Handbook of Pharma Generic Develop. - Part II (2000)

ORAL TABLETS DOSAGE FORM Dr ug Devel opment
I m m e d i a t e R e l e a s e
HANDBOOK OF PHARMACEUTICAL
GENERIC DEVELOPMENT
ORA L
Tablets
VOLUME I - Part TWO
Dr ug Devel opment - Sol i d Or al Dosage For ms
GENERI C DEVELOPMENT
H a n d b o o k o f P h a r m a c e u t i c a l
Ge n e r i c D e v e l o p m e n t S e r i e s
H Handbook of P Phar maceutical G Gener ic D Development 24 volume Dr ug Development Ser ies
H a n d b o o k o f P h a r m a c e u t i c a l
G e n e r i c D e v e l o p m e n t S e r i e s
Compiled by :
J . D . B L O C K
BSc. MPS. D/PHARM.
Research Director Generic & Innovative Drug Development Division, Locum International Group.
Science Editor - International Journal of Generic Drugs & International Journal of Drug Development
School of Pharmacy University of the Witwatersrand and Witwatersrand Technikon
Johannesburg RSA.
Edited: I A G I M S c i e n t i f i c C o m m i t t e e
Review Process: Generic & Innovative Drug Development Division
Research Center - Locum International Research
Handbook of Pharmaceutical Generic Development
Part I (Development) & Part II (Development ANDA or EU Dossier)
Vol. 1 - Tablets Oral
Vol. 2 - Capsules
Vol. 3 - Semisolids
Vol. 4 - Liquids
Vol. 5 - SG Capsules
Part I (Development Pharmaceutical Stability) & Part II (Analytical PAI)
Vol. 6 - e-SOPs / SOPs
Vol. 7 - Suspensions
Vol. 8 - Eye & Nose
Vol. 9 - Aerosols MDI
Vol. 10 - Tablets CR/MR
Vol. 11 - Capsules ER
Vol. 12 - Tablets Oral DR
Part I (Method Validation) & Part II (Analytical Methods 1994-2003)
Vol. 13 - Analytical
50 Generic SI Assay Methods)
Handbook of Pharmaceutical Innovative Development Vol. 14 - Tablets Oral
Handbook of Pharmaceutical Innovative Development Vol. 15 - Capsules Oral
Handbook of Pharmaceutical Innovative Development Vol. 16 - Suspensions
Handbook of Pharmaceutical Drug Development (1-5)
(Master Formula & Manufacturing Instructions Parts 1 - 5)
Vol. 17 - MF and MMI
(Master Formula & Manufacturing Instructions Parts 6 - 10)
Vol. 18 - MF and MMI
(Part I, Part II & Part III.(Development, Manufacturing &
Engineering)
Vol. 19 - Validation
Protocols/PAI-Checklists
Vol. 20 Sterile Injections
Available either on Online, CD ROM or via electronic mail attachment.
Additional Drug Specific Volumes in Preparation. An on-going electronic and print series
Available either as Hard Bound, Soft Bound or Soft Spiral Cover (for Updating).
For Drug Specific Handbooks refer to the 120+ Dr ug Devel opment Ser i es
READY-TO-GO DRUG DEVELOPMENT SERIES
http://www.locumusa.com/2go & http://www.iagim.or g
ANDA De v e l o p m e n t
Pa r t T w o T w o
TABLETS
O Or a l
p p p
Locum I nt er nat i onal Publ i sher s
H a n d b o o k o f
Phar mac eut i c al
Gener i c
De v e l o p me n t
Copyright 1995-00 - Locum Publishing
House Inc. All Rights Reserved.
Neither this book nor any part may be
reproduced or transmitted in any form or
by any means, electronic or mechanical,
including photocopying, microfilming and
recording, or by any information storage
and retrieval system, without the
permission of the publishers.
SERIAL NUMBER - DO NO REMOVE! - REGISTERED WITH
LOCUM INTERNATIONAL PUBLISHERS REGISTRATION SERVICES
WARNING: THIS ISSUE A IS MULTIPLE PAGE UV ENCODED EDITION.
HPGD 24 Vol . SERI ES - ORAL TABLETS - Par t I I
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.
ISSN 0793 8632
ISSN 0793 8640 - Electronic Version (Diskette, CD ROM and e-mail attachment version)
Handbook Development 24 volume series
General Generic Development ISSN Series number 0793 7407
General Generic Development ISSN Series number 0793 7792 - Electronic Issue (Diskette
and e-mail attachment 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 $1 per page is paid directly to the Copyright
Clearance Center (CCC) 222 Rosewood Drive, Danvers, MA 01923 USA. For
organizations that have been granted a photocopy license by CCC, a separate
system of payment has been arranged.
For additional information, contact the Publications Department Locum International
Publishing House; PO Box 874, 50 Gilad Street, Kochav Yair, 44864 Israel.
UK Fax: +(44) 207-900 2096
US Fax: +(1) 435-408 1665
Fax: +972 97-494 532
E-mail: info@locum. co. il
h t t p : / / www. l o c u m. c o . i l
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PRINTED IN USA
PRINTED IN ISRAEL
Current Printing (last digit) : 10 9 8 7 6 5 4 3 2 PRINTED IN REPUBLIC OF SOUTH AFRICA
Acknowledgments
I.A.G.I.M. (R&D) Foundation.
I.A.G.I.M. Members (1994 - 2000).
Contributions - Generic & Research Firms
Associate Universities, Technicons and Consultants.
Handbook Series Coordinating Committee.
International Journal of Drug Development.
Journal of Pharmaceutical Development.
International Journal of Generic Drugs.
I.A.G.I.M. Drug Development Archives
Locum International Archives.
FDA/OGD/CDER Maryland
Guides and Guidelines
Library of Congress.
AIC Conferences.
Editorial Board.
Pharm. Eur.
USP/NF.
USPC.
BP.
To Dor i bel l e
f o r h e r y e a r s o f s u p p o r t a n d h e l p
t o Se a n f o r h i s e x p e r t k n o wl e d g e o n c o mp u t e r i z a t i o n
t o Da v i d a n d Ar i f o r r u n n i n g t h e p r o j e c t ' s c o mp u t e r s
a n d l a s t l y t o Pa t f o r h i s i n e s t i ma b l e
c o n t r i b u t i o n .
24 Vol ume Ser i es
Handbook of Generic development
Thi r d Int er nat i onal Edi t i on.
L O C U M P U B L I S H I N G H O U S E

I NTRODUCTI ON
Handbook of Gener i c Devel opment - Or al Tabl et Dosage For m
This handbook is the third international edition of the ongoing 24 volume series
under the cumulative title of Handbook of Generic Drug Development. It is a hands-
on, technical presentation that portrays the current drug requirement steps
necessary at the time of going to print, of the Abbreviated New Drug Application for
oral tablet dosage form, namely tablets and caplets. It is written in conjunction with
Part Two of the Handbook which models as a representative ANDA and as an
example of the drug development process required for solid oral dosage forms The
Handbook is available in electronic format (CD ROM) and e-format (on-line). The
Handbook is up-dated to current regulatory requirements once or twice annually.
Complete updates are available without charge to Association Members of the Drug
Development Association - IAGIM.
This handbook provides a proven pathway to solid oral dosage form development.
Modern commercial formulations highlight the common tablet/caplet development
routes namely the classical wet granulation, spray granulation, dry granulation and
finally slugging and direct compression. Low active dosage (<10mg) and high
potency (>50%) examples are specially chosen to demonstrate the formulation steps
and process stages as a prerequisite to developing stable, elegant and rugged
formulas.
This second edition of the Handbook includes additional data on analytical method
validation has been redesigned to meet the January 2000 Guidance for Industry -
Organization of an Abbreviated New Drug Application and an Abbreviated Antibiotic
Application as well as all FDA guideline and requirements of the Center of Drug
Evaluation and Research (CDER) until January 2000. Editor-in-Chief.
Third International Edition

