Division [Generic Company Name Inc. Ltd. ]
Sect: 19.5
ANDA Development
ANDA DEVELOPMENT
SECTION XIX
SECTION 19
___________________
Date
Plant Manager Pharmaceutical Manufacturing Division [Generic Company Name Inc. Ltd.]
___________________
Date
Director Quality Assurance Unit Pharmaceutical Manufacturing Division [Generic Company Name Inc. Ltd.]
333
Sect: 19.6
ANDA Development
ANDA DEVELOPMENT
SECTION XX
SECTION 20
TABLE OF CONTENTS
(Overall ANDA Guideline Requirements for this Section).
19.1
19.2 19.3
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
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] ------------------------------------------------[Name of Responsible Person] --------------------------------------Date
__________________________
[Name 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.
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] ------------------------------------------------[Name of Responsible Person]
--------------------------------------Date
Sect: 20.3
ANDA Development
ANDA DEVELOPMENT
Sect: 20.4
ANDA Development
ANDA DEVELOPMENT
SECTION XX
SECTION 20
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.
US APPOINTED APPLICANT
[Applicant Company Contact Numbers] Contact Person. Responsibility. Director of Registration Quality Assurance Director
Tel.
Fax.
4
24 VOLUME DRUG DEVELOPMENT SERIES:
Sect: 20.5
ANDA Development
ANDA DEVELOPMENT
SECTION XXI
SECTION 21
Additional Information
OVERVIEW
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.
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:
DMF NO.
DMF DMF 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:
LOA DATE.
LOA LOA Cert. Cert. LOA LOA LOA LOA LOA LOA LOA LOA LOA DMF DMF DMF DMF LOA LOA LOA LOA LOA LOA LOA LOA LOA LOA LOA
No LOA date greater than two years. Change in Ownership show new DMF Holder. 1 Note: Child Resistant Closures consist of both an inner and outer component.
Sect: 21. 4
Topical SEMISOLID.
ANDA DEVELOPMENT
SECTION XXII
SECTION 22
Sterilization Assurance
TABLE OF CONTENTS
(Overall ANDA Guideline Requirements for this Section).
Section XXII.
Sect: 22.1
ANDA Development
ANDA DEVELOPMENT
ANDA DEVELOPMENT
ANDA DEVELOPMENT
International Association
Drug2000Manufacturers
High Quality Low Cost Drug Development & Manufacturing Excellence World Wide
US CHEMISTRY MANUFACTURING CONTROL Know How Technology & EU DOSSIERS Know How Technology
ANDA DEVELOPMENT
ANDA DEVELOPMENT
I n t e r n a t i o n a l
A s s o c i a t i o n
Drug2000Manufacturers
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
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.
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
Volume
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
Part
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
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
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
ANDA DEVELOPMENT
ANDA DEVELOPMENT
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
+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
Generic Development ISSN Series number 0793 7407 Generic Development ISSN Series number 0793 7792 - Electronic Issue (Disk/CD ROM)
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
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