p2000p
COPYRIGHT 1995-00
ISSN 0793 8632

A n o n - g o i n g s e r i e s
A d d i t i on al V ol u m e s i n P r e p ar at i on
General Drug Development Series ISSN 0973 7601
Electronic Drug Development Series ISSN 0973 761X
HANDBOOK OF GENERIC DRUG DEVELOPMENT info@iagim.org ANDA DEVELOPMENT
24 V 24 Volume D Dr ug D Development S Ser ies Sect: 1 1.1 ANDA DEVELOPMENT
SECTION I SECTION 1
Appl i c at i on/ Tabl e of Cont ent s
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 ANDA
1
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:
Purpose of Submission
Type of Submission
(Original ANDA)
(Supplement)
(Amendment)
(Annual Report)
(Re-submission)
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)
Compare
OLD & NEW
Data
- NEW 1999/2000
Requirements
Indicate Type:-
Change being Effected
Expedited review requested
Preapproval Supplement
SUPAC Supplement
SUPAC Changes:-
Describe Change
Reference Exact SUPAC Guidance
& Guidance Section
Cover letter Header
"This Submission is based on a
SUPAC DOCUMENT"
SECTION I SECTION 1
Application/ Table of Contents
'This Submission is based on a SUPAC Document'
COVER LETTER
Date: ______________
Office of Generic Drugs
CDER, Food and Drug Administration
Document Control Room - No. 150
Metro Park North II
7500 Standish Place
ROCKVILLE MD 20855-2773.
ORIGINAL ABBREVIATED NEW DRUG APPLICATION
[Generic name] Specific Oral Dosage Form [USP]
Dear Sir,
We submit herewith an ABBREVIATED NEW DRUG APPLICATION for the drug
product [Generic name] Tablets/Capsules IR/MR/CR/ER [000/000]mg.
(delete where appropriate)
Enclosed are the archival and review copies in accordance with the Office of
Generic Drugs Guidance for Industry dated February 1999. These copies are
presented in a total of nine (9) volumes, FOUR [4] for the archival and FIVE [5] for
the review copy.
We furthermore commit to fully resolve any appropriate post approval issue
identified in the methods validation process.
The Application contains a full report of an in-vivo Bioequivalence study. The Study
compares Tablets / Capsules IR / MR / CR / ER [000/000]mg
manufactured by [Generic Manufacturing Co. Inc./ Ltd.] to the reference listed drug
under [food / fasting] conditions. This section is submitted in PRINT and the
prescribed ELECTRONIC format.
The Application does/does not contain Sterility Assurance Data in section XXII
We look forward to your review and comment.
Yours Sincerely.
Our Best Wishes,
S i gnature
Name of Responsible Person. Dated __________________
Regul at or y Af f ai r s Di r ec t or
Enclosures - Nine files
Clear Brief
Introductory Statement
Letter Header
For SUPAC submissions
only.
(Place on envelop as well)
Specify - Type of Bioequivalence
Results of Fasting Study
Results of Food Study
Results of Multiple Dose Study
Dissolution Data
Waiver Request
SECTION I SECTION 1
TABLE OF CONTENTS
SECTION I
1.1 Cover Letter - basis for submission of an abbreviated application.
.2 Signed Application Form (Form FDA 356h or 3439) with original ink signature.
.3 Table of Contents - to CDER Guide to Industry Format, (from February 1999).
.4 Executive Summary - Introductory Outline on the organization of this ANDA
1
TABLE OF CONTENTS IS A REGULATORY REQUIREMENT (CFR 314(50)b.)
SECTION II
2.1 Section Page (with Color Section TAG) and brief descriptor of the section.
.2 Basis for ANDA Submission
SECTION III
3.1 Section Page (with TAG) and brief descriptor of the section.
.2 Patent Certification statement - (Paragraph I, II, III or IV)
.3 Little VIII Patent statement - i.e. no labeling claims on a new indication.
.4 Exclusivity Statement with reference to the RLD.
SECTION IV - Generic vs. RLD Comparison
.2 Comparison between Generic and Reference Listed Drug (RLD).
.3 Tabulate to show proposed product is the same as listed product namely: -
Use; Active Ingredients; inactive ingredients: Route: Dosage Form; Strength
.4 Rx or OTC Marketing Statement for proposed Generic Product.
.5 Side-by-side comparison of insert.
2
.6 Side-by-side comparison of label.
2
.7 Certification that proposed labeling is the same as listed drug.
.8 Innovators labeling - (obtain latest insert from FDA FOI).
SECTIONS V - LABELING
.2 Proposed Generic labeling (for capsules include formula for empty capsule shell)
.3 Four (4) copies of DRAFT labeling- (obtain latest insert from FDA FOI).
OR Twelve (12) copies of FINAL PRINTED labeling
1
Strongly 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.)
SECTION I SECTION 1
TABLE OF CONTENTS
SECTIONS VI - BIOAVAILABILITY / BIOEQUIVALENCE STUDY
6.0 Title Page (with TAG) and brief narrative statement of what this section contains.
.1
Financial Certification / Disclosure Statement - (Form 3454 or 3455)
.2
Formula Composition of GENERIC product
.3
Percent Composition of Formula
.4
Comparative Ingredients List between Innovator & Generic
.5
Certificates of Analysis of Generic Drug Product - (all strengths)
.6
Certificates of Analysis for Innovators Product - (all strengths)
.7
Comparative Dissolution Protocol using 12 dosage units each - (all strengths)
.8
Comparative Dissolution Protocol (CDP study results, statistics, tables and
graphs)
.9
Request for Waiver for Biostudy for other strengths (multiple strength application)
.10
Outline of packaging container closures - proposed marketing packs.
.11
Schematic Trail of all packed units
.12
INVIVO Biostudy PROTOCOL and Study Reports conducted on pivotal batch
SECTIONS VII - Components and Composition
.2 List of Components - in order of manufacture (name & grade).
.3 Formula Composition of Generic Product
.4 Percent Composition of Generic Product.
.5 Comparative composition summary by batch size (qualitative & quantitative)
SECTIONS VIII - RAW MATERIAL CONTROL
Active ingredients
.2 Outlines of SOP for handling Raw Materials including Retest Procedure/Period
.3 VENDORS Certificates of Analysis (CofA) ; Specifications and Test Results
.4 GENERIC FIRM'S Certificates of Analysis (CofA) ; Specifications and Test Results
.5 Disclosure of Active ingredients Source. (Type II DMF Authorization Letter)
.6 DMF of Manufacturer via Letter of Access from Active Manufacturer.
.7 Active Material Monograph, Spectra and Chromatographs for REFERENCE &
TEST Samples supplied by GENERIC FIRM'S QC laboratory
SECTION I SECTION 1
TABLE OF CONTENTS
Active & Inactive ingredients (cont.)
ACTIVE SUBSTANCE
.9 CoA from Generic Firms QC laboratory, plus supporting:
- Identification IR or UV spectra of ACTIVE
- HPLC chromatograms (Assay - Impurities) - label peaks
- Photocopy of TLC chromatograms (Assay - Impurities)
.10 CoA from ACTIVE Manufacturer, - plus supporting:
- Identification IR or UV spectra of ACTIVE
.11 ACTIVE IR Identification Spectra of Reference Standard (Pharmacopoeial).
Physical Specifications from ACTIVE Manufacturer:
- Bulk Density
- Particle Size (note: water insoluble material)
.12 ACTIVE Physical and Analytical Test Methods.
.13 Routine Testing Protocol and Frequency of tests for ACTIVE Material
.14 ACTIVE Material Data Safety Sheet - source of data for manufacturing cautions.
NON-ACTIVE EXCIPIENTS
.15 Monographs of each NON-ACTIVE from Generic QC lab
.16 Coating Colors and Dyes - US Source with Batch Certification
.17 - Composition of Approved Pigments and Dyes
.18 CoA from Generic QC lab (Applicants Release Certificate)
.19 CoA from Approved Manufacturer (Suppliers Release Certificate)
.20
Routine Testing Protocol and Frequency of tests for Inactive Material
.21 Statement that other suppliers may be used subject to meeting pharmacopoeial
standards.
.22 SOP Outline of vendor qualification requirements (outlines are unsigned)
.23 SOP Outline of retesting procedures and schedule (micro. NMT 12 months)
.24 SOP Outline of RM environmental storage temperatures (15
o
-25
o
(30
o
C).
.25 Composition of tablet/caplet Printing Inks (CFR, Food grade)
.26 Capsule Cap and Body Specifications from Generic QC lab
SECTION I SECTION 1
TABLE OF CONTENTS
Empty Hard Gelatin Capsules
8.25 Title Page and brief narrative statement of what this section contains:-
.26 Letter of Access referring DMF # of Capsule Manufacturer
.27 Empty Capsule Specifications (Cap and Body) from vendor
.28 CoA of Empty Capsule from Approved Capsule Manufacturer
.29 CoA of Empty Capsule from Generic/Development QC lab
.30 Composition of Empty Capsules
- Composition of Capsule Approved Pigments and Dyes
- Composition of Capsule Printing Inks (CFR, Food grade)
.31 Raw Materials Laboratory Capsule Test Protocol (Incoming tests performed).
SECTIONS IX - Description of Manufacturing Facility
.2 Statement of commercial - Site address of Manufacture(s).
.3 Statement of commercial - Packaging & Labeling - site address.
.4 Statement of commercial - Site of Distribution - site address.
.5 Address of Facility for QC and Stability Testing.
.6 Brief description of facilities for MNF testing equipment and stability equipment
and key personnel (no personnel CVs).
.7
Statement on the GMP Certification of Compliance for the generic manufacturing
site
.8 Generic Manufacturing Site - Central File No (CFN)
SECTION I SECTION 1
TABLE OF CONTENTS
SECTIONS X
Outside Firms & Contract Testing Laboratory
.2
Name and Site Address of all Contract Laboratories.
.3
Registration No. of each Contract Laboratory.
.4
List of Test(s) or FUNCTIONS to be Performed by Contract Laboratory.
.5
Certification letter of GMP/GLP Compliance of Contract Laboratory.
.6
Statement on the cGMP Status and Certification of Compliance re:
- a contract manufacturing site
- a contract labeler or packaging site.
- environmental assessment or a claim for categorical exclusion
SECTIONS XI
Proposed Manufacturing and Processing Instructions
.2
Outlines of Manufacturing, equipment listing and Packaging SOP.
.3
Summary of In-process controls and reprocessing statement.
.4
Flow Chart of Manufacturing Procedure.
.5
Blank forms for Intended Production runs for LARGEST commercial batch size
w i t h pr oc essi ng equi pment spec i f i ed (Note 1:10 pivotal ratio).
.6 Bl ank f or ms shoul d i nc l ude t he f ul l manuf ac t ur i ng pr oc ess suc h as:
-- Blank forms - Master Formula (Commercial batch size)
- Blank forms - Manufacturing Procedures (English translations)
- Blank forms - In-process specifications for dried milled material
- Blank forms - In-process specifications sheet for final blend.
- Blank forms - In-process test result sheet of the blended mix
- Blank forms - In-process specifications for filled capsules
- Blank forms - In-process test results sheet of filled capsules
- Blank forms - In-process Specifications for ink jet printed CAPSULES
- Blank forms - In-process test results of ink jet printed CAPSULES
- Blank forms - In-process control sheets (English translations)
- Blank production forms for in-process weight controls
- Blank forms for production yields and weighing print-outs attachments
11.7
Finished Product Release Specifications.
.8
Outline Packaging Operations and packaging equipment listing
.9
Blank Packaging Records.
.10
Side-by-side comparison of Pivotal & Production Batches (Formulation,
Equipment, QC, Production Operating Personnel, SOPs).
.10
Reprocessing statement.
SECTION I SECTION 1
TABLE OF CONTENTS
SECTIONS XII
Pivotal Manufacturing and Processing Instructions
.2
Outline of In-process SOPs.
.3
In Process Controls and sampling plan summary.
.4
Executed Manufacturing Procedure Flow Chart.
.5
Pivotal Batch Record Title page
.6
Pivotal Batch Records.
.7 Executed Batch with signatures
.8
- Master Formula for pivotal size
.9
- Executed forms - Master Formula (Commercial batch size).
.10
- Executed forms - Manufacturing Procedures (English translations.)
.11
- Executed forms - In-process control sheets (English translations).
Granulates may be wet/dry granulated, slugged & milled prior to blending, add the
documentation for the slug and milling procedures, including production yields.
.12
- Executed forms - In-process specifications for dried milled material.
.13
- Executed forms - In-process specifications for blended mix.
.14
- Executed forms - In-process test results sheet of the blended mix
.15
- Certificate of Batch Homogeneity (showing test results.)
.16
- Executed forms - In-process specifications.
.17
- Executed forms - In-process test results sheet.
.18
- Executed forms - In-process specifications for filled capsules
- Executed forms - In-process test results sheet of filled capsules
- Executed forms - In-process Specifications for printed CAPSULES
- Executed forms - In-process test results of printed CAPSULES
- FILL weight Verification study and results
.19
Individual and overall production yields
Executed forms for production yields and weighing print-outs attachments
- Stage I - (End of Drying).
- Stage II - (End of Blending)
- Stage III - (End of filling)
- Stage IV - (End of online printing)
.20
Finished Product Release Specifications
.21 Manufacturing (Mnf's) Deviation Reports (MDRs) - (translations)
.22 Executed forms production forms for in-process weight controls (translations)
.23
Production Packaging Work Sheets - (translations)
.24
Production Packaging Control Forms - (translations)
.25
Distribution of Pivotal lot into various container-closures systems (Packaging)
.26
Pivotal Batch Packaging Trail - (overall disposition of UNITS i.e. net yield, QC
sampling, reserve samples, stability samples, Biostudy, Packaging formats.)
SECTION I SECTION 1
TABLE OF CONTENTS
SECTION XIII
Packaging and labeling Procedures
.2 Summary / Outline of Packaging and Labeling Procedures
.3 Summary of Container-closure-liner system used for each strength.
CONTAINERS, GLASS OR THERMOPLASTIC - (REQUIREMENTS FOR EACH
CONTAINER.)
.4 Description of Packaging Components - pack sizes for each strength.
.5
i. LoA from manufacturer referencing their container Type I I I DMF #.
.6 ii. LoA from resin mnf. referencing their resin DMF # used in container - (Obtain
separate letters for each resin type used in plastic containers.)
.7 Manufacturer's Container Specifications or Certificate of Conformance, including;
.8 - drawings/diagrams and dimensions
.9 - test protocol and Certificates meeting USP and 21 CFR requirements
- DSC thermal analysis (for thermoplastic containers only)
- Manufacturers Container CoA
.10
Testing Specifications / Protocol ; Acceptance Criteria and TEST RESULTS (CoA)
of Applicant Lab.
.11 CoAs of Containers from Applicant Lab.
.12 Batch Compliance Results
SECTION I SECTION 1
TABLE OF CONTENTS
METAL CAPS AND THERMOPLASTIC CLOSURES
(PER EACH CLOSURE.)
.13 LoA from closure manufacturer referencing DMF # of cap (+ GMP statement.)
.14
LoA from resin manufacturer referencing thermoplastic resin DMF #. (Obtain
separate letters for each resin type used in thermoplastic closures)
.15
Mnf's Closure Specifications or Certificate of Conformance, including;
- drawings/diagrams and dimensions
- test protocol and certificates meeting all USP and 21 CFR requirements
- DSC thermal analysis (only for thermoplastic closures)
- Manufacturers CoA
.16 Testing Specifications / Protocol ; Acceptance Criteria and TEST RESULTS (CoA)
of Applicant Lab.
.17 Batch Compliance Results.
INNER CLOSURE LINER:
13.18
Item description and use - meets current CFR and USP requirements.
.19 LoA from manufacturer to applicant referencing their DMF # of inner liner.
.20 Inner liner Specifications or Certificate of Conformance from manufacturers.
of Applicant Lab.
.22 CoA or test results of inner liner from Generic packaging Lab.
.23 Batch Compliance Statement.
FOAM SEALS, PRESSURE SENSITIVE, TAMPER RESISTANT, ADHESIVE,
INNER SEALS:
13.24 Item description and use - meets current CFR and USP requirements.
.25 LoA from manufacturer to applicant referencing their DMF # of foam seal.
.26 Foam seal Specifications or Certificate of Conformance from manufacturers
of Applicant Lab.
.28 CoA or test results of Foam seal from Applicant Lab.
SECTION I SECTION 1
TABLE OF CONTENTS
Cotton Coil
13.30 Item description and use USP requirements.
.31 LoA from manufacturer to applicant referencing their DMF # of cotton coil.
.32 Cotton Coil Specifications or Certificate of Conformance from
manufacturers.
of Applicant Lab.
.34 CoA or test results of cotton coil from Applicant Lab.
Silica Gel Drying Agent
LoA referencing DMF # of drying agent manufacturer (if relevant)
.36 Specifications or Certificate of Conformance from manufacturers
of Applicant Lab.
.38 CoA or test results of drying agent from Applicant Lab.
.39 CoA of drying agent from manufacturers QC Lab.
Section XIV - Controls for the Finished Dosage Form
14.1 Title Page (with TAG) and brief summary statement of what this section contains
.2 State if drug product is:
- Compendial and test methods used are USP
- Non-Compendial and test methods in-house and validated.
- Non-Compendial and test methods based on and validated.
14.3 Certificate of Analysis of Pivotal Batch(es), including
- HPLC, TLC, GC, UV chromatograms and spectra e.g.:
- CoA for _______ [product] USP [Strength #1] mg + HPLC chromatograms
Stability Indicating Assay; Impurity Limit Tests; Dissolution Assay
USPC Inc. Pharmacopeial Forum, FDA
SECTION I SECTION 1
TABLE OF CONTENTS
Section XV - Analytical Methods
15.1 Title Page (with TAG) and brief narrative statement of what this section contains.-
State if drug substance and drug product is:
- Compendial and test methods used are USP
- Non-Compendial and test methods in-house and validated.
- Non-Compendial and test methods based on and validated.
Drug Substance / Active material
.2 Active Ingredient Test Method
.3 Active Ingredient Test Method Validation
In-process Material
.4 Final Blend Test Methods (especially Uniformity of Content)
Finished Product
.5 Finished Product Test Methods (QC Release)
- physical tests
- chemical tests
- microbiological tests
.6 Finished Product Test Methods - (Stability Check)
- stability Indicating Test Methods.
- impurity limit tests.
- dissolution test procedure.
.7 Finished Product Analytical Validation methodology
- stability Indicating Assay.
- impurity limits or specific Impurity Quantitation.
- dissolution.
RESERVED SECTION
NOT FOR CURRENT USE
SECTION I SECTION 1
TABLE OF CONTENTS
Section XVI
Stability of Finished Dosage Form
16.1
Title Page (with TAG) and brief narrative statement of what this section contains.
.2 Stability Protocol for Post Approval Production Batches (ANDA commitment).
.3 Package Configuration/sizes (largest and smallest) used in stability studies.
.4 Expiration Dating Period Statement.
.5 Stability Protocol used for Pivotal lot.
.6 Stability Reports Results of Pivotal Lot from 3 months accelerated and controlled
room temperature studies.
.7 Stability Data Summary Report (graphs).
Section XVII
Reserved
17.0 Title Page (with TAG) and brief statement that section is reserved.
17.1 Reserved
Section XVIII
Samples of the drug and articles used as
components
.2 Statement on Sample Submission Procedures to FDA on request on
.3 - Submission of Drug Substance
.4 - Submission of Drug Product / Finished Dosage Form
.5 - Submission of Appropriate Reference Standards (where required)
SECTION I SECTION 1
TABLE OF CONTENTS.
Section XIX
ENVIRONMENTAL IMPACT ANALYSIS REPORTS
19.2 Environmental Exclusion Assessment
- Development Site
- Manufacturing Site
19.3 Applicable Environmental Laws (National / State / Local /Foreign):
- Development Site
- Contract Manufacturers
19.4 Site Environmental Certification:
- Development Site
19.5 Statement on Environmental Compliance:
- Development Site
Commercial Plant Manager and QA Director Signatures.
Section XX
ADDITIONAL INFORMATION
20.1 Certification Pursuant to the Generic Drug Enforcement Act of 1992.
20.2 US Agents Letter of Authorization
Section XXI
ADDITIONAL INFORMATION
21.2 Reference to previously submitted Information
21.3 Original Data / Literature Publication where English translation is submitted
21.4 Outline of manufacturing re-work study.
21.5 Table of DMF Numbers (with LOA dates).
21.6 Letters of Authorization (LOA) - TWO PHOTOCOPIES
1
21.7 Field Copy Certification
1
TWO PHOTOCOPIES OF LETTERS OF AUTHORIZATION WITH RECENT DATES
(i.e. where possible in the same year as the ANDA submission.)
SECTION I SECTION 1
TABLE OF CONTENTS
Section XXII - ADDITIONAL INFORMATION
22.2
General Information
a. Copy of cover letter (or page reference)
b. Label/package insert copy (or page reference)
c. Summary of manufacturing process including components and
composition
statement (or page reference)
d. Copies of pages from completed batch production record containing
holding times, filtration integrity testing, and sterilization records (or page
reference).
22.3
If the microbiology section is presented in a separate volume, provide copies of the
indicated information in other micro sections of the application - NOT page references
STERILIZATION ASSURANCE INFORMATION AND DATA.
Note: This section can be provided as a separate volume for ease of review. Use the
Guideline 'Submission of Documentation for Sterilization Process Validation in Applications
for Human and Veterinary Drug Products'
Where a section is not applicable It is included in the Table of Contents with the statement:
' THIS SECTION IS NOT APPLICABLE TO THE SUBMITTED APPLICATION '
COMPOSITION OF ALL ANDA SUBMISSION COPIES
ANDA
SECTION
ARCHIVAL
COPY
[Full]
RED
COPY
[CMC]
ORANGE
COPY
[Biostudy]
FIELD
COPY
[Full]
I
II
III
IV
V
VI (Bio) -
VII
VIII - XX
(Chemistry)
-
XXII (Micro) -
CMS - Chemistry manufacturing and Controls containing No Biostudy.
Review Copies - Red and Orange Copies.
Archive and review Copies - send by courier or special parcel service
SECTION I SECTION 1
FDA FORM 3439
or
FDA FORM 356h
[REVISED]
J an 8, 1998
(The FDA revised Form 365h - Federal Register July 8, 1997)
The revised "all purpose" form was official from January 8, 1998.
(NOTE: All DMF numbers stated on this form to be exactly the same as shown
in Section 21 ).
GLOSSARY
Abbreviated Application: An application described under 21 CFR 314.94,
including all amendments and supplements to the application.
Archival Copy: A complete copy of the abbreviated application intended to serve
as the official reference source for the Agency. It is retained by the Agency and
serves as the sole file copy of the approved application.
Electronic Format: The voluntary submission of parts of an ANDA in electronic
media for use to facilitate the review process and in conjunction with the requisite
hard copy of the application.
Field Copy: A duplicate of the archival copy to be submitted for use by FDA
investigators.
Review Copy: A duplicate of the archival copy for use by Agency reviewers. It is
destroyed after approval of the application.
Correct pagination between text and Table of Contents is essential.
(Page numbers in the actual application must be placed at bottom center of each
page and run consecutively to the end of the submission i.e. up to Section 21/22)
Do not number volumes - FDA will number the volumes.
End of Section 1.
24 V 24 Volume D Drug D Development S Ser ies Sect: 2 2.1 ANDA DEVELOPMENT
SECTION II SECTION 2
Basi s f or ANDA Submi ssi on
TABLE OF CONTENTS
2.O Section Page and Title. The information in this section summarizes the four
critical structures supporting the legal basis for this abbreviated new drug application
2.1.0 Basis for ANDA Submission is submitted as follows and is;
2.1.1 Based on an Abbreviated New Drug Application
or
2.1.2 Based on an approved ANDA Suitability Petition
and
3.0 Based on Active Ingredient (same as RLD) and current approved labeling
and
4.0 Based on Route of Administration, Dosage Form and Strength
and
5.0 Based on Bioequivalency Data submitted (Applicant Generic Drug vs. RLD)
NOTE:-
MODEL Letters are provided in Section IV highlighting each of four critical structures
and supporting documentation stating the legal basis for this abbreviated new drug
application
4
Basis for ANDA Submission
BASIS FOR ABBREVIATED NEW DRUG APPLICATION
[a] Listed Drug.
This applications refers to the Reference Listed Drug [NAME] qTablet /
qCapsule manufactured by [RLD Company Name Inc. / Ltd.].
The basis for [Applicant Company Name Inc. / Ltd.] proposed ANDA for 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])
BASIS FOR ABBREVIATED NEW DRUG APPLICATION (continued)
ACTIVE INGREDIENT [00000]
21 CFR 314.94 [A][5][i]
he active ingredient of [Applicant Company Name Inc. / Ltd.] Generic qTablet
/ qCapsule is the same as that of the RLD brand name
We refer the reviewer to [Applicant Company Name Inc. / Ltd.] annotated labeling
and the current approved labeling of the RLD as shown in Section IV-05 of this
ANDA (Refer pages [00] to [00])
ROUTE OF ADMINISTRATION DOSAGE FORM AND STRENGTH
21 CFR 314.94 [A][5][i]
he Route of Administration, Dosage Form and Strength [Applicant Company's
Name Inc. / Ltd.] of Generic qTablet / qCapsule is the same as for [RLD
brand name]
Again we refer the reviewer to [Applicant Company Name Inc. / Ltd.] annotated
labeling and the current approved labeling of the RLD as shown in Section IV-05 of
this ANDA (Refer pages [00] to [00])
BIOEQUIVALENCY DATA [00000]
21 CFR 314.94 [A][7][i]
[Applicant Company Name Inc. / Ltd.] bioequivalent study on [Generic qTablet /
qCapsule Name] was successfully conducted in terms of current approval
parameters by Clinical Research Laboratories [Name and Address]
The Full Bioequivalence Report is attached to Section VI of this ANDA (Refer pages
[000] to [000])
[S i gnature of R esponsi bl e P erson]
------------------------------------------------ -----------------------------------------
[ Name of Responsi bl e Per son] Date
Regulatory Affairs Director
[Applicant Company Name Inc. / Ltd.]
[Two typical examples of this section are given below]
T
T
EXAMPLE 1:
Listed Drug.
This applications refers to the Reference Listed Drug [RLD] Imodium
1
/
Imodium
2
Generic qTablet / qCapsule manufactured by [RLD
Company Name Inc. / Ltd.]
3
.
A copy of the Orange Book 20th (2000) Edition listing is enclosed
herewith.
According to the information published in the 20th Edition List, the
reference listed drug is covered by [ no / one / two] use patent which is
addressed in Section III of this application.
Exclusivity.
There are [ONE] / [two] / [no] exclusivitys for the listed drug.
I-184 - expires Sept 24, 2000
I-185 - expires Sept 24, 2000
------------------------------------------------ -----------------------------------------
------------------------------------------------ -----------------------------------------
1
INNOVATOR NAME COUNTRY US or EU
2
USA RLD 375 / 500 mg - Application Number 000000
3
INNOVATOR
EXAMPLE 2:
Listed Drug.
This applications refers to the Reference Listed Drug [RLD] Imodium
1
/
Imodium
2
qTablet / qCapsule manufactured by [RLD Innovator
Company Name Inc. / Ltd.]
3
.
A copy of the Orange Book 20th (2000) Edition listing is enclosed
herewith.
According to the information published in the 20th Edition List (2000), the
reference listed drug [RLD] is covered by [ no / one /two] use patent(s)
which is addressed in Section III of this application.
Exclusivity.
According to the information published in the 20th Edition of the Orange
Guide (2000), there are [one] / [two] / [no] exclusivitys for the listed
drug.
I-000 - expires MM DD, 2000
I-000 - expires MM DD, 2000
------------------------------------------------ -----------------------------------------
------------------------------------------------ -----------------------------------------
1 INNOVATOR
2 USA RLD IS REGISTERED AS STRENGTH 0 mg +00 mg
INNOVATOR Application Number [00000]
3 INNOVATOR
ANDA SUITABILITY PETITION APPROVAL LETTER
Date:
Metro Park North II
7500 Standish Place
ORIGINAL ABBREVIATED NEW DRUG APPLICATION
[Generic name] Oral Tablets/Capsules
Dear Sir,
We submit herewith the ANDA SUITABILITY PETITION APPROVAL LETTER
for the drug product [Generic name qTablet / qCapsule [000 / 000] mg.
------------------------------------------------ -----------------------------------------
[ANDA SUITABILITY PETITION APPROVAL LETTER
Attached in Section XXII]
4
End of Section 2.
24 V 24 Volume D Drug D Development S Ser ies Sect: 3.1 ANDA DEVELOPMENT
SECTION III SECTION 3
Pat ent Cer t i f i c at i on / Ex c l usi vi t y
TABLE OF CONTENTS
ection Page (with Color Section TAG) and brief narrative of the section.
Enclosed in this sections is a statement of patent certification for [Applicant
Company Name Inc. / Ltd.]new drug application [Drug Name]. Also enclosed (if
applicable) are the statements concerning the required notices to the patent owners
and NDA holder. These statements are in accord with the FD&C Act as amended
September 24, 1984 and with the final regulations effective November 2 1994.
3.1 Patent Certification statement -
State Paragraph I
State Paragraph II
State Paragraph III
State Paragraph IV
3.2 Little VIII Patent Statement - i.e. no labeling claims on a new indication.
3.3 Exclusivity Statement with reference to the RLD.
3.4 Certification Pursuant to the Generic Drug Enforcement Act of 1992.
4
S
Patent Certification / Exclusivity
Patent Certification Statement
Paragraph I Certification
[21 CFR 314.94(a)(12)(i)]
n accord with the Food, Drug and Cosmetic Act as amended September 24, 1984
and with the final regulations effective November 2 1994 Patent certification is
hereby provided for our Abbreviated New Drug Application for [Generic Drug
Name].
e the undersigned hereby certify to the best of our knowledge and in [Generic
Company Name Inc./Ltd.]s opinion patent information has not been submitted
to the FDA on Patent No [00-0000-00] which claims the reference listed drug [RLD]
DRUG Name [USP] [000.0] mg. NDA # 00-000
his certification is made in accordance with Section 505 (j)(2)(A)(vii)(I) of Title I
the Food, Drug and Cosmetic Act, as amended September 24, 1984 and
pursuant to 21 CFR 314.94 (a)(12)(i)(A)(1).
------------------------------------------------ -----------------------------------------
I
W
T
Paragraph II Certification
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
US. Patent No. 0-0000-0000 expiring Dec 31, 1999
US. Patent No. 0-0000-0000 expiring Dec 31, 1999
------------------------------------------------ -----------------------------------------
[Applicant Company Name Inc./Ltd.]
I
W
T
Paragraph III Certification
Name].
[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
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.
------------------------------------------------ -----------------------------------------
Note the Bolar amendment allows the sale of the bulk active material and the
development manufacture testing of the developed generic product SOLELY
for the purposes and under the condition of getting it approved as an ANDA
I
W
I
Alternative Certification
Paragraph III Certification
he undersigned hereby certifies to the best of our knowledge and in [Generic
Company Name Inc./Ltd.]s opinion there is [one] patent which claims the listed
drug [RLD] DRUG Name [USP] [000.0] mg. NDA # 00-000.
I
n accordance with Section 505 (j)(2)(A)(vii)(III) of the Food, Drug and Cosmetic
Act, as amended [Generic Company Name Inc./Ltd.] certifies that the Company will
not engage in the commercial manufacture, use or sale of the drug Product until this
aforementioned patent has expired .
------------------------------------------------ -----------------------------------------
Attached:
Page Number: [00]
The Prescription Drug Product List of the APPROVED DRUG PRODUCTS WITH
THERAPEUTIC EQUIVALENCE EVALUATIONS EDITION 20th - 2000 US
Department of Health and Human Sciences.
4
T
Paragraph IV Certification
Name].
[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.
------------------------------------------------ -----------------------------------------
1
Select the appropriate language that constitutes the basis of the patent challenge namely:
[the patent will not be infringed]
[the patent is invalid]
[the patent is unenforceable] or
[ANDA applicant hold a licensing agreement for the Patent Holder]
1
Special Note of Notification:
If the owner of the patent, subject to a paragraph IV Certification, is a person or entity other
than the registered NDA holder, then the applicant, is required to notify, under separate
cover, both parties - namely the Patent Holder and the NDA Holder.
(Certified mail return receipt cards often get damaged in the mail - thus avoid use, as
system is ineffective. Where Fedex , UPS or DHL etc. is used to advise of a
notification it is essential to obtain the recipient approval to use Fedex , UPS or DHL
couriers PRIOR to notification).

1
Where 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).
I
W
Patent Holder & NDA Holder
Statement Concerning Notice
To Patent Holder and NDA Holder
21 CFR 314.94(a)(12)(1)(A)(iv) & 21 CFR 314.95
n accordance with Section 505 (j)(2)(B) of the Food, Drug and Cosmetic Act, as
amended and 21 CFR 314.94(a)(12)(1)(A)(iv) & 21 CFR 314.95 certifies that
[Generic Company Name Inc./Ltd.] hereby states that our firm, upon receipt from
the FDA of an acknowledgment letter stating that this ANDA is sufficiently complete
to permit a substantive review, will give the notice required by Section 505 (j)(2)(B)
of the Food, Drug and Cosmetic Act, as amended, and 21 CFR 314.95 to [RLD
Company Name Inc./Ltd.] the holder of the approved application for the Branded
Product, [RLD] DRUG Name [USP] [000.0]mg and the owner of US Patent Number
[5-0000-00] issued on MM DD, YY.
The notice to the Branded Product [RLD] DRUG Name] shall be sent certified mail,
return receipt requested and shall meet the requirements of 21 CFR 314.95 (a) and
21 CFR 314.95 (c)
Concurrently with mailing the notice to the [RLD Company Name Inc./Ltd.] the
pertaining to the Branded Product - [RLD] DRUG Name] the [Generic Company
Name Inc./Ltd.] will as required by 21 CFR 314.95(b) amend it ANDA for [Generic]
DRUG Name [USP] [000.0]mg to include a certification that the notice has been
provided to each person identified under CFR 314.95(a) and that the notice met the
contents of CFR 314.95(c).
------------------------------------------------ -----------------------------------------
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.
I
' No relevant Patent ' Statement
21 CFR 314.94(a)(12)(ii)
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].
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.
------------------------------------------------ -----------------------------------------
Background
This specification is not specifically described under the FD&C Act but appears in the FDA final
regulations dated Nov 2, 1994. The purpose of the "No relevant Patents Statement " appears to be
designed to aid and help the internal FDA OGD reviewers to assure them that your firm's omission to
include a patent certification is a deliberate action and not simply a regulatory oversight.
Note: The intention of the regulations and the preamble to the regulations is to provide a positive
statement that the submitted ANDA should not contain any of the FOUR Patent Certification
Statements (i.e. No Paragraph I ; II ; III or IV statement) - Thus, it is necessary to submit a "No
relevant Patents Statement " if and only if, no patent(s) exist that should be the subject of a Patent
Certification - i.e. stating the negative condition and thus eradicating the element of an regulatory
oversight.
I
T
W
Method of Use Patent Statement
21 CFR 314.94(a)(12)(iii)
Method of Use Patent
n accord with the Section 505 (j)(2)(A)(viii) of Title I the Food, Drug and Cosmetic
Act, as amended September 24, 1984, [Generic Company Name Inc./Ltd.] hereby
states, with respect to method of Use Patent, US Patent No [000-000-00], submitted
by [RLD Company Name Inc./Ltd.] for listing in respect to [RLD Branded Drug
Name], that of Use Patent No [000-000-00] does not claim a use for which [Generic
Company Name Inc./Ltd.] is seeking approval for [Generic Drug Name]
e the undersigned hereby certify to the best of our knowledge that of Use
Patent No [000-000-00] is limited to the following claim (specific therapeutic
use), the use for which [Generic Company Name Inc./Ltd.] now seeks approval in
this ANDA, as evident by the attached proposed labeling (Refer to Page [00]), is for
use indication _________, which is beyond the reach of claims of Patent No [000-
000-00] .
------------------------------------------------ -----------------------------------------
T
I
W
Exclusivity Statement
21 CFR 314.94(a)(3)(ii)
[RLD] Product [000.0] mg. NDA # 00-000
he undersigned hereby certifies to the best of our knowledge and in [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.
------------------------------------------------ -----------------------------------------
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
T
A
HANDBOOK OF GENERIC DRUG DEVELOPMENT ANDA DEVELOPMENT
24 V 24 Volume D Dr ug D Development S Ser ies Sect: 4.1 DEVELOPMENT Or al Or al Tablets
SECTION IV SECTION 4
Gener i c and RLD Compar i son
TABLE OF CONTENTS
4.1 Section Page (with Color Section TAG) and brief narrative of the section.
4.2 Comparison between Generic and Reference Listed Drug (RLD) / Innovator
Tabulate to show proposed product is the same as listed product namely: -
Conditions of Use
Active Ingredients
Inactive ingredients (OGD Interim Inactive ingredient Policy - 'Q&Q'
policy of Nov 17 1994 - does not apply to oral dosage forms i.e. tablets
[and suspensions])
Route of Administration & Dosage Form
Strength
Inactive Ingredients with supporting data
Labeling Comparison (Add section V data)
4.3 Rx or OTC Marketing Statement for proposed Generic Product.
FDA's Published January 1999 ANDA Guideline 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
Generic and RLD Comparison
Information required under 314.94 (a)(4) through (6) of the ANDA Regulations final
rule issued April 28 1992.
[RLD] TABLETS / [Generic name] TABLETS
[RLD Company Name]. [Generic Co. Name].
Conditions of Use
The conditions of use
prescribed or recommended
or suggested for [RLD]
TABLETS [USP] may be
found in the package insert
(see section V).
The conditions of use prescribed,
recommended or suggested for
[Generic name] TABLETS [USP]
are the same for [RLD]
TABLETS [USP] and may be
found in the package insert (see
Section V).
Active Ingredient [Active Material] is the same [Active Material] is the same
Non-active
Ingredient
There are no safety issues
concerning the proposed
formulation as the inactive
ingredients are essentially
similar to the reference
listed drug
Inactive ingredients in both
product are similar and do not
require to be identical in terms of
Q&Q policy (Nov 17 1994)
Dosage Form TABLETS [USP]
(I R dosage Form)
TABLETS [USP]
(I R dosage Form)
Administration Oral Oral
Strengths
Number of
Strengths
000.0 mg
000.0 mg
000.0 mg
000.0 mg
000.0 mg
000.0 mg
000.0 mg
000.0 mg
Bioequivalent
Data
Bioequivalent Bioequivalent
Labeling Essentially Similar Essentially Similar
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.
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.
Rx / OTC Statement
[Generic name] TABLETS [USP] [000.0] mg.
Prescription Drug R
x
-
This drug is limited in its labeling and by this application to use under the
professional supervision of a practitioner licensed by law to administer the
prescription drug.
or
if not a prescription drug
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.
------------------------------------------------ -----------------------------------------
4
Labeling
PROPOSED GENERIC CONTAINER LABEL LABELING
SI DE-BY-SI DE COMPARI SON
GENERIC CONTAINER
LABEL
INNOVATIVE CONTAINER
LABEL
Present full Generic CONTAINER
LABEL identical to innovators (caution
restrictions on indications still on patent
- these may not be included )
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.
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
differences in the INNOVATIVE
where differences appear.
NOTE:-
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.
Labeling
Labeling similarity and differences between Generic and Brand RLD insert
GENERIC INSERT
LABELING
RLD INSERT
LABELING
Description Description
Differences are:- Differences are:-
Trade Name Trade Name
Color, shape and embossing/printing Color, shape and embossing/printing
Similarities are:- Similarities are:-
Dosage Form Dosage Form
Strength Strength
Dispensing information Dispensing information
All text is identical except for [one] use
indication namely [indication]
All text is identical except for [one]
patented use indication namely
[indication]
Clinical to Administrative
Section
Section
Specific use patent indication excluded Specific use patent indication under
exclusivity rights
Strength Strength
How Supplied How Supplied
Addresses (Applicant & Distributing) Addresses
NDC # NDC #
Strength Strength
Quantities Quantities
Labeling
ATTACHMENTS
24 Volume Dr ug Development Ser ies Sect: 5.1 DEVELOPMENT Or al Dosage For m
SECTION V SECTION 5
Label i ng
TABLE OF CONTENTS
Section Page (with Color Section TAG) and brief descriptor of the section.
Included in this section is a copy of the currently approved labeling for the
Reference Listed Drug [RLB Name] and the draft labeling for the [Applicant
Company Name Inc. / Ltd.] Drug Product.
The annotated side-by-side labeling comparison with the labeling of the Generic
Drug and Reference Listed Drug [RLB Name] that also appears in Section IV-5
1. Proposed Generic container panel labeling for each strength & pack size.
2. Proposed Generic Insert / Outsert
3. Innovators Insert / Outsert - (obtain latest insert from FDA FOI).
4. Innovators container panel labeling for each strength and pack size
5. Side-by-side comparison of package leaflet (insert or Outsert.) Statement
of labeling similarity and differences between Generic and Brand RLD.
6. Side-by-side comparison of label for each strength and pack size. Statement
of labeling similarity and differences between Generic and Brand RLD.
7. Certification that proposed labeling is the same as listed drug (RLD).
4
SECTION V SECTION 5
Labeling
PROPOSED GENERIC CONTAINER PANEL LABELING
000 Tablets [USP]
Main Panel NDC [0-00-000-00]
[Generic Name] Tablets [USP]
000 mg
_________________________
Each Tablet contains:
[Active Material] 000 mg
Caution: Federal law prohibits dispensing without prescription
000 TABLETS [USP]
Side Panel Usual Adult dosage : One tablet twice a day.
See package for full prescribing information
Keep tightly closed. Store at controlled room temperature 15

-
30 C (59 - 86 F).
Protest from exposure to temperatures above 40 C (104 F)
and moisture.
Dispense contents in tight light resistant containers as defined
in the USP with a child resistant closure (as required)
KEEP THIS AND ALL MEDICATIONS OUT OF REACH OF
CHILDREN
01/98.
MANUFACTURED BY
[Generic Company Name Inc. / Ltd.]
[Address]
Distributed By:
[Distributing Company Name Inc. / Ltd.]
[Address]
SECTION V SECTION 5
Labeling
PROPOSED GENERIC CONTAINER PANEL LABELING
0000 Tablets
Main Panel NDC [0-00-000-00]
[Generic Name] Tablets [USP]
000 mg
_________________________
000 TABLETS [USP]
Side Panel Usual Adult dosage : One tablet twice a day.
See package for full prescribing information

-
30 C (59 - 86 F).
Protest from exposure to temperatures above 40 C (104 F)
and moisture.
Dispense contents in tight light resistant containers as defined
in the USP with a child resistant closure (as required)
KEEP THIS AND ALL MEDICATIONS OUT OF REACH OF
CHILDREN
01/98.
MANUFACTURED BY
[Manufacturing Company Name Inc. / Ltd.].
[Short Address]
Distributed By:
[Short Address]
Lot #
&
Exp.
Date
SECTION V SECTION 5
Labeling
PROPOSED GENERIC LABELING FOR PRESENTATIONS IN:
BLISTER PACKAGING (FOIL / PVC)
QUANTITY: [00] Tablets
Name
000 mg
Name
000 mg
Name
000 mg
Name
000 mg
Name
000 mg
Name
000 mg
Name
000 mg
Name
000 mg
Name
000 mg
Name
000 mg
PVC / PVDC / Aluminum Foil Printing:
1. Generic name and dosage strength (per cell).
2. MNF Lot #.
3. Expiration date.
Note:
Tablet / caplet thickness upper limits critical to fit blister mold.
SECTION V SECTION 5
Labeling
PROPOSED GENERIC PACKAGE INSERT LABELING
SIDE-BY-SIDE COMPARISON
An annotated side-by-side comparison of package leaflet (insert or Outsert.) and
container label of the generic drug product and the Brand RLD. Labeling similarities
and differences between Generic and Brand RLD are highlighted both below and on
the side-by-side comparison itself
GENERIC PACKAGE INSERT INNOVATIVE PACKAGE INSERT
Present full Generic package insert
identical to innovators (caution
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.
Present full Innovative package insert of
package insert must be used - obtain
from FOI services
PACKAGE INSERT - use line side bars
NOTE:-
The differences in the package insert
should be restricted to Innovative
and Product reference Numbers
NOTE:
requirements. Note: the FDA provide a significant number of the latest package inserts
for Generics - on the Internet - See FDA Website. Note the approved labeling MAY
NOT the market place label. Recheck section V data just prior to submission in case of
any approved labeling changes.
SECTION V SECTION 5
Labeling
PROPOSED GENERIC CONTAINER LABEL LABELING
SI DE-BY-SI DE COMPARI SON
GENERIC CONTAINER
LABEL
INNOVATIVE CONTAINER
LABEL
Present full Generic CONTAINER
LABEL identical to innovators (caution
where differences appear as shown:
NOTE:-
LABEL should be restricted to Generic
and Product reference Numbers.
Present full CONTAINER LABEL of
package CONTAINER LABEL must be
used - obtain from FOI services
NOTE:-
LABEL should be restricted to
Innovative product name and different
addresses for Applicant Manufacturer,
Distributor and Product reference
Numbers
NOTE:
requirements
SECTION V SECTION 5
Labeling
PROPOSED GENERIC CONTAINER ADHESIVE LABELING
000 TABLETS [USP]
(Show ALL fill sizes)
NDC [0-00-000-00]
[GENERIC Name] Tablets [USP]
000 mg
000 TABLETS [USP]

- 30 C (59 - 86 F). Protest from
exposure to temperatures above 40 C (104 F) and moisture. Dispense contents in tight light resistant
containers as defined in the USP with a child resistant closure (as required). KEEP THIS AND ALL
MEDICATIONS OUT OF REACH OF CHILDREN
Distributed By:
NOTE:
Examine innovator's labeling carefully and reproduce meeting all regulatory
requirements. Obtain the latest printing of the innovator's product labeling.
SECTION V SECTION 5
Labeling Certification Statement
INNOVATIVE CONTAINER ADHESIVE LABELING
000 TABLETS [USP]
(Show ALL fill sizes)
NDC [0-00-000-00]
[INNOVATIVE Name] Tablets [USP]
000 mg
000 Tablets [USP]

- 30 C (59 - 86 F). Protest from
exposure to temperatures above 40 C (104 F) and moisture. Dispense contents in tight light resistant
containers as defined in the USP with a child resistant closure (as required). KEEP THIS AND ALL
MEDICATIONS OUT OF REACH OF CHILDREN
[Innovative (RLD) Company Name Inc. / Ltd.]
NOTE:
Examine innovators labeling carefully and reproduce meeting all regulatory
requirements
SECTION V SECTION 5
Labeling Certification Statement
[Generic name] TABLETS[USP] [000.0] mg.
Certification.
Drug's proposed labeling same as listed drug.
The undersigned hereby certifies to the best of our knowledge and in
[Generic Company Name Inc. / Ltd.]s opinion the proposed labeling is
the same as listed drug [RLD] TABLETS [USP] NDA # 00-000.
------------------------------------------------ -----------------------------------------
SECTION V SECTION 5
Labeling
Labeling similarity and differences between Generic and Brand RLD insert
GENERIC INSERT
LABELING
RLD INSERT
LABELING
Description Description
Color, shape and embossing/printing Color, shape and embossing/printing
Strength Strength
Dispensing information Dispensing information
All text is identical except for [one] use
indication namely [indication]
All text is identical except for [one]
patented use indication namely
[indication]
Section
Section
Specific use patent indication excluded Specific use patent indication under
exclusivity rights
Strength Strength
How Supplied How Supplied
Addresses (Applicant & Distributing) Addresses
NDC # NDC #
Strength Strength
Quantities Quantities
24 Volume Dr ug Development Ser ies Sect: 6.1 DEVELOPMENT Or al Tablets
SECTION VI SECTION 6
Bi oavai l abi l i t y / Bi oequi val enc e
TABLE OF CONTENTS
6.1 Title Page and brief summary statement of what this section contains.
6.2 Formula Composition of Generic product
6.3 Percent Composition of Formula
6.4 Comparative Ingredients List between Innovator & Generic (all strengths)
6.5 Certificates of Analysis of Generic Drug Product - (all strengths)
6.6 Certificates of Analysis for Innovators Product - (all strengths)
6.7 Comparative Dissolution Protocol using 12 dosage units each - (all
strengths).
6.8 Comparative Dissolution Profile
CDP study results
Statistics
Tables
CDP Graphs
6.9 Request for Waiver for Biostudy for other strengths
(in multiple strength applications).
6.10 Outline of packaging container closures - proposed marketing packs.
6.11 Tablet trail of all packed units.
6.12 Biostudy protocol
Biostudy Study Reports (conducted on pivotal batch).
*(Biostudy = Bioavailability / Bioequivalence Study)
4
Bioavailability / Bioequivalenc e
Section 6.1 contains the Biostudy reports of the in vivo Bioequivalence study
conducted. The lot numbers of test product and reference product compared in this
study are:
Generic Product
[Generic name] Tablets [USP] [000.0] mg. Lot: [IA-000-00]was manufactured at
[Generic Company Name Inc./Ltd.] [Address] facility, utilizing the production area
and incorporating standard production staff, procedures and equipment. The Batch
size was: [0000 000] Tablets [USP].
Reference Product
[RLD Company Name Inc./Ltd.], [RLD] Tablets [USP] [000.0] mg lot: Lot:
AA000 Expiry Date: Month 199? / 200?
This Section contains:
Statement of composition of the generic product [Generic name] Tablets [USP]
[000.0] mg.
Percent composition of the generic product [Generic name] Tablets [USP]
[000.0] mg.
Qualitative comparative Ingredient List Reference Listed Product and Generic.
Certificates of Analysis for both products used in the Bioequivalence namely:
[Generic name] Tablets [USP] [000.0] mg. Lot: [000-00]
CoA No: [0000]
[RLD] Tablets [USP] [000.0] mg. Lot: [AA000]
CoA No: [0000]

Comparative Dissolution Profile of the following:
Reference Product
[RLD] Tablets [USP] [000.0] mg. Lot: [AA000]
CoA No: [0000]
Generic Product
CoA No: [0000]

Packaging and Disbursement Summary for [Generic Company Name Inc./Ltd.]
pivotal Lot: [000-00]
6.2 FORMULA COMPOSITION
Composition of the drug, stating the name and amount of each ingredient, whether
active or not, contained in a stated quantity of the drug, in the form in which it is to be
distributed.
[Generic name] Tablets [USP] [000.0] mg.
(equivalent to [000.0] mg [Active Material]
Ingredients Amount per Unit
per 20 mg Tablet (in milligrams)
[Active Material] 23.60
1
Active
Povidone USP 9.00 Non-active
Colloidal Silicon Dioxide NF 2.10 Non-active
Starch NF 5.30
2
Non-active
Starch NF (Re-dried) 27.00 Non-active
Anhydrous Lactose NF 230.00 Non-active
Magnesium Stearate NF 3.00 Non-active
Total 300.00
Calculation for Active Material Weight on a Dry Basis.
Weight Adjustment Calculation:
1
Note: [00.0] mg for [Active Salt] is equivalent to 00 mg of [Active] base.
Quantity of [Active Salt] to be weighed = [Lot Size] x [00.0] x 100
100 -LOD
Where LOD = Loss on Drying of for [Active Salt] =
2
The actual quantity of [Excipient] NF used in the formula will depend on the WEIGHT for
[Active Salt] used.
6.3 PERCENT COMPOSITION OF THE PRODUCT
Ingredients
per 00 mg Tablet
Each Tablet
Contains - (%)
[Active Material] 7.87
1
Povidone USP 3.00
Colloidal Silicon Dioxide NF 0.70
Starch NF 1.76
2
Starch NF (Re-dried) 9.00
Anhydrous Lactose NF 76.67
Magnesium Stearate NF 1.00
Total 100.00
Calculation for Active Material Weight on a Dry Basis.
1
Quantity of [Active Salt] to be weighed = [Lot Size] x [00.0] x 100
100 -LOD
2
The actual quantity of [Excipient] NF used in the formula will depend on the WEIGHT for
[Active Salt] used.
QUALITATIVE COMPARATIVE INGREDIENTS LIST
[Active Material]
[RLD] Tablets [USP] [00.0] mg.
[Active Material]
[RLD Company Name Inc. / Ltd.]*
[Active Material] [Active Material]
Povidone USP Povidone
Colloidal Silicon Dioxide NF Colloidal Silicon Dioxide
Starch NF Starch
Starch NF (Re-dried) Lactose
Anhydrous Lactose NF Magnesium Stearate
Magnesium Stearate NF Another ingredient
* Reference Source - PDR 1998/200Y
CERTIFICATES OF ANALYSIS REPRESENTING THE DRUG PRODUCTS USED IN
BIOEQUIVALENCY STUDY
[Generic name] Tablets [USP] [000.0] mg. Lot: [IA-000-00]
CoA No: [00-00]
[RLD] Tablets [USP] [000.0] mg. Lot: AA000
CoA No: [00-00]
The analytical results of the Certificates of Analysis for [Generic Company Name Inc.
/ Ltd.] and [RLD Company Name Inc. / Ltd.] Drug Product lots were obtained from
the Analytical Research Laboratories at [Generic Company Name Inc. / Ltd. &
Address].
Attached:
Certificate of Analysis Number 0006 Date: Month DD 1998
Certificate of Analysis Number 0007 Date: Month DD 1998
COMPARATIVE DISSOLUTION PROFILE FOR DRUG PRODUCT LOTS
USED IN BIOEQUIVALENCE STUDIES:
[Generic name] Tablets [USP] [000.0] mg. Lot: [IA-000-00]
CoA No: 0000
[RLD] Tablets [USP] [000.0] mg. Lot: AA000
CoA No: 0000

Dissolution conditions used for Comparative Dissolution Profiles (IR):
Volume : : 000 mL
Media : : 0.0 N [Media Type / Buffer]
Surfactant (where used) : : [0.0%] [Surface Active Agent]
pH : : [0.0 0.05] pH
Temperature : : 37 Degrees C 0.5
Apparatus : : No. 1 USP (basket) / (Paddle),
Speed: : : 000 rpm (calibrated)
Tolerance (IR) : : NLT 00% (Q) in 000 minutes
Attached:
Dissolution ProfileNumber 00006 Lot: [IA-000-00] Date: Month DD 200Y
Dissolution ProfileNumber 00007 Lot: AA000 Date: Month DD 200Y
RLD Product Batch No:______ Exp.___
Generic Drug Batch No:______ Exp.___
COMPARATI VE DI SSOLUTI ON PROFI LE
12 Dosage Units
Method
SI-00-00
Percentage Assay of the labeled amount dissolved in:-
Edition #
00-00
20 min 30 min 45 min 80 min
Dosage
Unit No.
RLD
[name]
Generic
[name]
RLD
[name]
Generic
[name]
RLD
[name]
Generic
[name]
RLD
[name]
Generic
[name]
Unit 1
00.0 00.0 00.0 00.0 00.0 00.0 00.0 00.0
Unit 2
00.0 00.0 00.0 00.0 00.0 00.0 00.0 00.0
Unit 3
00.0 00.0 00.0 00.0 00.0 00.0 00.0 00.0
Unit 4
00.0 00.0 00.0 00.0 00.0 00.0 00.0 00.0
Unit 5
00.0 00.0 00.0 00.0 00.0 00.0 00.0 00.0
Unit 6
00.0 00.0 00.0 00.0 00.0 00.0 00.0 00.0
Unit 7
00.0 00.0 00.0 00.0 00.0 00.0 00.0 00.0
Unit 8
00.0 00.0 00.0 00.0 00.0 00.0 00.0 00.0
Unit 9
00.0 00.0 00.0 00.0 00.0 00.0 00.0 00.0
Unit 10
00.0 00.0 00.0 00.0 00.0 00.0 00.0 00.0
Unit 11
00.0 00.0 00.0 00.0 00.0 00.0 00.0 00.0
Unit 12
00.0 00.0 00.0 00.0 00.0 00.0 00.0 00.0
X (Mean)
RSD
22.9
1.4
22.7
1.5
45.8
1.5
48.0
1.3
65.0
1.7
68.0
1.6
102.0
1.5
100.7
1.5
Model values supplies.

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

Figure No. 1. Comparative Dissolution Profile
Generic Tablets vs RLD 00mg
0
20
40
60
80
100
120
0 20 40 80
TIME (min)
% DISSOLVED
S-12345
RLD AA0000
0 20 40 80 0 20 40 80
Limits: NMT 5% variation between Generic and RLD data points.


Tolerance: NLT 00 % (Q) in 00 mins.
12 Tablets [USP]
Stress Study - 3 months Stability at 40C / 75% RH
Figure No. 2. Comparative Dissolution Profile
Generic Tablets vs RLD 00mg - Stressed
0
20
40
60
80
100
120
0 30 60 120
TIME (min)
% DISSOLVED
S-12345
RLD-AA000
IMPORTANT NOTE:
Evaluate Comparative Dissolution Profiles (CDP) with 3 to 4 different dated RLD batch
Lots obtained at 1-3 month intervals apart, from time of manufacture.
Stressed Profiles: CDP using 3 to 4 different dated RLD batch Lots placed on stability
at 40C / 75% RH for 3 - 6 months. (Evaluate Assay and Impurity profiles).
It is significant to evaluate the variability in the RLD product at normal, post stressed
and at different RLD manufacturing dates (RLD products made at different times).
Success of a costly Bioequivalence study may hinge or depend on the detail of the
RLD's data (i.e. Multiple lots at different manufacturing date, normal, and aged
studies). The intra-batch and inter-batch variability of the RLD should be evaluated
with care.
CERTIFICATE OF ANALYSIS
RLD: Lot No: Exp. Dat e: Anal ysi s Dat e: Fi l l Si ze
Standard Chromatogram
Barr spec.15 26/9/97 10:03
Assay Innovator Tablets 20mg
Sample
D-3400
method SI- 00-00 Tabs. Tag 44 CH: 1 Vial : 8
File 15 Calc-Method: AREA HEIGHT Conc. BC No:
RT AREA HEIGHT Conc. BC No:
3.63 445 56 0.0008 BB 1
7.61 5553456 553456 99.995 BB 2
14.63 645 66 0.0011 BB 3
15.93 445 96 0.0008 BB 4
Total
Lab book Ref.
GENERI C: Lot No: Exp. Dat e: Anal ysi s Dat e: Fi l l Si ze
St andar d Chr omat ogr am
Barr spec.16 26/9/97 10:43
Assay Generic Tablets 20mg
Sample
D-3400
method SI- 00-00 Tabs Tag 45 CH: 1 Vial : 11
File 15 Calc-Method: AREA HEIGHT Conc. BC No:
RT AREA HEIGHT Conc. BC No:
3.63 445 56 0.0008 BB 1
7.62 5553456 553456 99.995 BB 2
14.63 445 66 0.0008 BB 3
15.93 445 96 0.0008 BB 4
Lab book Ref.
REQUEST FOR WAIVER OF
IN-VIVO BIOAVAILABILITY STUDIES
STATUS OF EACH STRENGTH:
[Generic Product] Tablets 20 mg - Bioequivalence Study Submitted in this ANDA.
[Generic Product] Tablets 10 mg - Waiver hereby being requested.
WAIVER REQUEST
[Generic Firm] hereby request a waiver of evidence of in-vivo bioavailability for
[Generic Product] Tablets 10 mg,
An in-vivo bioavailability study was conducted on [Generic Product] Tablets 20 mg and
a full report of the biostudy is included in section VI of this ANDA.
The [Generic Product] Tablets 20 which is the subject of this application, has the same
geometric proportional formulation as the [Generic Product] Tablets 10 mg. The
milligrams per tablet and comparative percent compositions of the two strengths are
shown for purposes of similarity.
The [Generic Product] Tablets 20 mg, (this application), has a dissolution profile which
is essentially identical to that of the [Generic Product] Tablets 10 mg.
Comparative dissolution profiles are included herewith. We also include a dissolution
profile of three batches of the innovator product (TRADE) (Active material).
The variation in the innovators product profile is demonstrated statistically.
Dissolution testing was performed on 12 individual Tablets from each lot, using USP
apparatus and method. Samples were taken at [20], [30], [45] and [80] min and
assayed for (Active material) and expressed as a percentage of the labeled amount.
Dissolution testing was performed under the following conditions:
Method No. 00-00 Edition No. 00-00
Volume : : 000 mL
Media : : 0.0 N [Media Type / Buffer]
Surfactant : : [0.0%] [Surface Active Agent]
pH : : [0.0 0.05] pH
Temperature : : 37 Degrees C 0.5
Apparatus : : No. 1 USP (basket) / (Paddle),
Speed: : : 000 rpm (calibrated)
Tolerance (IR) : : NLT 00% (Q) in 000 minutes
Data submitted in support of request for waiver of in-vivo
bioavailability studies.
Profile 1. [Generic] 20mg Batch No. Exp. 00/99
Profile 2. [Generic] 10mg Batch No. Exp. 00/99
COMPARATI VE DI SSOLUTI ON PROFI LE
12 Dosage Units
Method
SI-00-00
Percentage Assay of the labeled amount dissolved in:-
Edition #
00-00
20 min 30 min 45 min 80 min
Dosage
Unit No.
20g
Generic
10g
Waiver
20g
Generic
10g
Waiver
20g
Generic
10g
Waiver
20g
Generic
10g
Waiver
Unit 1
00.0 00.0 00.0 00.0 00.0 00.0 00.0 00.0
Unit 2
00.0 00.0 00.0 00.0 00.0 00.0 00.0 00.0
Unit 3
00.0 00.0 00.0 00.0 00.0 00.0 00.0 00.0
Unit 4
00.0 00.0 00.0 00.0 00.0 00.0 00.0 00.0
Unit 5
00.0 00.0 00.0 00.0 00.0 00.0 00.0 00.0
Unit 6
00.0 00.0 00.0 00.0 00.0 00.0 00.0 00.0
Unit 7
00.0 00.0 00.0 00.0 00.0 00.0 00.0 00.0
Unit 8
00.0 00.0 00.0 00.0 00.0 00.0 00.0 00.0
Unit 9
00.0 00.0 00.0 00.0 00.0 00.0 00.0 00.0
Unit 10
00.0 00.0 00.0 00.0 00.0 00.0 00.0 00.0
Unit 11
00.0 00.0 00.0 00.0 00.0 00.0 00.0 00.0
Unit 12
00.0 00.0 00.0 00.0 00.0 00.0 00.0 00.0
X (Mean)
RSD
22.9
1.4
23.5
1.5
45.2
1.5
46.0
1.3
66.0
1.7
67.0
1.6
101.0
1.5
100.7
1.5
Model values supplies.
FORMULA COMPOSITION OF BIOSTUDY and PROPOSED WAIVER STRENGTH
[Generic name] Tablets [USP] [20.0] and [10.0] mg.
Ingredients Amount per Strength
per Tablet (in milligrams)
[Active Material BP / Ph. Eur]
20.00 10.00
(Biostudy) (Waiver)
[Active Material] 23.60 11.80
Povidone USP 9.00 4.50

1.05
Starch NF
Purified Water
5.30 2.65
2
qs
2
qs
2
Starch NF (Re-dried) 27.00 13.50
Anhydrous Lactose NF 230.00 115.00
Magnesium Stearate NF 3.00 1.50

Total 300.00 150.00
2
Processing solvent only.
SUMMARY
The following summary supports the request for the for waiver of in-vivo
bioavailability studies
FORMULATION & MANUFACTURE:
Same Active material from same Approved Supplier
Identical granulate manufactured with identical manufacturing equipment
Geometric proportion of non-active ingredients
ANALYTICAL & STABILITY
12 point Dissolution Profile of both strengths do not vary by more than 5%
Stability Profile and impurity profile essentially similar to study formulation.
4
Biostudy Section of
Packaging and Disbursement
Summary for Pivotal Lot: [IA-000-00]
30cc H.D.P.E. Container with Child Resistant Cap Closure [33 mm]
H.D.P.E = High Density polyethylene
30cc H.D.P.E. Container with Metal Cap Closure [33 mm]
Refer to Section 12 for complete Packaging and Disbursement summary of
Pivotal Lot: [IA-000-00]
4
500 units x 30 tablets = 15,000 tablets
Packaging date: Month DD, 200Y
Nov.28, 1996
5 units x 30 tabs
QC Testing
Month DD, 200Y
40 units x 30 tabs
Biostudy (European Market)
Month DD, 200Y
400 units x 30 tabs
Balance stored in
Pivotal Warehouse
55 units x 30 tabs
Release & Stability Testing
Month DD, 200Y
Nov.28, 1996
9 units x 100 tabs
QC Testing & Reserve units
Month DD, 200Y
25 units x 100 tabs
Month DD, 200Y
40 units x 100 tabs
Biostudy & Retained Samples
Month DD, 200Y
60 units x 100 tabs
Balance stored in
Pivotal Warehouse

FINAL BIOEQUIVALENCE REPORT
(Summary Report Here)

FULL BIOEQUIVALENCE PRESENTED IN SEPARATE BINDINGS AS
STAND ALONE VOLUME(S) USING FDA BIO JACKET COVERS (RED).
Bioavailability/ Bioequivalence
24 VOLUME DRUG DEVELOPMENT SERI ES Sect: 6.15 Oral Dosage Forms
FINAL REPORT
TITLE
BIOEQUIVALENCE Evaluation
of two Oral [Active Material] Preparations
in [00] Healthy Volunteers.
Attached (page Ref.: 00-00) are the actual results including graphs, curves, tabulated results of
data, individual subject data and summaries and analysis for the invivo bioequivalence for
[Applicant Company Name Inc. / Ltd.] the bioequivalence study also contains a description of
the analytical and statistical methods used in the study. Also Attached (page Ref.: 00-00 -
Section 4) is the protocol for the invivo bioequivalence performed by [CRO Testing Lab Name
Inc. / Ltd.] for [Applicant Company Name Inc. / Ltd.]. the study was conducted with the
informed consent regulations in 21 CFR 50 and in compliance with the institutional review
board regulations in 21 CFR 56 (page Ref.: 00-00 - Section 4).
SPONSOR [Applicant Company Name Inc. / Ltd.]
[Address]
INVESTIGATION SITE [CRO Company Name Inc. / Ltd.]
ANALYTICAL CENTER
[CRO Testing Lab Name Inc. / Ltd.]
BIOMETRICAL CENTER [CRO Biometrics Center Name Inc. / Ltd.]
PRINCIPAL INVESTIGATOR
[ Name of Pr i nc i pal I nvest i gat or ]
Pr i nc i pal I nvest i gat or Qual i f i c at i ons
CLINICAL STUDY DATES
Start Date
Completion date
Month DD, 2001
Month DD, 2001
Month DD, 2001
DATE OF COMPLETION
OF FINAL REPORT
Month DD, 2001
Report Code No [S00/00/00]
TABLE OF CONTENTS
VOLUME ONE
1. Section : : Project Summary
2. Section : : Rationale for [Food] / [Fasting] study.
3. Section : : Summary of Statistical Analysis
4. Section : : Study protocol, Protocol amendments, Informed Consent, IRB
Approval, and Clinical Report.
5. Section : : Summary of Bioavailability Data.
6. Section : : Individual Linear and Semi-log graphs
7. Section : : Statistical report on [Active Material] and [Active Metabolite M1]
in Plasma
8. Section : : Analytical Report for [Active Material]
9. Section : : Analytical Report for [Active Metabolite M1]
10. Section : : Results of [Active Material] in Plasma
11. Section : : Statistical Data of Standards and Quality Control Samples for
[Active Material] in Plasma
12. Section : : Chromatograms of [Active Material] in Plasma
VOLUME TWO
1. Appendix : : Validation of [Active Material] in Plasma
2. Appendix : : Validation Report for [Active Material] in Plasma
3. Appendix : : Validation of [Active Metabolite M1] in Plasma
4. Appendix : : Validation Report for [Active Metabolite M 1I] in Plasma
5. Appendix : : Chromatograms of [Active Material] in Plasma
6. Appendix : : Chromatograms of [Active Metabolite M 1] in Plasma
7. Appendix : : Data for [Active Metabolite M 1]
8. Appendix : : Statistical Data of Standards and Quality Control Samples
for [Active Metabolite M 1] in Plasma
9. Appendix : : Short description of Testing Facilities
Testing Facilities in US
Testing Facilities in Europe
BIOMETRICAL Center in US
VOLUME THREE
1. Appendix : : Case Records Forms.
STATEMENT OF STUDY FACILITY
This report is respectfully submitted to [Applicant Company Name Inc. / Ltd.]
[Address]
The signature below attests to the content and accuracy of the clinical part of this final
report based on the aspects of the investigation performed at the facilities of [Testing
Facilities Inc. in US] situated [Address].
Month DD, 2000
-----------------------------------------
[ Name of Pr i nc i pal I nvest i gat or ] Date
Pr i nc i pal I nvest i gat or
STATEMENT OF TESTING FACILITY
The undersigned hereby conforms that our testing facility in [Address] operates in
compliance with all regulatory requirements of the US Food and Drug Administration.
[CRO Testing Facilities in US] [Address] guarantees that at the time of the analysis of
biological samples performed in the Study No [0000] the [Testing Facilities in US] had
no current outstanding deficiencies as cited by the FDA or other government agency
and that the facility fully met the performance requirements for current Good Laboratory
Practice (cGLP) of the US Food and Drug Administration and US Code 21 Federal
Register.
------------------------------------------------ ---------------------------------
[ Name of CEO / Pr esi dent ] Date
CEO / President
STATEMENT OF BIOMETRICAL FACILITY
his report is respectfully submitted to [Applicant Company Name Inc./Ltd.]
[Address]
The signature below attests to the content and accuracy of the biometrics part of this
final report based on the aspects of the investigation performed at the facilities of
[Testing Facilities in US] [Address].
Month DD, 200Y
------------------------------------------------ - -----------------------------------------
Pr i nc i pal Phar mac ok enet i c i st
T
PROJ ECT SUMMARY
his report is respectfully submitted to [Applicant Company Name Inc./Ltd.]
[Address]
This project was designed as a randomized, single dose two way crossover
comparative study of the Bioequivalence and pharmacokinetics of the test preparation:
Dosage Form [00] mg (Generic Company)
ver sus t he
Dosage Form [00] mg (Merck)
The Study was performed in health male volunteers who received a [10] mg single dose
of [Active Material] under [Food] / [Fasting] conditions.
Determination of [Active Material] and [Active Metabolite M 1] were performed
according to SOP 00 on the samples collected following administration of the drugs.
[Active Material] concentration in plasma was determined by a validated [GC-MS] /
[HPLC] method.
[Active Metabolite M 1] concentration in plasma was determined by a validated [GC-
MS] / [HPLC] method.
Based on the results of the study the test product is comparable in rate and extent of
absorption for the reference product for[Active Material] and [Active Metabolite M 1]
In addition, for [Active Metabolite M 1] the principle metabolite responsible for the
majority of the pharmacological affects of oral doses of [Active Material], the
requirements for Bioequivalence are met.
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.
-----------------------------------------
Pr i nc i pal I nvest i gat or
T
TITLE:
BIOEQUIVALENCE EVALUATION
in [00] Healthy Volunteers
Vol ume One
STUDY DATA
Project Summary
Section : :
Summary of Statistical Analysis
Section : : Rationale for [ Food] / [Fasting] study
Section : :
Study protocol, Protocol amendments, Informed Consent, IRB Approval,
and Clinical Report
Section : :
Summary of Bioavailability Data
Section : :
Individual Linear and Semi-log graphs
Section : :
Statistical report on [Active Material] and [Active Metabolite M1] in
Plasma
Section : :
Analytical Report for [Active Material]
Section : :
Analytical Report for [Active Metabolite M1]
Section : :
Results of [Active Material] in Plasma
Section : :
Statistical Data of Standards and Quality Control Samples for Active
Material] in Plasma
Section : :
Chromatograms of [Active Material] in Plasma
Section : :
TITLE:
Vol ume Tw o
APPENDIXES
ACTIVE MATERIAL
Appendix: :
Validation of [Active Material] in Plasma
Appendix: :
Validation Report for [Active Material] in Plasma
Appendix: :
Data for [Active Material]
Appendix: :
Chromatograms of [Active Material] in Plasma
ACTIVE METABOLITE - WHERE PRESENT
Appendix: :
Validation of [Active Metabolite M1] in Plasma
Appendix: :
Validation Report for [Active Metabolite M 1I] in Plasma
Appendix: :
Chromatograms of [Active Metabolite M 1] in Plasma
Appendix: :
Data for [Active Metabolite M 1]
Appendix: :
Statistical Data of Standards and Quality Control Samples for
[Active Metabolite M 1] in Plasma
FACILITIES
Appendix: :
Short description of Testing Facilities
Appendix: :
Testing Facilities in US [Address]
Testing Facilities in Europe [Address]
BIOMETRICAL Center in US [Address]
TITLE
Vol ume Thr ee
Case Records Forms
Appendix : : Case Records Forms.
At t ac hment s:
Disclosures & Certification
Attached (page Ref.: 00-00) are the signed and completed copies of Certification Financial
Interest & Arrangements of Clinical Investigators Form FDA 3454 (3/99) and Disclosure
Financial Interest & Arrangements of Clinical Investigators. Form FDA 3455 (3/99) as
appropriate to the bioequivalence study sponsored by [Applicant Company Name Inc. / Ltd.]
and consistent with 21CR Part 54.
1. Certification Financial Interest & Arrangements of
Clinical Investigators
Form FDA 3454 (3/99)
2. Disclosure Financial Interest & Arrangements of
Clinical Investigators.
Form FDA 3455 (3/99)
SECTION VII SECTION 7
Component s and Composi t i on
TABLE OF CONTENTS
7.1 Title Page and brief summary statement of what this section contains
7.2 List of Components - in order of manufacture (name & grade)
7.3 Formula Composition of Generic Product
7.4 Percent Composition of Generic Product
This section contains:
List of components
Formula Composition
Percent Composition
4
Components and Composition
LI ST OF COMPONENTS
Following is a full list of the articles used as components of the drug product:
[Active Material] (Active Suppliers Name)
Povidone USP
Colloidal Silicon Dioxide NF
Starch NF
Starch NF (Re-dried)
Anhydrous Lactose NF
Magnesium Stearate NF
4
FORMULA COMPOSITION
Composition of the drug, stating the name and amount of each ingredient, whether active or
not, contained in a stated quantity of the drug in the form in which it is to be distributed.
Formula
Ingredients
Amount in mg
per [00] mg Tablet
[Active Material] (Active Suppliers Name) 23.60
1
Povidone USP 9.00
Starch NF 5.30
Total 300.00
Calculation for Active Material Weight on a Dry Basis
1
Quantity of [Active Salt] to be weighed = Batch Size x[00.0] x 100
100 - LoD
Where LoD = Loss on Drying of for [Active Salt] =
2
The actual quantity of Starch NF used in the formula will depend on the WEIGHT of
[Active Salt] used.
4
PERCENT COMPOSI TI ON OF THE PRODUCT
Formula
Ingredients
Each 00 mg Tablet
contains (Percentage)
[Active Material] (Active Suppliers Name) 7.87
1
Povidone USP 3.00
Starch NF 1.76
TOTAL 100.00
Calculation for Active Material Weight on a Dry Basis
1
Note: 00.0 mg for [Active Salt] is equivalent to 00 mg of [Active] base.
Quantity of [Active Salt] to be weighed = Batch Size x 00.0 x 100
100 - LoD
Where LoD = Loss on Drying of for [Active Salt] =
2
The actual quantity of Starch NF used in the formula will depend on the WEIGHT of
[Active Salt] used.
4
SECTION VIII SECTION 8
Raw Mat er i al Cont r ol
TABLE OF CONTENTS
Active Ingredient(s)
8.1 Title Page and brief summary statement of what this section contains
8.2 Outlines of SOPs for handling Raw Materials (Retest procedure max. 12
months)
- Outlines of SOP for Qualification of Vendors
- Outlines of SOP for Acceptance Criteria
- Outlines of SOP for Retesting Schedules
- Outlines of SOP for Raw Materials storage
8.3 Disclosure of Active ingredients Source
8.4 DMF of Manufacturer via Letter of Access from Active Manufacturer (Type II)
8.5 Active Monograph supplied by QC laboratory
8.6 CoA from Generic Firms QC laboratory, plus supporting
- Identification IR or UV spectra of Active
8.7 CoA from Active Manufacturer, - plus supporting
- Identification IR or UV spectra of Active
8.9 IR Identification Spectra of Reference Standard (Pharmacopoeial)
8.10 Physical Specifications from Active Manufacturer
- Bulk Density,
- Particle Size (note: water insoluble material)
- Physical and analytical test methods
8.11 Outline of Material Data Safety Sheet (MDSS)
(source of data for manufacturing instructions precautions).
9.0 Inactive Ingredients
9.1 Testing Specifications (ID and characterization)
9.2 Suppliers Certificate of Analysis (Specifications and Test Results)
4
13 of 13
Raw Material Control
Outline of the Standard Operating Procedures for Raw Materials
Summary of Lot Numbers of Active and Inactive Ingredients
Disclosure of Active Ingredient Source (approved supplier)
Active Ingredient DMF Authorization Letter
Active Ingredient Certificates of Analysis
Active Ingredient Supporting Data (Spectra)
Outline of Material Data Safety Sheet (MDSS)
Inactive Ingredient Certificates of Analysis
Inactive Ingredient Testing Monographs/Test Procedures
Routine Testing Protocols
4
OUTLINE OF STANDARD OPERATING PROCEDURES FOR
HANDLING RAW MATERIALS AND PACKAGING MATERIALS
1. Vendors Approval
All chemical raw materials used in the manufacturing of commercial products and
primary stability batches, must be supplied by approved vendors.
The approval of vendors is a shared responsibility of the QA Department of the plant
and the Purchasing Department. For pilot batches, the R&D Department is
responsible.
The Purchasing Dept. submits an application to approve a vendor to the QA
Department, specifying the full details of the vendor and samples identified by the
manufacturer, including the Certificates of Analysis of the manufacturer. The
manufacturer must have a DMF (Drug Master File) submitted to the FDA.
The QC Laboratory tests must confirm that the Certificate of Analysis, which must
accompany the raw material, meets the raw material requirements.
In the absence of a pharmacopoeia monograph, compliance to an approved in-house
monograph is required. The in-house monograph forms part of the requirements.
The use of an alternative active raw material from a new vendor, not stated in the
ANDA, is subject to the prior approval of the FDA.
After obtaining satisfactory results, and if required the approval of the appropriate
health authority, the QA Unit approves the new vendor.
2. Acceptance Criteria
All raw materials are quarantined after receipt at the firms warehouse, pending tests
and analysis.
With the arrival of raw materials, the existence of a purchase order is checked,
including the line number of the order. The status of the vendor and the condition in
which the goods arrived is full examined.
All lots are sampled. Each lot must have a manufacturers Certificate of Analysis for
the QC department review.
The initial batches of an approved vendor are tested according to the full monograph.
When the reliability of the vendors Certificate of Analysis is established and the
vendor is approved, the use of an abbreviated monograph is evaluated.
A full compendial monograph is performed every 6 months on all incoming raw
material lots.
On receipt, each sample undergoes at least one (1) identification test. Further routine
tests are performed as required by the respective testing program.
Rejected Batches:
Raw materials samples not approved for use by the laboratory will be marked by a
laboratory issued red Rejected label, affixed to the sample by a quality assurance
unit, and transferred to the Rejected area of the warehouse.
Rejected materials will remain in the Rejected area until a final decision is reached
whether to return them to the supplier or to destroy them.
3. Retest Schedule
Each lot of raw material remaining in the inventory is retested based on the previous
date of analysis.
Retest period for highly sensitive materials (actives and excipients) and materials
requiring microbiological testing, is 12 months.
All other active and excipient materials are retested after 24 months, or as stipulated in
the laboratory documents. [Active Material] (Approved Supplier) will be retested
after 12 months.
4. Storage
Quarantine Storage
1. Raw materials shall be stored in controlled environmental areas under monitored
environmental storage temperatures, held between 15
o
to 25
o
C.
2. Raw materials received shall be marked with identification labels QUARANTINE -
Do Not Use! Materials shall be sampled and then transferred, for holding in the
quarantine area, pending QC release.
3. The quarantine for raw materials requiring cooling or freezing shall be stored in
controlled and routinely monitored refrigerators or deep freezers, capable of
maintaining the correct temperature conditions for the appropriate raw material.
4. The raw materials shall be stored, off the floor, on a shelf, on a palette, in cages or
in appropriate refrigerated units.
5. The raw materials shall remain in the quarantine area throughout the QC Analytical
Laboratory material acceptance testing.
Release from Quarantine
1. Raw materials released by the QC laboratory for use in production, shall receive a
green Released label. The label is printed by the QC Lab computer and attached
over the orange part of the label marked QUARANTINE - Do Not Use!.
2. The expiration dates for the released raw materials are printed on the labels by the
QC lab computer. Materials having a green Released label will be transferred to the
released materials storage area. 3
Summary of Batch Numbers of Active and Inactive Raw Materials Used
in the Executed (Pivotal) Batch - Lot: [IA-00-000]
Raw Material Raw Material Batch Numbers
Used for MNF of Lot:
Lot: [IA-00-000]
Representative
Certificate of Analysis
(a)
[Active Material]
(Approved Supplier)
Lot # [IA-000] CoA # [IA-000]
Purified Water USP Lot # [IA-000] CoA # [IA-000]
Povidone USP Lot # [IA-000] CoA # [IA-000]
Colloidal Silicone Dioxide NF Lot # [IA-000] CoA # [IA-000]
Starch NF BP Lot # [IA-000] CoA # [IA-000]
Starch NF (Re-dried) Lot # [IA-000] CoA # [IA-000]
Lactose Anhydrous NF Lot # [IA-000] CoA # [IA-000]
Magnesium Stearate NF Lot # [IA-000] CoA # [IA-000]
(a)
A Certificates of Analysis is provided for each ingredient lot used in the manufacture of
the Executed Pivotal batch - Lot: [IA-00-000].
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.
Active Material Control
The manufacturer and approved supplier of the active ingredient
[Active Material] (Approved Supplier) is:
Appr oved Su pplier : [Name] Pharmaceutical and Chemical Company
Address:
[Na me] Ph a r ma ceu t ica l a n d Ch emica l Compa n y
St r eet
Town St at e Zi p Code
Cou n t r y
Commitment to Compendial Requirement Testing
THE COMPANY commits to perform future pharmacopoeial analyses in accordance
with all compendial testing (or otherwise approved testing) at the time the active
material are used in the manufacture of [Generic name] Tablets [USP] [000.0] mg.
[Active Material] (Approved Supplier name) 3
DMF STATUS
No US DMF for Active Material has been lodged with the FDA drug master file
listing (at the time of printing this edition)
Attached URL of all current operational Drug Master Files lodged with the FDA
DMF SEARCH
DRUG MASTER FILES
http://www.iagim.org/search
P h y s i c a l S p e c i f i c a t i o n s
of Active Materials
TEST
METHODS
PHYSICAL SPECIFICATIONS
[ACTIVE MATERIAL]
SPECIFICATIONS
TEST
RESULTS
TEST METHOD
Bulk Density
Suppliers CoA - C0000
06-07g/cc Complies SI-A076-01
Particle Size
Suppliers CoA - C0000
d
90
< 250 Complies SI-A076-02
Bulk Density
In-house CoA - C0000
06-07g/cc Complies SI-A076-01
Particle Size
In-house CoA - C0000
d
90
< 250 Complies SI-A076-02
Notes:
Active Material Full Monograph from QC laboratory indicating all chemical, Physical
and microbiological tests is attached.
Certificate of Analysis and Spectra of Active and Reference Materials
Active Material Certificate of Analysis and Spectra Numbers.
Document Material
Supplied by:
Certificate
number
Remarks
[Active Material]
CoA
Approved
Supplier
# [C076-98] In-house CoA
[Active Material]
CoA
Approved
Supplier
# [C076-98] Suppliers CoA
[Active Material]
CoA
In-house Ref.
Material
[Active Material]
I R Spectra (or UV)
Approved
Supplier
# [C076-98] In-house I R
[Active Material]
I R Spectra (or UV)
Approved
Supplier
# [C076-98] Suppliers I R
[Active Material]
I R Spectra (or UV)
Approved
Supplier
Ref. F In-house Ref.
material
[Active Material]
Typical HPLC Spectra
Approved
Supplier
# [C076-98] In-house HPLC
[Active Material]
Approved
Supplier
# [C076-98] Suppliers HPLC
[Active Material]
In-house Ref.
material
Ref. G
In-house HPLC
[Active Material]
Typical TLC Photocopy
Approved
Supplier
# [C076-98] In-house TLC
[Active Material]
Approved
Supplier
# [C076-98] Suppliers TLC
[Active Material]
In-house Ref.
material
Ref. G
In-house TLC
Attachments.
Page No. ___ to Page No: ___ .
Active Ingredients:

CoA and supporting graphs/Spectra
Three (3) active material Certificates of Analysis attached as per table.
Three (3) active material - I R Spectra - as per table.
Three (3) active material - Typical UV Spectra - as per table.
Three (3) active material - Typical HPLC Spectra - as per table.
Three (3) active material - Typical TLC Spectra - as per table.
(Presented in the order of tabulation).

Supporting Documentation
Active Ingredient DMF Authorization Letter
Active Material Full Monograph from QC laboratory.
Bulk Density and Particle Size test methods
Outline of Material Data Safety Sheet (MDSS)
Non active Ingredients
CERTI FI CATES OF ANALYSI S
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.
Commitment to Compendial Requirement Testing
THE COMPANY commits to perform future analyses in accordance with all
compendial testing or otherwise approved testing at the time such raw materials are
used in the manufacture of [Generic name] Tablets [USP] [000.0] mg.
THE COMPANY may use other raw material suppliers subject to meeting in-house
approved supplier requirements and pharmacopoeial standards.
T
Summary of Certificate of Analysis Numbers of Non-active Raw Materials
Used in the Executed (Pivotal) Batch.
Raw Material Certificate of Analysis (CoA) Numbers.
Approved
Suppliers
Used in MNF.
Lot: [ICA00-00]
Representative
C of As
Purified Water USP In-house
[CA0326-98] [CA388-98]
Povidone USP GAF USA
[CA0526-98] [CA237-98]
Colloidal Silicone Dioxide NF DaGussa US
[CA0126-98] [CA0637-98]
Starch NF GP Corp. USA
[CA0325-98] [CA0224-98]
Starch NF (Re-dried) GP Corp. USA
[CA0076-98] [CA0572-98]
Lactose Anhydrous NF GP Corp. USA
[CA0024-98] -
MAGNESIUM STEARATE NF -
Synpro - vegetable grage
Ferro Corp [CA0111-98] [CA0111-98]
Note:
Where excipients manufacturers have more than one plant the name of the 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 (January
1998)
Raw Material Control -
Attachments.

CoAs
Twelve (12) Certificates of Analysis attached as per table.
(Presented in the order of tabulation).
Supporting Documentation
Seven (7) Testing Monographs of non-active materials
Seven (7) Routine Testing Protocols
(List of Routine tests Performed on non-active materials)
Page Ref er enc es:
CoAs Page No. ___ to Page No: ___ .
Testing Monographs Page No. ___ to Page No: ___ .
Routine Testing Protocols Page No. ___ to Page No: ___ .
ROUTI NE TESTI NG
ROUTINE TESTING PERFORMED ON EACH BATCH OF INACTIVE INGREDIENTS.
STARCH NF
(Trade Name)
Description
Identification Test
Viscosity
Microbial Limits
STARCH NF (DRIED)
(Trade Name)
Description
Identification Test
Viscosity
Microbial Limits
Lactose Anhydrous NF
(Trade Name)
Description
Identification Test
Povidone K90 USP ()
Description
Solubility
Identification Test
K-Value
Purified Water USP
Per week - Microbial Testing
Per month - Full USP Monograph
Colloidal Silicon Dioxide NF
(Trade Name)
Description
Identification Test
(Trade Name)
Description
Identification Test
Microbial Limits
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
SECTION IX SECTION 9
Desc r i pt i on of Manuf ac t ur i ng Fac i l i t y
TABLE OF CONTENTS
Section Page (with Color Section TAG) and brief descriptor of the section. The
manufacturer of the final dosage form of the new drug for which this application is
submitted is [Generic Company Name Inc. / Ltd.]. The applicant performs all of the
manufacturing, packaging, testing and stability test functions of the submitted drug
product.
[Generic Company Name Inc. / Ltd.] does not manufacturer the active drug
substance, the excipients or the container closure system used in the manufacturing
and packing operations for the finished dosage forms. Details concerning the bulk
active drug substance appears in section VIII as those of the excipients while details
for the container closure system appear in section XIII.
No / [One / Two] contract firms are involved in the finished [product testing],
[packaging components] or [stability testing] requirements as filed in this ANDA
(Delete where required)
9.1 Statement of commercial site address of Manufacture(s)
9.2 Statement of commercial packaging & Labeling site address
9.3 Statement of commercial site of Distribution site address
9.4 Address of Facility for QC and Stability Testing
9.5 Brief description of facilities for MNF, testing and stability (no personnel
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
This section contains:-
Addresses of RESEARCH Facilities
Description of Facility
Responsible Personnel (Key Staff)
List of Production Equipment
Blueprint of Facility
GMP Certification Statement
Addresses of Scale-up Facilities
Description of Facility
Responsible Personnel (Key Staff)
List of Production Equipment
Blueprint of Facility
Addresses of Manufacturing Facilities
List of Responsible Personnel (Key Staff)
Blueprint of Facilities
GMP Certification Statement
Drug Establishment Registration No [#00-00-00-00]
NOTE:
Applicant facilities with more than one site who perform special functions at the
specific site (such as analytical or stability testing) need to describe these facilities in
section VIII and X. A separate GMP certificate for that specific site needs to be
included in the application.
4
Description of Research Facility
Resear c h & Sc al e-up Fac i l i t i es
LIST OF RESPONSIBLE PERSONNEL
(A) List of research facilities key personnel in the situation
where the ANDA research site is geographically separated from
the proposed manufacturing site (i.e. in another city, state or
country.)
Li st of Smal l Sc al e Manuf ac t ur i ng Equi pment
(B) List of research and small scale facilities equipment in the
situation where the pivotal batch was manufactured at a site
other than the proposed manufacturing site (e.g. Another city,
state or country).
Blueprint of Research & Scale-up Facilities.
Note: The first three commercial batch lots manufactured at the
proposed manufacturing site are required to be validated. [In
addition - to the above OGD's requirements, lot validation may
be initialized at the remote or foreign site].
Process Qualification Batch and/or Pivotal Batch
4
LIST OF RESPONSI BLE PERSONNEL
1. Management 11. Weighing Center
2. Validation Unit 12. Granulation Department
3. Stability Unit 13. Drying Department
4. Packaging Materials Lab. 14. Milling Department
5. Physical Lab. 15. Sieving Department
6. Microbiology Lab. 16. Blending Department
7. QC Lab. / QA Lab. 17. Slugging Department
8. Development (R&D) Lab. 18. Compression
9. Warehousing 19. Coating Department
10. Housekeeping 20. Other Departments
LIST OF PRODUCTI ON EQUIPMENT
+ [Type of Equipment] [Equipment ID. Number] [Equipment Document No.]
1. Scale-up Department 11. Weighing Center
2. Validation Unit 12. Granulation Department
3. Stability Unit 13. Drying Department
4. Packaging Materials Lab. 14. Milling Department
5. Physical Lab. 15. Sieving Department
6. Microbiology Lab. 16. Blending Department
7. QC Lab. / QA Lab. 17. Slugging Department
8. Development (R&D) Lab. 18. Compression
9. Warehousing 19. Coating Department
10. Housekeeping 20. Packaging Department
4
BLUEPRINT OF MNF FACILITY
Manufacturing, Testing and Storage Areas blueprints - showing facilities layout.
ADDRESSES OF FACILITIES
Manufacturing, processing, bulk packaging, bulk labeling, handling and storage of
the bulk [Generic name] DRUG [USP] [000.0] mg. will take place at the
pharmaceutical manufacturing facility identified below:
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:
Pharmaceutical Packaging Division
[Town] [State] [Zip Code] [Country].
The packaged and labeled product will be distributed through the [Address]
warehouse located at:
Pharmaceutical Warehouse Division
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:
Analytical Research / QC Laboratories
(Additional information on these sites is provided herein.)
4
STATEMENT OF GMP
[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]
------------------------------------------------ -----------------------------------------
Plant General Manager
------------------------------------------------ -----------------------------------------
QA Manager
(Signed GMP statement required for all processing, warehousing and testing sites.)
24 V 24 Volume D Dr ug D Development S Ser ies Sect: 10.1 ANDA DEVELOPMENT
SECTION X SECTION 10
Out si de f i r ms and Cont r ac t Fac i l i t i es
TABLE OF CONTENTS
10.1 Title Page and statement
10.2 Name and Site Address of all Contract Laboratories
10.3 Registration No. of each Contract Laboratory
10.4 List of Test(s) or functions to be Performed by Contract Laboratory
10.5 Certification letter of GMP/GLP Compliance of Contract Laboratory
10.6 Statement on the cGMP Status and Certification of Compliance w.r.t
- a contract manufacturing site
- a contract labeler or packaging site.
10.7 Statement on the PAC-ALTS (Post-approval Changes - Analytical testing
Laboratory Sites)
FDA's Published January 1999 ANDA Guideline requirements:-
Section X.
Outside Firms, Including Contract Testing Laboratories
1. Full address
2. Functions
3. CGMP certification/GLP
4
Outside firms and Contract Facilities
Cont r ac t Fac i l i t i es
[Generic Company Name Inc./Ltd.] does not intend the use of any outside
manufacturing contract facilities at the prevailing time. If a contract outside facility is
desired in the future, the appropriate documentation will be submitted to this ANDA.
(and / or)
Cont r ac t Test i ng Labor at or i es
[Generic Company Name Inc./Ltd.] does not intend the use of any contract testing
laboratories facilities at the prevailing time. If a contract laboratory or outside
laboratory is required in the future, the appropriate CBE documentation according to
PAC-ALTS (Post-approval Changes - Analytical testing Laboratory Sites, April 1998)
will be submitted to this ANDA.
------------------------------------------------ -----------------------------------------
QA Manager
Pharmaceutical Quality Assurance Unit
[Generic Company Name Inc./Ltd.]
------------------------------------------------ -----------------------------------------
Production Manager
4
(or where used)
Cont r ac t Test i ng Labor at or i es
The following contract testing laboratory was used during the development of [Drug
Product] [00] mg & [00] mg: [Contract Laboratory Name Inc./Ltd.] [Address]
The above laboratory developed and validated the analytical method for testing
[Organic Volatile Impurities.] This method was transferred to [ Gener i c Company
Name I nc . Lt d.] and the active raw material for the pivotal batches was tested
according to this method.
Future commercial production batches will be tested also according to this method in
[ Gener i c Company Name I nc . Lt d.] .
Enclosed [Contract Laboratory Name Inc./Ltd.] annual registration of drug
establishment for the year 200Y.
------------------------------------------------ -----------------------------------------
QA Manager
------------------------------------------------ -----------------------------------------
Production Manager
4
ADDRESSES OF FACILITIES
Manufacturing, processing, bulk packaging, bulk labeling, handling and storage of the
bulk [Generic name] Drug [000.0]mg [USP]. will take place at the pharmaceutical
manufacturing facility identified below:
[Third Parties Company Name Inc. / Ltd.]
[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:
Pharmaceutical Packaging Division
(and / or)
The packaged and labeled product will be distributed through the [Address]
warehouse located at:
Pharmaceutical Warehouse Division
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
Analytical Research / QC Laboratories
STATEMENT OF GMP OF
[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.
------------------------------------------------ -----------------------------------------
General Manager
Pharmaceutical Division
------------------------------------------------ -----------------------------------------
QA Manager
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
Gener i c Dr ug Enf or c ement Ac t - 1992
Third Party Letterhead
STATEMENT
Where Company has NO previous convictions
AND does not use a debarred person in connection with the ANDA
Certification Made Pursuant
to the
Generic Drug Enforcement Act of 1992.
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.
------------------------------------------------ -----------------------------------------
[3rd Party Company Name Inc. / Ltd.]
__________________________ ______________________
Di r ec t or Qual i t y Assur anc e Uni t
O
Third Party Letterhead
STATEMENT
Where Company has a previous conviction
but does not use a debarred person in connection with the ANDA
to the
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
certification.
------------------------------------------------ -----------------------------------------
4
End of Section 10.
O
STATEMENT OF PAC-ATLS
[Gener i c Company Name I nc . Lt d.]
[Gener i c Company Name I nc . Lt d.] 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.
------------------------------------------------ -----------------------------------------
QA Manager
------------------------------------------------ -----------------------------------------
Production Manager
HANDBOOK of GENERIC DRUG DEVELOPMENT ANDA Development
SECTION XI SECTION 11
Pr oposed Manuf ac t ur i ng I nst r uc t i ons
TABLE OF CONTENTS
Thi s sec t i on c ont ai ns:
Description of Manufacturing Process
Manufacturing Procedure Flow Chart
Blank Master Production Batch Records for intended production lots
Blank Packaging Records for intended production lots
Formula comparison
Equipment Comparison
Description of Packaging Operation
Reprocessing Statement
4
Proposed Manufacturing Instructions
OUTLINE OF STANDARD OPERATING PROCEDURES FOR :
MANUFACTURING AND PROCESSING
1. Production Planning - Prepares a production order file for each production
batch according to the production schedule.
2. Production Planning - Assigns batch numbers, according to the existing
code procedure, and enters these numbers in the batch numbers log.
3. Production Planning - A photocopy of the master formula record and
manufacturing instructions is prepared with the specific manufacturing batch
number.
4. Production Planning - 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.
5. 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.
6. 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.
7. Production Planning - forwards a Standard Packaging Sheet with the
computerized order to the packaging department.
8. Packaging Department - forwards the Standard Packaging Sheet and the
computer order to the packaging materials warehouse.
9. Packaging Department - Authorizes packaging startup, in-process
compliance, on the Packaging Work Sheet.
10. After packaging, the packaged goods are transferred to the
warehouse/holding area under a quarantine status, pending QC release.
11. The product is tested by the QC analytical laboratory.
12. Production records and test results are analyzed by QA Department and on
release the product is moved to the warehouse ready for shipment.
13. The batch records are archived by the Quality Assurance Department.
14. Shipping Department - maintains a complete and traceability record of the
dispatches of each product batch number and its final destination.
MANUFACTURING INSTRUCTIONS FOR COMMERCIAL PRODUCTION
Identification of Batch Parameters.
Product name: [Generic name] Tablets [USP] [000.0] mg.
Batch Number: [000-00]
Department: ______________ Batch Size: [000-00] units
Precautions: Sub-lot No: 1 2 3
Caution: Manufacture Date: Month DD, 199Y
Cat./Formula No: # 00000 Cores : Coated Tablets
Based on Validation: Batch # 00000 Validation Lot
Commercial Lot
Change Control for this document: Original - No Change : Change
Change made: - none
KEY: KEY:
Precautions: Wear Mask and Gloves
Wear disposable overalls
Use air stream face visor with AIR filter
Use Mask, Gloves and Safety glasses
Caution: Avoid exposure to light / Protect form light
Store in well closed containers
Potential danger to pregnant women
Pregnant women prohibited in this area
Do not heat above 00 C
Room humidity below 30%
Special Note:
A BLANK manufacturing process for film-coated tablets is provided as
an example of how to prepare the manufacturing instructions.
Each 'information or data field' is part of the essential record in order to
meet current US cGMP and FDA Pre-approval expectations. Section 12
includes a DIRECT COMPRESSION (Alendronate) example.
PROPOSED COMMERCIAL BATCH MASTER FORMULA
Batch No: Weighing Date:
Per
UNIT
mg
%
Exc
ess
Raw Material Names
RM.
Lot
No
per [000 000] units
Sign
weigh.
Dept.
Kg g mg L mL A B
PART ONE - GRANULATION
SUBLOT ONE

00.0 [Active Ingredient] 00 000
00.0 [Intra-granular excipient NF] 00 000
GRANULATI NG SOLUTI ON 1
- [Purified Water USP] 00 000
- [Purified Water USP] q.s. 00 000
00.0 [Granulating Agent NF] 00 000
- [Alcohol USP 95%] 00 000
- [Alcohol USP 95%] q.s. 00 000
000.0 Theoretical End Weight. 00 000
SUBLOT TWO

[Active Ingredient] 00 000
- [Alcohol USP 95%] 00 000
- [Alcohol USP 95%] q.s. 00 000
PART TWO - BLENDING
SUBLOTS: ONE + TWO

000.0 Combined Granulates - Sublots 1 +2
00.0 [Extra-granular Disintegrant NF] 00 000
00.0 [Extra-granular Glidant NF] 00 000
00.0 [Extra-granular Lubricant NF] 00 000
Edition Number:
01
Effective Date:
APPROVED
Ed. Status:
New
DD/MM/200Y _____________ __________ _______________ _________/________
Department R &D RA QC / QA
PROPOSED COMMERCIAL BATCH MASTER FORMULA
[Generic name] Tablets [USP] [000.0 ] mg. Lot: [ 0000-00]
Per
UNIT
mg
%
Exc
ess
Raw Material Names
RM.
Lot
No
per [000 000] units
Sign
weigh.
Dept.
Kg g mg L mL A B
PART THREE - AQUEOUS FILM
COAT SUSPENSION

-
00
Aqueous Film Coating Suspension - -
- Purified Water USP 00 000
00.0 0PADRY OY-S-0000 [color] 00 000
- Theoretical End Weight. 00 000
PART FOUR - FILM COATING,
SUBLOT 1 1

000.0 [Name] Tablets [000] mg CORES 000
00.0
Name] Tablets [000] mg CORES
Aqueous Film Coating Suspension
000
000.0 Theoretical End Weight. 000
PART FIVE - FILM COATING,
SUBLOT 2 2

000.0 [Name] Tablets [000] mg
CORES
000
00.0
000
PART SIX - FILM COATING,
SUBLOT 3 3

CORES
000
00.0
000
Edition Number:
01
Effective Date:
APPROVED
Ed. Status:
New
DD/MM/200Y _____________ __________ _______________ _________/________
Aqueous film coat suspension contains 00.% solids
Solids remaining in film coat. Each strength has a full set of manufacturing instructions.
MANUFACTURING INSTRUCTIONS
Machine
No:
S
i
g
n
S
i
g
n
Date
1 Identify the equipment and verify the cleanliness prior to use.
PART ONE
2. Put into the [Diosna 000] (Type & No) the ingredients in the following
order:
[Active Material]
[DRY INGREDIENT NF]
[DRY INGREDIENT NF]
and mix for [ 0 ] minutes at mixer speed I / II and Chopper I / II .
3. Granulation Solution Preparation
(i) Weigh [00] Kg [PURIFIED WATER USP] into a stainless steel vessel
fitted with a roller mixer. (#0)
(ii) Operate the mixer and add the [INGREDIENT NF] and mix until fully
dissolved.
(iii) While mixing, add the [ALCOHOL USP 95%].
4 Add the granulating solution in the set time to the [Diosna 000] (Type
& No) while mixing at mixer speed II and chopper speed II. Total Mixing
Time is 45 seconds.
Time of adding Solution - [40] seconds
Time of mixing - [ 5] seconds
5. If necessary, add the [ALCOHOL USP 95%]. q.s. and/or mix at the
same conditions as in stage 4.
Amount of additional [ALCOHOL USP 95%]: __________ Kg.
Additional mixing time ___________
Seconds
6. Discharge the wet granulate to the FBD mobile bed (Type & No) while
mixing at mixer speed I.
Dry the wet granulate in the FBD (Type & No) under the following
settings:
Inlet Air Temperature NMT 00C (Target: 00C)
Outlet Air Temperature NMT 00C (Target: 00C)
Attach the temperature graph of the FBD (Type & No) to the
manufacturing instructions. Immediately add the batch number to the
temperature graph and date and sign it.
7. Mill about 1Kg. 'check portion' the dried granulate through a
OSCILLATING GRANULATOR (Type & No) fitted with a [0.0 mm]
screen.
Machine Sign Date
7b. Check the milled granulate portion for Loss on Drying (LOD).
Use (Type & No) IR machine with temperature set at temperature 00C
Record First result: __________ [0.0%]
LOD Limits: [0.0 to 0.0%]
7c. If necessary, continue to dry the bulk granulate under the same
conditions as stage 6, until the LOD is close to the midpoint of the given
range limits and check moisture again.
Record Second result: __________[ 0.0%]
8. Pass the remainder of the dried granulate through the OSCILLATING
GRANULATOR (Type & No) fitted with a [0.0 mm] screen into a [000]
liter container or bin.
9. Weigh the milled granulate. ______Kg. Immediately add the batch
number to the scale print-out, attach to the manufacturing instructions,
date and sign the print-out.
10. Theoretical Weight [00.0] Kg. Yield ___________ %
(Yield Limits: NLT 95% of Theoretical Weight.) Bins ___________
PART TWO
11. Transfer the milled granulate from stage 10 of both sub lots to a twin
shell blender / Flow bin (Type & No).
12. Add to the twin shell blender / Flow bin (Type & No).
[INGREDIENT NF]
13. PASS the following material through a sieve (Type & No) fitted with a
[00.0] mm screen
[GLIDANT INGREDIENT USP]
[DISINTEGRATING AGENT USP]
14. Add the sieved materials from stage 13 to the blender / Flow bin
(Type & No) from stage 12 and mix/blender for [00] minutes. Speed:
[00.0] rpm.
Mixing Start Time: _________
Mixing Stop Time: _________
15. Collect 10 samples, each equivalent to the approximate weight of
one tablet (000 mg) in labeled sample containers. Collect samples from
upper, middle and lower part of the container. Send the samples to the
QC laboratory for Blend Uniformity Testing.
16. Weigh the final blended material
Actual weight: [00.0] Kg.
Theoretical Weight [00.0] Kg. Yield ___________ %
No. of containers _____ .
(Yield Limits: NLT 98% of total actual weight from the (2) / (3) sublots,
including the dry ingredients added at stage 12 & 14).
Machine Sign Date
PART THREE
Tabletting - Compression
17. Identify and verify the cleanliness of the tabletting equipment in use
Compress the final blend according to the written product specifications
Tabletting machine: (Type & No).
Machine Speed _______ Tablets per hour
Limit of rpm NLT _______ rpm ; NMT _______ rpm
18. Weigh the tablets:
Actual production weight: [00.0] Kg.
Weight of Samples taken: [00.0] Kg.
Vacuum and rejects Weight: [00.0] Kg.
Total weight [ 00.0] Kg
No of Bulk Containers [ 0 ]
Theoretical Weight [00.0] Kg. Yield ________ %
(Yield Limits: NMT 2% unexplained loss compared to the final blend
weight from stage 16.
19. Seal the double PE plastic bags (clear inner, black outer) with plastic
ties then close all containers, and attach (bar coded) labels to the Bulk
Containers for transport to the holding area.
PART FOUR
20. Identify and verify the cleanliness of the coating equipment.
Weigh [00] Kg PURIFIED WATER USP into a stainless steel vessel
21. ADD gradually while mixing the [OPADRY S-0000 - Color] to the
PURIFIED WATER USP and mix to a uniform dispersion - about 45
minutes Mixing time ________minutes.
22. PASS the AQUEOUS FILM COATING SUSPENSION through a [00]
mesh screen into a stainless steel container and close well.
23. SPLIT the AQUEOUS FILM COATING SUSPENSION into two
equal sublots and label with (bar-coded) batch number and Sublot
number.
24. STIR the AQUEOUS FILM COATING SUSPENSION continuously
during the coating process.
Edition Number:
01
Effective Date:
APPROVED
Ed. Status:
New
DD/MM/200Y _____________ __________ _______________ _________/________
Machine Sign Date
PART FOUR
Coating Procedure:
25. Identify and verify the cleanliness of the coating equipment in use
Sublot Size ________ Kg. Equal to ___________ tablets.
SUB LOT No 1.
PREHEATING OF CORES:
Coating machine (Type & No) :
Extraction Air Temperature: 00C - 00C
Incoming Air Temperature: 00C - 00C
Total Warming time: [0] Minutes
Drum Speed: _________ rpm (minimum speed)
Jogging cycle: One cycle every [0] minutes.
Limit of rpm: NLT _[0]_ rpm: NMT _[0]_ rpm.
SPRAYING PARAMETERS
Pump type: Peristaltic
Spray rate: 000 - 000 g/min
Nozzles: [0] - [0.0] mm
Angle of Guns to Bed: 90 degrees
Height above Bed: [00] cm
Incoming Air Temperature: 00C - 00C (Target: 00C)
Extraction Air Temperature: 00C - 00C (Target: 00C)
26. Coat tablet cores at a drum speed of [0] - [0] rpm and a spray rate of
[000]-[000] g/min until the target COATED tablet weight of [000] mg is
obtained.
COATING COMPLETION PROCEDURE
27. Reduce drum speed to minimum rpm and perform the following:
- Reduce set point of incoming air temperature to 00C
- on reaching this temperature - close the inlet air
- continue drum speed until the Extraction Air Temperature reaches 00C
- 00C
28. TRANSFER coated tablets into containers lined with two PE plastic
bags (clear inner, black outer) Seal bags with plastic ties and close
containers, and attach (bar coded) labels to the Bulk Containers for
transport to the holding area.
29. Attach the temperature graphs (Type & No) to the manufacturing
instructions. Immediately add the batch / Sublot number to the
temperature graph(s) and date and sign graph.
30. Weigh of Coated tablets
Actual production weight: _______ [00.0] Kg. No of Containers _____
Edition Number:
01
Effective Date
APPROVED
Ed. Status:
New
DD/MM/200Y _____________ __________ _______________ _________/________
Machine Sign Date
PART FIVE
Coating Procedure:
SUB LOT No 2.
SPRAYING PARAMETERS
Nozzles: [0] - [0.0] mm
obtained.
- 00C
Edition Number:
01
Effective Date
APPROVED
Ed. Status:
New
DD/MM/200Y _____________ __________ _______________ _________/________
Machine Sign Date
PART SIX
Coating Procedure:
SUB LOT No 3.
SPRAYING PARAMETERS
Nozzles: [0] - [0.0] mm
obtained.
- 00C
Edition Number:
01
Effective Date
APPROVED
Ed. Status:
New
DD/MM/200Y _____________ __________ _______________ _________/________
ATTACHMENTS:
THE FOLLOWING ATTACHMENTS ARE PLACED HERE:
Drying
Attachment # 1 Temperature Print-Outs of Drying Process - Sub lots I, II, III
Milled granulate
Attachment # 2 LOD Print-Outs of the Milled Granulate - Sub lots I, II,
III
Attachment # 3 Weight Print-Outs of the Milled Granulate - Sub lots I, II, III
Final Blend
Attachment # 4 Mixing time Print-Out of the Final Blend of Sub lots I, II, III
Attachment # 5 Weight Print-Out of the Final Blend
Attachment # 6 Weight Print-Out of the total cores
Coated Tablets - weight
Attachment # 7 Weight Print-Out of the coated tablets sub lot I.
Attachment # 8 Weight Print-Out of the coated tablets sub lot II.
Attachment # 9 Weight Print-Out of the coated tablets sub lot III.
Coated Tablets - Temperature
Attachment # 10 Temperature profile Print-Out of the coated tablets sub lot I.
Attachment # 11 Temperature profile Print-Out of the coated tablets sub lot II.
Attachment # 12 Temperature profile Print-Out of the coated tablets sub lot III
IN-PROCESS CONTROL SPECIFICATION
GRANULATION AND TABLETTING SUMMARY
PROPOSED FULL SIZE COMMERCIAL BATCH
Product: [Generic name] Tablets [USP] [000.0] mg. Lot No: [0 0 0 0 ]
Quantity [ 0 0 0 0 0 ] [ 0 0 0 0 0 ] MNF Date: Month DD, 199Y
Dried Granulation Limit: 0.0 - 0.0 %
Moisture Content
Milled Granulation Yield Limit: NLT 98.0%
Total Final Blend Yield Limit: NLT 98.0% (based on actual quantities
processed).
In-Process
Final Blend Uniformity Limit: 94.0 - 106.0% of labeled amount
RSD 6.0% (as per attached specifications)
Tabletting Yield NMT 2.0% unexplained loss from the
previous final blend step.
Overall Production Yield NLT 95.0%
Recorded on Statistical Data Work Sheets.
IN-PROCESS CONTROL SPECIFICATION - TABLET
CORES
SUMMARY
Product: [Generic name] Tablets [USP] [000.0] mg. - CORES
Labeled Amount: Each core contains [Active Material] [000.0] mg.
In-process Specifications for cores.
Punch Diameter 00.00 mm
Punch No [00]
Die No. [00]
Description [Color] (white to off-white) [shape] (round
biconvex) core debossed with the number /
letters [abc] on one face of the tablet core
and [xyz] on the opposite face.
Scoring [not scored] [scored on one side]
Core Diameter Nominal 00.0 Limit: 00.0 - 00.0 mm
Individual core weight (7.5%) Nominal 000.0 Limit: 000.0 - 000.0 mg:
Average core weight (5.0%) Nominal 000.0 Limit: 000.0 - 000.0 mg:
Thickness Nominal 00.0 Limit: 00.0 - 00.0 mm
Hardness Target: 00 SCU NLT 0.0 - NMT00 SCU.
Friability NMT 0.0 %
IN-PROCESS CONTROL SPECIFICATION - COATING PROCESS
SUMMARY
Product: [Generic name] Tablets [USP] [000.0] mg. Lot No: [0 0 0 0 ]
Quantity [ 0 0 0 0 0 ] [ 0 0 0 0 0 ] MNF Date: Month DD, 199Y
Film Coating Controls Before Coating After Coating
Theoretical Tablet weight (mg) 000.0 -
Target Coated weight (mg) - 000.0
Weight of 100 tablets #1 (g) 000.0 000.0
Average tablet 100 weight (g) 000.0 000.0
Average tablet weight (mg) 000.0 000.0
In-Process Yields
Yield after coating vs. Pre-coating 00.0%
Yield after coating to theoretical 00.0%
Film Coating Yield NMT 2.0% unexplained loss
from the previous step (tabletting)
Recorded on Statistical Data Tablet Coating Work Sheets.
Difference
in dissolution profile
for controlled release
dosage forms
RELEASE SPECIFICATION FOR COATED CR/MR TABLETS [USP]
SUMMARY
Product: [Generic name] Tablets [USP] [000.0] mg.
Labeled Amount: Each tablet contains: [Active Material] [000.0] mg.
Description [Color] (white to off-white) shaped (round
biconvex) Tablet debossed with the number/
letters [abc] on one face of the Tablet and
[xyz] on the opposite face
Identification A The Infra Red Absorption Spectrum
conforms to the Reference Standard
Identification B The Chromatogram of the sample solution
exhibits a peak with the same retention time
as the standard solution.
Individual Tablet weight (7.5%) Nominal 000.0 Limit: 000.0 - 000.0 mg
Average Tablet weight (5.0%) Nominal 000.0 Limit: 000.0 - 000.0 mg
Uniformity of Dosage Units Conforms to the current USP
Content Uniformity
Dissolution Equipment: USP App. No 1 or 2 (Paddle)
4 hr. 10 - 30 % Media: 000 mL, 37 C. [00]% of [Sodium
8 hr. 35 - 75 % lauryl Sulphate in 0.1N Phosphate Buffer]
12 hr. 50 - 90 % pH 0.0 RPM 00
24 hr. 75 %
Impurities /Degradation
Products determination
- Each Individual: NMT 0.5% of the labeled amount
- Any other Individual: NMT 0.5% of the labeled amount
- Total: NMT 2.0% of the labeled amount
Assay Limit: 90.0 - 110.0% of labeled amount
[00.0] - [00.0] mg / Tablet
Note:
Residual Solvent if present in the coating solution require a release specification such as;
Residual Solvents
- Acetone NMT 500 ppm
- Ethanol NMT 1000 ppm
- Isopropanol NMT 10 000 ppm
RELEASE SPECIFICATION FOR COATED IR TABLETS [USP]
SUMMARY
PROPOSED FULL SI ZE COMMERCI AL BATCH
Product: [Generic name] Tablets [USP] [000.0] mg.
Description [Color] (white to off-white) shaped (round
letters [ABC] on one face of the Tablet and
[XYZ] on the opposite face.
Individual Tablet weight (7.5%) Nominal 000.0 Limit: 000.0 - 000.0 mg
Average Tablet weight (5.0%) Nominal 000.0 Limit: 000.0 - 000.0 mg
Content Uniformity
Media: 000 mL, 37 C. [00]% of [Sodium
lauryl Sulphate in 0.1N Phosphate Buffer]
pH [0.0] RPM [00]
Tolerance: NLT [00]% (Q) of the labeled
is dissolved in [00] minutes.
[00.0] - [00.0] mg / Tablet
IR = IMMEDIATE RELEASE ER = EXTENDED RELEASE
CR = CONTROLLED RELEASE DR = DELAYED RELEASE (ENTERIC COATED)
COMPARISON OF EXECUTED (PIVOTAL) AND PRODUCTION FORMULAE
INGREDIENT
AMOUNT PER
TABLETS
(MG)
EXECUTED
BATCH
200,000 TABLETS
(KG)
PRODUCTION
BATCH
800 000
TABLETS
(KG)
Active Ingredient [Source]
Povidone USP
Colloidal Silicon Dioxide
NF
Starch NF
Starch NF (Re-dried)
Anhydrous Lactose NF
Total
140.000
28.000
98.000
Adjust where applicable (i.e. if moisture content of active is greater than 0.5-1.0%):
1
Note: [00.0] mg for [Active Salt] is equivalent to [00.0] mg of [Active] base.
Quantity of [Active Salt] to be weighed = Batch Size x [00.0] x 100
100 - LOD
2
The actual quantity of a non active ingredient such as Starch NF used in the formula will
depend on the WEIGHT for [Active Salt] used.
COMPARISON OF EQUIPMENT AND MANUFACTURING CONDITIONS
BETWEEN EXECUTED AND PRODUCTION BATCHES
IMMEDIATE RELEASE TABLETS
Equipment and
Manufacturing
Conditions
Executed
Batch
200,000 units
Production
Batch
800,000 units
Premixing Diosna 25 Diosna 300
Granulating - High Speed
Granulator Diosna 25 Diosna 300
Drying FBD 30 FBD 120
Milling - Oscillating
Granulator
Frewitt Frewitt
Blending Y-cone 50 Y-cone 120
Tabletting Machine FETTA 2000 /
Kilian T-300
FETTA 2000 /
Kilian T-300
Coating Suspension
Mixing Equipment
Stainless Steel
Container
with Roller Mixer
80 mesh Screen
Stainless Steel
Container
with Roller Mixer
80 mesh Screen
Coating Unit AccelaCota AC
48/150
AccelaCota AC
48/150
Equipment Variation NONE NONE
Manufacturing Area Production Production
Staff Production Production
SOP Production Production
DIRECT COMPRESSION
MODEL
ALENDRONATE TABLETS
5.0 AND 10 mg
DC TABLETS
Identification of Batch Parameters.
Product name: Alendronate Tablets 5.0 and 10 mg.
Batch Number: IA97-06
Department: ______________ Batch Size: 1000 000 units
Caution: Manufacture Date: 200Y
Cat./Formula No: # MF-104 Cores : Coated Tablets
Based on PQ: Batch # PQ106 PIVOTAL BATCH
Validation Lot Commercial Lot
Change made: - none
KEY t o :
Material causes extreme irritation to skin and eyes
Do not expose to skin or exposed areas.
Store in well closed containers and minimize or avoid
exposure to environmental air
Raw material has to be stored at 5 C - hold active
material at 25
o
C for one hour to reach room temperature
before weighing, sampling or processing
Potential danger to pregnant women, pregnant women
are prohibited in this area
Do not heat above [00] C
Maintain Room humidity below 50%
ALENDRONATE TABLETS 5.0 /10mg LOT: IA97-06
Batch No: IA97-06 Weighing Date: 97-06
Per
100
mg
%
Exc
ess
Raw Material Names
RM.
Lot
No
per 1 000 000 units
Sign
weigh.
Dept.
Kg g mg L mL A B
PART ONE - DRY MIXING

24.50
Lactose Monohydrate NF
(Spray dried)
24 500
17.00
Microcrystalline Cellulose NF
(Avicel PH-200)
17 000
6.525 Alendronate Na (calculated as
equivalent salt)*
6 525
PART TWO - DRY MIXING
DRY BLENDING

24.50
Lactose Monohydrate NF
(Spray dried)
24 500
17.00
Microcrystalline Cellulose NF
(Avicel PH-200)
17 000
3.475
Povidone USP
(PVP K-30)
3 475
5.50
Sodium Starch Glycolate NF
(Primojel)
5 500
PART THREE
DRY BLENDING

0.75
Silicon Dioxide NF
(Aerosil 200)
0 750
0.75
0 750
100 Tablet weight 5 mg
200 Tablet weight 10mg
Edition Number:
02
Effective Date:
APPROVED
Ed. Status:
SPDS 01
DD/MM/200Y _____________ __________ _______________ _________/________
* 13.05 mg of sodium salt is equivalent to free acid
ALENDRONATE TABLETS 5.0 /10 MG LOT: IA97-06
Machine Sign Date
Step 1.
IDENTIFY the equipment in room number [ ] and verify the
equipment and room cleanliness prior to use.
PART ONE
Step 2.
PLACE into an appropriate blender [Sigma or Ribbon Blender]
(state specify Type & No) the ingredients in the following order:
Microcrystalline Cellulose NF - (Avicel PH-200)
Lactose Monohydrate NF - (Spray dried lactose)
Alendronate Sodium
MIX for 8 minutes at 20 ( 2) rpm .
Record the mixing time:-
Mixing time - Start _______
Mixing time - Stop _______
Total Mixing Time is 8 minutes.
PART TWO
Step 3.
Put into the blender [Sigma or Ribbon Blender] (Type & No) the
balance ingredients in the following order:
Microcrystalline Cellulose NF - (Avicel PH-200)
Lactose Monohydrate NF - (Spray Dried Lactose)
Povidone USP - (PVP K-30)
Sodium Starch Glycolate NF - (Primojel)
and mix for 15 minutes at 20 ( 2) rpm .
Record the mixing time
Total Mixing Time is 23 minutes.
Edition Number:
02
Effective Date:
APPROVED
Ed. Status:
SPDS 01
DD/MM/200Y _____________ __________ _______________ _________/________
Machine Sign Date
Step 4.
DISCHARGE and transfer the contents of the blender [Sigma or
Ribbon Blender] from step 3 into a Y-cone / twin shell blender or
Flow bin (Type & No) and blend for [15] minutes. Speed: 10.0 (
2) rpm.
Record the blending time
Total blending Time is 15 minutes.
Step 5.
SIFT the Magnesium Stearate NF through a vibrating sieve (Type
& No) fitted with a 100.0 mesh screen.
Step 6.
ADD the sieved material Magnesium Stearate NF
from step 5 to the twin shell blender / Flow bin (Type & No).
Step 7. ADD the Silicon Dioxide NF (Aerosil 200) to the blender /
Flow bin and blend for [5] minutes. Speed: 10.0 ( 2) rpm.
Record the blending time
Mixing time - Start _______ Mixing time - Stop _______
Total blending Time is 20 minutes.
Step 8. Collect 10 samples, each equivalent to the approximate
weight of three tablet (300 [5mg tab] or 600mg [10mg tab]) in
labeled sample containers. Collect samples from upper, middle
and lower part of the blender. Send the samples to the QC
laboratory for Blend Uniformity Testing.
Step 9. Weigh the final blended material
No. of containers _____. Actual weight: [ ] Kg.
(Yield Limits: NLT 98% of total actual weight including the dry
ingredients added at stage 5 & 6).
Immediately add the batch number to the scale print-out, attach to
the manufacturing instructions after dating and signing it.
Number of Bins __________
Edition Number:
02
Effective Date:
APPROVED
Ed. Status:
SPDS 01
DD/MM/200Y _____________ __________ _______________ _________/________
Machine Sign Date
PART THREE - STORAGE
Step 10.
Discharge the material into drums lined with two polyethylene bags or into the
Flow-Bin
PART FOUR - COMPRESSION
CAUTION - IMPORTANT NOTE
Ensure that the relative moisture of the air in the compartment does
not exceed 50% - remove vacuum line from the rotating table of the
tabletting machine
Step11.
Tabletting - Compression unit, room number [ ]. Identify and verify
the cleanliness of the tabletting equipment in use.
Step12
Compress the final blend according to the written product
specifications
Target Machine Speed _______ Tablets per hour
Limit of rpm NLT 70 % of rpm ; NMT 120 of target rpm
Step13
Weigh the tablets:
Actual production weight: [100.0] Kg - 5mg Tabs
Actual production weight: [200.0] Kg - 10mg Tabs.
Weight of Samples taken: [ ] Kg.
Vacuum and rejects Weight: [ ] Kg.
Total weight [ ] Kg
No of Bulk Containers [ ]
Theoretical Weight [ ] Kg.
Calculate the actual production yield:
Yield ___________ %
(Yield Limits: NMT 2% unexplained loss compared to the final
blend weight from Step 8.
Step14.
Seal the double PE plastic bags (clear inner, black outer) with
plastic ties then close all containers, and attach (bar coded) labels
to the Bulk Containers for transport to the holding area.
Edition Number:
01
Effective Date:
APPROVED
Ed. Status
New
DD/MM/200Y _____________ __________ _______________ _________/________
HANDBOOK of GENERIC DRUG DEVELOPMENT ANDA DEVELOPMENT
ATTACHMENTS:
Mixing Time
Attachment # 1 Mixing time Print-Out - Step 2
Attachment # 2 Mixing time Print-Out - Step 3
Final Blend
Attachment # 3 Mixing time Print-Out of the intermediate Blend - Step 4
Attachment # 4 Mixing time Print-Out of the Final Blended material - Step 7
Attachment # 5 Weight Print-Out of the Final Lubricated material - Step 9
Compressed Tablets
Attachment # 6 Weight Print-Out of the bulk tablets - Step 13
IN-PROCESS CONTROL SPECIFICATION - BLENDED MATERIAL
SUMMARY OF YIELD AND LIMIT VALUES FOR
ALENDRONATE TABLETS 5.0 /10 mg LOT: IA97-06
Product: ALENDRONATE TABLETS 5.0 /10mg LOT: IA97-06
Quantity 1000 000
Yields
Final Blend Yield Limit: NLT 98.0%
processed).
In-Process
Tabletting Yield NMT 2.0% unexplained loss from the
previous final blend step.
TABLET / CORES
Product: ALENDRONATE TABLETS 5.0 /10 mg LOT: IA97-06
Labeled Amount: Each tablet contains ALENDRONATE 5.0 or 10.0 mg.
In-process tablet specifications
Punch Diameter 5.0mg 6.5 mm
Punch Diameter 10.0mg 8.00 mm
Punch No - 5.0 mg [P044]
Die No. - 5.0 mg [D044]
Punch No - 10.0 mg [P025]
Die No. - 10.0 mg [D125]
Description White to off-white round biconvex tablet
debossed with the number /letters [5 or 10 ]
on one face of the tablet
Scoring [not scored]
Core Diameter 5mg Nominal 6.5 mm Limit: 6.4 - 6.6 mm
Core Diameter 10mg Nominal 8.0 mm Limit: 7.9 - 8.1 mm
5 mg TABLET
10 mg TABLET
Individual weight (7.5%) Nominal 200.0 Limit: 185.0 - 215.0 mg:
Average weight (5.0%) Nominal 200.0 Limit: 190.0 - 210.0 mg:
Thickness 5.0mg Nominal 3.0 Limit: 2.80 - 3.80 mm
Thickness 10.0mg Nominal 4.0 Limit: 3.80 - 4.80 mm
Hardness 5.0mg Target: 8 SCU NLT 6.0 - NMT 14 SCU.
Hardness 10.0mg Target: 10 SCU NLT 8.0 - NMT 16 SCU.
RELEASE SPECIFICATION FOR TABLETS
PRODUCT: ALENDRONATE TABLETS 5.0 / 10 mg LOT: IA97-06
Labeled Amount: Each tablet contains ALENDRONATE 5.0 or 10.0 mg
Description
White to off-white) round biconvex tablet
debossed with the number /letters [5 or 10 ]
on one face of the tablet
5 mg TABLET
10 mg TABLET
Content Uniformity
Dissolution Equipment: USP App. 2 (Paddle)
Media: 900 mL, 37 C. Deaerated Water
pH 6.8 RPM 100
(1)

5mg Equal to [4.75] - [5.25] mg / Tablet.
10 mg Equal to [9.5] - [10.5] mg / Tablet.
(1)
Vendor or approved supplier dependent.
50%
50%
50%
50%
ALENDRONATE TABLETS 5.0 /10 mg LOT: IA97-06
Manuf ac t ur i ng Fl ow c har t [ I I ]
Tumbl er Y-c one
5 mi n @10 r pm
Bl ender
8 mi n @20 r pm
Bl ender
15 mi n @20 r pm
COMPRESS
Tar get 80 000 t abs/hr
DC TABLETS
LACTOSE
(49%)
Active Material
(6.525%)
Lubricant
AEROSIL (0.75%)
Mag. stearate (0.75%)
MICROCRYSTALLINE
CELLULOSE (17%)
Si eve
100 MESH
SODIUM STARCH
GLYCOLATE (5.5%)
Si eve
(Where necessary)
0.8 mm
To Filling
IPQC
ID
Content Uniformity
QC
Weight uniformity
Thickness
Hardness
Disintegration
PVP K30 (3. 5%)
MICROCRYSTALLINE
CELLULOSE (17%)
Tumbl er Y-c one
15 mi n @10 r pm
RELEASE
ID
Assay
Content Uniformity
Dissolution
COMPARISON OF EXECUTED (PIVOTAL) AND PRODUCTION FORMULAE
ALENDRONATE TABLETS 5.0 /10 mg
LOT: IA97-06
Ingredient
Amount per
tablets
(mg)
Executed Batch
1 000,000
tablets
(kg)
Production Batch
2 000 000 tablets
(kg)
Alendronate Sodium 6.525 6.525 13.050
Microcrystalline cellulose
NF
34.000 34.000 64.000
Lactose monohydrate Spray
Dried NF
49.000 49.000 98.000
Povidone K30 USP 3.475 3.475 6.950
Sodium Starch Glycolate NF 5.500 5.500 11.000
Colloidal Silicon Dioxide
NF
0.750 0.750 1.500
Magnesium Stearate NF 0.750 0.750 1.500
Total
100.000 100.000 200.000
GENERAL PACKAGI NG OPERATI ON DESCRI PTI ON
TABLETS [USP] - SCHEMATIC PRESENTATION
Stage One.
PACKAGING COMPONENTS:
1. Bulk Product
2. HDPE Containers
3. Package Insert / Outsert (Product Leaflets)
4. Desiccant (Silica Gel)
5. Container Label
6. Master Cartons
7. Carton Shipping Labels
Stage Two
PACKAGING PROCEDURE:
HDPE Container & Bulk Line Feed
HDPE Container Cleaning

Process
(Air and Vacuum)
Tablet Count & Fill
Cotton Coil
Insert / Leaflet
Capping (Screw or CRC)
Closure Torque Test
or Outsert Attaching
Container Label
Packed in Master Shipping

Cartons
SCHEMATIC PACKAGING OPERATION - EQUIPMENT LISTING:
[Generic name] Tabl et s [USP] [000.0] mg. Lot: [00-0000]
No. Machine Operation Manufacturer
Supplier
Type Serial # Output
CONTAINERS
per min
(2)
1
Schenck HDPE Bottle
or Amber
Glass
Feeding
Schenck Process
GMBH Darmstadt
1000-S
AccuRate
No:
543123
50 Low
100 High
2
King Air Cleaning C.E. King Ltd, UK SuperKleen MK-
2994
50 Low
100 High
3
Lakso Counting &
Filling Tablets
Lakso MA US SLAT
FILLER
(1)
L-333
L-334
Count
4
RSP Coiler Dessicant
Insertion
H.G. Kalish Inc.,
Canada
5329 2169-
0003
50 Low
100 High
5
RSP Coiler Cotton
insertion
H.G.Kalish Inc.,
Canada
KOTNR-120-
8440
2234-
9987
50 Low
100 High
6
Groninger Capping Groninger & Co
Germany
DFVK
6000
2232-
2234
50 Low
100 High
7.
Groninger Outserter Groninger & Co
KarlsHeim,
Germany
DFVK
3000
5664
50 Low
100 High
8.
Prestek Labelling &
Printing
Prestek Ltd Science
Park Nottingham
UK
SmartDate
Intelligent
Thermal
Transfer
Printer
53342
50 Low
100 High
(1)
Average figures for containers per minute output for Slow and High Speed.
(2)
All indicated machine outputs are adjusted to the Tablet Slate Filler rate.
50 100
50* 100*
REPROCESSING STATEMENT
(Delete statement where appropriate)
The COMPANY is unable to anticipate what manufacturing qualifying factors, if any,
may lead to the need for reprocessing at this time. If reprocessing of a batch 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.
------------------------------------------------ ---------------------------------------
Plant Manager
------------------------------------------------ ----------------------------------------
Director Quality Assurance Unit
------------------------------------------------ -----------------------------------
Director Pharmaceutical Research & Development
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
Tablet Weight
Tablet Hardness
Tablet Thickness
Tablet Friability
Tablet Dissolution at lower hardness limit
Tablet Dissolution at target hardness limit
Tablet Dissolution at upper hardness limit
At 3 months stability station (40
o
C / 60% 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 the reworking of Stage Two (slugging and Milling) 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.
------------------------------------------------ --------------------------------------
Plant Manager
[ Gener i c Company Name I nc . / Lt d.]
------------------------------------------------ -------------------------------------
Director Quality Assurance Unit
[ Gener i c Company Name I nc . / Lt d.]
Set of I nst r uc t i ons f or eac h st r engt h
A complete set of manufacturing instructions must be provided for each
strength of dosage form.
If the dosage form has 5 strengths e.g. 10mg, 20mg, 30mg, 40mg, 80mg -
five sets of manufacturing and packaging instructions is presented in the
ANDA file.
Set of spec i f i c at i ons f or eac h st r engt h
A complete set of specifications (in-process, tablet cores and film coated
tablets) must be provided for each strength of dosage form.
five sets of specifications are presented in the ANDA file.
Set of Tabl es f or eac h st r engt h
A complete set of Tables (equipment listing, comparison of equipment etc.) must
be provided for each strength of the dosage form.
five sets of Tables are presented in the ANDA file.
Fi l e TI P.
REMEMBER THIS PRINCIPLE APPLIES TO SECTION 12 AS WELL WHERE A
COPY OF THE ACTUAL EXECUTED BATCH RECORD INCLUDING ALL
SPECIFICATIONS PER STRENGTH IS PROVIDED.
REMEMBER IF ANY DOCUMENTS ARE PROVIDED FOR ONE DOSAGE
STRENGTH - THEN THE SAME DOCUMENT SET MUST BE PROVIDED FOR ALL
OTHER DOSAGE STRENGTHS APPLIED FOR.
24 V 24 Volume D Drug D Development S Ser ies Sect: 12.1 DEVELOPMENT Or al Or al Tablets
SECTION XII SECTION 12
Pi vot al Manuf ac t ur i ng and Cont r ol s
TABLE OF CONTENTS.
(as stated in FDA Feb. 1999 Guidance for Industry).
12.1 Copy of the executed Pivotal batch manufacturing record with
- equipment used
- batch reconciliation
12.2 Copy of the executed Pivotal batch packaging record with
- equipment used
- label reconciliation
IN-PROCESS CONTROLS
12.3.1 Sampling plans and testing procedures
12.3.2 Specifications and data
SPECIAL NOTE
Delete specific data or delete whole sections which are not applicable to
this Section 12 of the ANDA
Note the use of bold and square brackets e.g. [00]
where actual names or figures are inserted.
4
Pivotal Manufacturing and Controls
Outlines of Standard Operating Procedure for In-Process Controls
In-Process Control tabulation chart (Summary)
Executed Manufacturing Procedure Flow Chart
Executed Batch documents
Batch Record
Packaging Records
Summary of Tablet Hardness Verification
Packaging and Disbursement Summary
4
OUTLINE OF STANDARD OPERATING PROCEDURES FOR:
IN-PROCESS CONTROLS
1. At all stages of processing, appropriate control procedures are employed 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 Tablets.
3. In-process material testing is performed by Qualified Personnel.
4. The Quality Assurance Department reviews the batch test results and evaluates the
acceptance or rejection of each batch lot.
4
IN-PROCESS CONTROLS DURING TABLET COMPRESSION
In-process testing is conducted independently by both production and quality control
trained personnel. The tests specified in the underlying tables are performed in accord
with the in-process product specifications. When, a test is not required, according to
the written specifications, it will not be performed.
Production personnel test the physical specifications of random samples according
to the individual product specifications: A minimum sampling frequency is tabulated for
each eight hour (shift) period.
Production In-process Testing Schedule:
Test
PERFORMED
Sample
Size
Frequency
per shift
(1)
(min)
Acceptance
Criteria
(2)
Average Weight 10 At 15 min. intervals. Within specified range.
Thickness 10 3 times
(1)
NMT 2 tablets out of the 10 tested
can deviate from product
specifications.
No deviation is allowed from
Double Limits
(4)
specification.
Hardness 10 3 times
(1)
NMT 2 tablets out of the 10 tested
can deviate from product
specifications.
No deviation is allowed from
Double Limits
(3)
specification.
Friability
20 or 40
According to
each product
Twice
No deviation from product
specifications is permitted.
Disintegration 6 Twice No deviation from product
specifications is permitted.
KEY:
(1)
The testing frequency is performed twice when the overall compression time is less than four
hours.
(2) Deviations from specifications and acceptance criteria, arising during the in-process controls,
shall determine the corrective action to be performed on the tableting machinery during the
compression stage.
(3)
Double Limits for Tablet Hardness Test are defined as c-20% from the minimum and
maximum product specifications limits. When, there is a NLT 10 SCU Hardness specification, the
double limits may not exceed a minimum value of 8 SCU. (Not go below 8 SCU).
(4)
Double Limits for Tablet Thickness Tests are defined as c- 0.1 mm from the minimum and
maximum values in the specifications. C is the limit value
Quality 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
Sample
Size
(Tablets)
Frequency
per shift
(1)

(min.)
Acceptance
Criteria
(2)
Individual Tablet
Weight
20
(1)
Twice NMT 2 tablets out of the 20 tested can
deviate from product spec. No deviation
is allowed from Double Limits
(3)
spec.
Thickness 10
(1)
(4)
spec.
Hardness 10
(1)
(5)
spec.
Diameter
3
(1)
Once
at start
No deviation from product specification
is allowed.
Friability 20 -40
(1)
According to
product
Twice
No deviation from product specification
is allowed
Disintegration 6
(1)
Twice No deviation from product specification
is allowed
KEY:
(1)
Samples are taken, independently by QC personnel for batch release purposes, at least once
per hour throughout the tableting run, producing a total representative sample quantity of 300 -
500 tablets. This representative sample lot is for QC batch release purposes .
(2)Deviations from specifications and acceptance criteria, arising during the in-process controls,
shall determine the corrective action to be performed on the tabletting machinery during the
compression stage.
(3)Double Limits for the Individual Tablet Weight test are defined as the double value from the
minimum or maximum limit in relation to the nominal tablet value (i.e. target weight value).
(4)
Double Limits for Tablet Thickness Tests are defined as c- 0.1 mm from the minimum and
maximum specification limit values. Where C = limit value.
(5) Double Limits for Tablet Hardness Test are defined as c-20% from the minimum and
maximum product specifications limits.
When, there is a NLT 10 SCU Hardness specification, the double limits may not exceed a
minimum value of 8 SCU. (Not go below 8 SCU) .
Target Value Upper limit Lower Limit
Double this value Double this value
DOUBLE VALUES
SAMPLING PLAN OF PIVOTAL LOTS FOR STABILITY STUDIES
AND BIOAVAILABILITY STUDIES.
tandard Operating Procedures are in place at the commercial manufacturing
facility, defining the packaging procedures for pivotal lots and sampling of
representative packages for stability and bioavailability studies. These
procedures are summarized below.
The entire pivotal lot (100%) is packaged in the commercial production packaging
department, using production equipment, operated by the routine 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 packaging sampled, is calculated in order obtain
approximately equal numbers of each package 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 stability studies and
bioavailability studies.
The sampling plan is representative of the entire pivotal batch.
4
S
EXECUTED PIVOTAL BATCH MANUFACTURING INSTRUCTIONS
Product name: [Generic name] Tablets USP [000.0] mg.
Batch Number: [IA-000-00]
Department: ______________ Batch Size: 000-000 units
Caution: Manufacture Date: Month DD, YYYY
Cat./Formula No: # IAG0000 Cores : Coated Tablets
Based on PQ: Batch # IAG0000 PIVOTAL BATCH
Validation Lot Commercial Lot
Change made: - none
KEY: KEY:
Store in well closed containers
Potential danger to pregnant women
Pregnant women prohibited in this area
Do not heat above 00 C
Room humidity below 30%
Note:
(Manufacturing process for film-coated tablets is provided as an example
of how to prepare the manufacturing instructions. This specific set of
manufacturing instructions was chosen as it represents the written detail
required to produce clear manufacturing instructions).
Edition Number:
01
Effective Date
APPROVED
Ed. Status:
New
DD/MM/YY _____________ __________ ____________ _________/________
EXECUTED PIVOTAL BATCH MASTER FORMULA
[Generic name] Tablets USP [000.0] mg. [IA-000-00]
Per
UNIT
mg
%
Exc
ess
Raw Material Names
RM.
Lot
No
per [000 000] units
Sign
weigh.
Dept.
Kg g mg L mL A B
SUBLOT ONE

00.0 [Active Ingredient] 00 000
- [Alcohol USP 95%] 00 000
- [Alcohol USP 95%] q.s. 00 000
SUBLOT TWO

[Active Ingredient] 00 000
- [Alcohol USP 95%] 00 000
- [Alcohol USP 95%] q.s. 00 000
PART TWO - BLENDING
SUBLOTS: ONE + TWO

000.0 Combined Granulates - Sublots 1 +2
00.0 [Extra-granular Disintegrant NF] 00 000
00.0 [Extra-granular Glidant NF] 00 000
00.0 [Extra-granular Lubricant NF] 00 000
Edition Number: 01 Effective Date
APPROVED
Ed. Status:
New
DD/MM/YY _____________ __________ ____________ _________/________
EXECUTED PIVOTAL BATCH MASTER FORMULA
[Generic name] Tablets USP [000.0] mg. [IA-000-00]Batch No:
Weighing Date:
Per
UNIT
mg
%
Exc
ess
Raw Material Names
RM.
Lot
No
per [000 000] units
Sign
weigh.
Dept.
PART THREE - AQUEOUS FILM
COAT SUSPENSION

- 00 Aqueous Film Coating Suspension - -
- Purified Water USP 00 000
00.0 0PADRY OY-S-0000 [color] 00 000
- Theoretical End Weight. 00 000
PART FOUR - FILM COATING,
SUBLOT 1 1

000.0 [Name] Tablets [000] mg CORES 000
00.0
000
PART FIVE - FILM COATING,
SUBLOT 2 2

CORES
000
00.0
000
PART SIX - FILM COATING,
SUBLOT 3 3

CORES
000
00.0
000
APPROVED
Ed. Status:
New
DD/MM/YY _____________ __________ ____________ _________/________
Aqueous film coat suspension contains 00.% solids
Solids remaining in film coat
Machine Sign Date
1 Identify the equipment and verify the cleanliness prior to use.
PART ONE
Stage 1.
2. Put into the [Diosna 000] (Type & No) the ingredients in the following
order:
[Active Material]
[DRY INGREDIENT NF]
[DRY INGREDIENT NF]
and mix for [ 0 ] minutes at mixer speed I / II and Chopper I / II .
Stage 2.
3. Granulation Solution Preparation
(i) Weigh [00] Kg [PURIFIED WATER USP] into a stainless steel vessel
(ii) Operate the mixer and add the [INGREDIENT NF] and mix until fully
dissolved.
(iii) While mixing, add the [ALCOHOL USP 95%].
Stage 2a.
4. Add the granulating solution in the set time to the [Diosna 000] (Type
& No) while mixing at mixer speed II and chopper speed II. Total Mixing
Time is 45 seconds.
Time of adding Solution - [40] seconds
Time of mixing - [ 5] seconds
5. If necessary, add the [ALCOHOL USP 95%]. q.s. and/or mix at the
same conditions as in stage 4.
Amount of additional [ALCOHOL USP 95%]: __________ Kg.
Additional mixing time ___________
Seconds
6. Discharge the wet granulate to the FBD mobile bed (Type & No) while
mixing at mixer speed I.
Stage 3.
Dry the wet granulate in the FBD (Type & No) under the following
settings:
Inlet Air Temperature NMT 00C (Target: 00C)
Outlet Air Temperature NMT 00C (Target: 00C)
Attach the temperature graph of the FBD (Type & No). to the
Stage 4.
7. Mill a 1Kg. Check portion the dried granulate through a OSCILLATING
GRANULATOR (Type & No). fitted with a [0.0 mm] screen.
APPROVED
Ed. Status:
New
DD/MM/YY _____________ __________ ____________ _________/________
Machine Sign Date
7b. Check the milled granulate portion for Loss on Drying (LOD) Use
(Type & No) IR machine with temperature set at 00C
Record first result: __________[ 0.0%]
LOD Limits: [0.0 to 0.0%]
7c. If necessary, continue to dry the bulk granulate under the same
conditions as stage 6, until the LOD is close to the midpoint of the given
range limits and check moisture again.
Record second result: __________[ 0.0%]
Attach the temperature graph of the FBD (Type & No) to the
8. Pass the remainder of the dry granulate through an OSCILLATING
GRANULATOR (Type & No) fitted with a [0.0 mm] screen into a [000]
liter container / bin.
9. Weigh the milled granulate ______Kg. Immediately add the batch
number to the scale print-out, attach to the manufacturing instructions
after dating and signing it.
10. Theoretical Weight [00.0] Kg. Yield ___________ %
(Yield Limits: NLT 95% of Theoretical Weight.) Bins ___________
PART TWO
Stage 5.
11. Transfer the milled granulate from stage 10 of both sub lots to a twin
shell blender / Flow bin (Type & No).
12. Add to the twin shell blender / Flow bin (Type & No).
[INGREDIENT NF]
13. PASS the following material through a sieve (Type & No) fitted with a
[00.0] mm screen.
[GLIDANT INGREDIENT USP]
[DISINTEGRATING AGENT USP]
Stage 6.
14. Add the sieved materials from stage 13 to the blender / Flow bin
(Type & No) from stage 12 and mix/blender for [00] minutes. Speed:
[00.0] rpm.
Mixing Start Time: _________
Mixing Stop Time: _________
15. Collect 10 samples, each equivalent to the approximate weight of
one tablet (000 mg) in labeled sample containers. Collect samples from
upper,middle and lower part of the container. Send the samples to the
QC laboratory for Blend Uniformity Testing.
16. Weigh the final blended material No. of containers _____ .
Actual weight: [00.0] Kg.
(Yield Limits: NLT 98% of total actual weight from the (2) / (3) sublots,
including the dry ingredients added at stage 12 & 14).
APPROVED
Ed. Status:
New
DD/MM/YY _____________ __________ ____________ _________/________
Machine Sign Date
PART THREE
Stage 7.
Tabletting - Compression
17. Identify and verify the cleanliness of the tabletting equipment in use
Compress the final blend according to the written product specifications
Machine Speed _______ Tablets per hour
Limit of rpm NLT _______ rpm ; NMT _______ rpm
18. Weigh the tablets:
Actual production weight: [00.0] Kg.
Weight of Samples taken: [00.0] Kg.
Vacuum and rejects Weight: [00.0] Kg.
Total weight [ 00.0] Kg
No of Bulk Containers [ 0 ]
Theoretical Weight [00.0] Kg. Yield
___________ %
(Yield Limits: NMT 2% unexplained loss compared to the final blend
weight from stage 16.
19. Seal the double PE plastic bags (clear inner, black outer) with plastic
ties then close all containers, and attach (bar coded) labels to the Bulk
Containers for transport to the holding area.
PART FOUR
20. Identify and verify the cleanliness of the coating equipment.
Weigh [00] Kg PURIFIED WATER USP into a stainless steel vessel
21. ADD gradually while mixing the [OPADRY S-0000 - Color] to the
PURIFIED WATER USP and mix to a uniform dispersion - about 45
minutes Mixing time ________minutes.
22. PASS the AQUEOUS FILM COATING SUSPENSION through a [00]
mesh screen into a stainless steel container and close well.
23. SPLIT the AQUEOUS FILM COATING SUSPENSION into two
equal sublots and label with (bar-coded) batch number and Sublot
number.
24. STIR the AQUEOUS FILM COATING SUSPENSION continuously
during the coating process.
APPROVED
Ed. Status:
New
DD/MM/YY _____________ __________ ____________ _________/________
Machine Sign Date
PART FOUR
Stage 8.
Coating Procedure:
SUB LOT No 1.
SPRAYING PARAMETERS
Nozzles: [0] - [0.0] mm
obtained.
- continue drum speed until the Extraction Air Temp. reaches 00C - 00C
APPROVED
Ed. Status:
New
DD/MM/YY _____________ __________ ____________ _________/________
Machine Sign Date
PART FIVE
Coating Procedure:
SUB LOT No 2.
SPRAYING PARAMETERS
Nozzles: [0] - [0.0] mm
obtained.
- 00C
APPROVED
Ed. Status:
New
DD/MM/YY _____________ __________ ____________ _________/________
Machin
e
Sign Date
PART SIX
Coating Procedure:
SUB LOT No 3.
SPRAYING PARAMETERS
Nozzles: [0] - [0.0] mm
obtained.
- continue drum speed until the Extraction Air Temperature reaches 00C -
00C
instructions. Immediately add the batch / Sublot number to the temperature
graph(s) and date and sign graph.
APPROVED
Ed. Status:
New
DD/MM/YY _____________ __________ ____________ _________/________
ATTACHMENTS:
Drying
Attachment # 1 Temperature Print-Outs of Drying Process - Sub lots I, II, III
Granulate
Attachment # 2 LOD Print-Outs of the Milled Granulate - Sub lots I, II, III
Attachment # 3 Weight Print-Outs of the Milled Granulate - Sub lots I, II, III
Final Blend
Attachment # 4 Mixing time Print-Out of the Final Blend of Sub lots I, II, III
Attachment # 5 Weight Print-Out of the Final Blend
Cores
Attachment # 6 Weight Print-Out of the total cores
Coated Tablets
Attachment # 7 Weight Print-Out of the coated tablets sub lot I.
Attachment # 8 Weight Print-Out of the coated tablets sub lot II.
Attachment # 9 Weight Print-Out of the coated tablets sub lot III.
Temperature Profile
Attachment # 10 Temperature profile Print-Out of the coated tablets sub lot I.
Attachment # 11 Temperature profile Print-Out of the coated tablets sub lot II.
Attachment # 12 Temperature profile Print-Out of the coated tablets sub lot III
IN-PROCESS CONTROL SPECIFICATION - GRANULATION MATERIAL
SUMMARY
PIVOTAL BATCH
PRODUCT: [Generic name] Tablets USP [000.0] mg. [IA-000-00]
QUANTITY 000000 MNF Date: Month DD, 199Y
Yields
Milled Granulation Yield Limit: NLT 98.0%
processed).
In-Process
Tabletting Yield NMT 2.0% unexplained loss from the previous
final blend step.
TABLET CORES
SUMMARY
PIVOTAL BATCH
Product: [Generic name] Tablets [USP] [000.0] mg. - CORES
Labeled Amount: Each core contains [Active Material] [000.0] mg.
Core in-process Specifications
Punch Diameter 00.00 mm
Punch No [00]
Die No. [00]
Description [Color] (white to off-white) [shape] (round
biconvex) core debossed with the number /
letters [abc] on one face of the tablet core
and [xyz] on the opposite face.
Scoring [not scored] [scored on one side]
Core Diameter Limit: 000.0 - 000.0 mm: Nominal 000.0 mm
Thickness Nominal 00.0 Limit: 00.0 - 00.0 mm
Hardness Target: 00 SCU NLT 0.0 - NMT00 SCU.
Where the tablet is capsule shaped (i.e. a caplet) provide width, length and thickness
COATING PROCESS
SUMMARY
PIVOTAL BATCH
PRODUCT: [Generic name] Tablets USP [000.0] mg. [IA-000-00]
QUANTITY: [000000] MNF Date: Month DD, 199Y
Film Coating Controls Before Coating After Coating
Theoretical Tablet weight (mg) 000.0 -
Target Coated weight (mg) - 000.0
Average tablet 100 weight (g) 000.0 000.0
Average tablet weight (mg) 000.0 000.0
In-Process Yields
Yield after coating vs. Pre-coating 00.0%
Yield after coating to theoretical 00.0%
Recorded on Statistical Data Tablet Coating Work Sheets.
RELEASE SPECIFICATION FOR COATED TABLETS [USP]
SUMMARY
EXECUTED PIVOTAL BATCH
Product: [Generic name] Tablets USP [000.0] mg.
Description [Color] (white to off-white) [shaped] (round
letters [AA00] on one face of the Tablet
and [BB00] on the opposite face.
Content Uniformity
Media: 000 mL, 37 C. [00]% of [Sodium lauryl
Sulphate in 0.1N Phosphate Buffer]
pH 0.0 RPM 00
equal to [00.0] - [00.0] mg / Tablet.
IR = IMMEDIATE RELEASE ER = EXTENDED RELEASE
CR = CONTROLLED RELEASE DR = DELAYED RELEASE.
Where the tablet is capsule shaped (i.e. a caplet) provide width, length and thickness
MANUFACTURING PROCEDURE FOR EXECUTED BATCHES
[Generic name] Tablets [USP] [000.0] mg. - FLOW CHART

Finished Product
Step 1
High Speed Granulator
PREMIX
Step 4
Communition stage
MILLING
Step 2
GRANULATION
Step 2b
GRANULATION
Step 3
Fluid Bed Dryer
DRYING
[Active Material]
[intra-granular excipient]
[intra-granular excipient]
Extra-granular
Excipient
[Purified Water USP]
[Sodium Lauryl Sulfate]
Granulating Fluid
Add sub-lot 2/3
[Alcohol USP 95%]
Solvent
[Alcohol USP 95%]
if required
Step 6
Twin Shell / Flow Bin
Blending
Step 7
Compression stage
Tabletting
Step 5
Extragranular Addition
pre-blending
Step 8
Coating stage
[1/2/3] Sublots
Glidant
Disintegrant
Quick Sieve Stage 5
Sieve # [0]
IPQC testing
Blend Uniformity
Sieve Analysis
IPQC testing
Physical tests
Assay
Dissolution
IPQC testing
coated tablets- weight
IPQC Testing
% LOD analysis
Final Blend
Yield Analysis
Tabletting
Yield Analysis
Coating Yields
Overall Prod Yield
Yield Analysis
Milled Granulation Yield
BATCH RECORDS FOR EXECUTED BATCH
Tablets Lot No
Enclosed are the batch records of the executed batch (master, packaging and
labeling).
Note for Foreign Manufacturing Plants
Translation Policy:
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 tablets were manufactured on full size production equipment under
actual production conditions and SOPs.
The active material is manufactured by [Active Material] Pharmaceutical and
Chemical Manufacturing Company - [Address].
HARDNESS RANGE VERIFICATION
FOR TABLETS
The following hardness specification were given for the executed (pivotal) batch:
HARDNESS (SCU)
6 - 16
During the manufacture of the executed (pivotal) batch, hardness range verification
testing was performed.
Results of the 00 mg TABLET
The result demonstrate that compression of 0.0 mg Tablets within the proposed range
(minimum 6 SCU, maximum 14 SCU), does not adversely impact on dissolution.
The dissolution profile did not change from the original by more than 2.5 %
Results of the 00 mg TABLET
The result demonstrate that compression of 00 mg Tablets within the proposed range
(minimum 8 SCU, maximum 16 SCU), does not adversely impact on dissolution.
The dissolution profile did not change from the original by more than 2.5 %
COMMERCIAL HARDNESS RANGE
Therefore, this hardness range will be valid for routine commercial production batch.
4
HARDNESS RANGE VERIFICATION - Lot No:
SAMPLE
LOW HARDNESS HIGH HARDNESS
NO.
Tablet
Weight (mg)
Tablet
Thickness
(mm)
Tablet
Hardness
(SCU)
Friability
(%)
Tablet Weight
(mg)
Tablet
Thickness
(min)
Tablet
Hardness
(SCU)
Friability
(%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
14
16
17
18
19
20
AVG.
RSD %
USL
LSL
TARGET HARDNESS
INTERVAL SAMPLE
No
Tablet
Weight
(mg)
Tablet
Thickness
(mm)
Tablet
Hardness
(SCU)
Friability
(%)
1 11 199 201 3.1 3.2 9 8 0.4 0.3
2

12 199 200 3.1 3.1 9 9 0.4 0.5
3 13 198 200 3.1 3.1 8 8 0.5 0.4
4 14 198 201 3.1 3.1 9 9 0.4 0.4
1
5 15 197 201 3.1 3.1 8 8 0.3 0.4
6 16 199 200 3.1 3.1 9 8 0.3 0.5
7 17 200 203 3.1 3.1 8 10 0.3 0.5
8 18 202 202 3.1 3.1 8 9 0.4 0.5
9 19 199 202 3.1 3.1 8 9 0.5 0.3
10 20 202 201 3.1 3.1 8 8 0.5 0.3
1 11 199 201 3.1 3.2 9 8 0.4 0.3
2

12 199 200 3.1 3.1 9 9 0.4 0.5
3 13 198 200 3.1 3.1 8 8 0.5 0.4
4 14 198 201 3.1 3.1 9 9 0.4 0.4
2
5 15 197 201 3.1 3.1 8 8 0.3 0.4
6 16 199 200 3.1 3.1 9 8 0.3 0.5
7 17 200 203 3.1 3.1 8 10 0.3 0.5
8 18 202 202 3.1 3.1 8 9 0.4 0.5
9 19 199 202 3.1 3.1 8 9 0.5 0.3
10 20
202 201 3.1 3.1 8 8 0.5 0.3
1 11 199 201 3.1 3.2 9 8 0.4 0.3
2

12 199 200 3.1 3.1 9 9 0.4 0.5
3 13 198 200 3.1 3.1 8 8 0.5 0.4
4 14 198 201 3.1 3.1 9 9 0.4 0.4
3
5 15 197 201 3.1 3.1 8 8 0.3 0.4
6 16 199 200 3.1 3.1 9 8 0.3 0.5
7 17 200 203 3.1 3.1 8 10 0.3 0.5
8 18 202 202 3.1 3.1 8 9 0.4 0.5
9 19 199 202 3.1 3.1 8 9 0.5 0.3
10 20 202 201 3.1 3.1 8 8 0.5 0.3
AVG.
RSD %
USL
LSL
TABLET TRAIL
PACKAGING AND DISBURSEMENT
Tablets [USP] [ 10] mg
Batch No. Lot: [IA-00-00]
Bulk Material in Polyethylene Bags:
1,800,050 tablets packed in :
10 bulk containers x 180,050 tablets

2 bulk containers
Month DD, 200Y
8 bulk containers
Balance stored in
Pivotal Warehouse
[Active Material] TABLETS [USP] [ 20] mg
Batch No. Lot: [IA-00-00]
30cc HDPE Container
Child Resistant Cap Closure [33 mm]
30cc HDPE Container
Metal Cap Closure [33 mm]
590 Units x 30 tablets = 17,900 tablets
Nov.28, 1996
10 units x 30 tabs
Month DD, 200Y
50 units x 30 tabs
Month DD, 200Y
530 units x 30 tabs
Balance stored in
Pivotal Warehouse
Nov.28, 1996
10 unit x 100 tabs
Month DD, 200Y
30 units x 100 tabs
Month DD, 200Y
960 units x 100 tabs
Balance stored in
Pivotal Warehouse
[Active Material] TABLETS [USP] [ 20] mg - Batch No. Lot: [IA-00-00]
60cc HDPE Container
300cc HDPE Container
5 unit x 180 tabs
Month DD, 200Y
15 units x 180 tabs
Month DD, 200Y
Balance stored in
Pivotal Warehouse
5 unit x 1000 tabs
Month DD, 200Y
Month DD, 200Y
Balance stored in
Pivotal Warehouse
[Active Material] TABLETS [USP] 40 mg - Batch No. Lot: [IA-00-00]
30cc HDPE Container
30cc HDPE Container
Nov.28, 1996
5 units x 30 tabs
QC Testing
Month DD, 200Y
40 units x 30 tabs
Biostudy (European Market)
Month DD, 200Y
400 units x 30 tabs
Balance stored in
Pivotal Warehouse
55 units x 30 tabs
Month DD, 200Y
Nov.28, 1996
9 units x 100 tabs
Month DD, 200Y
25 units x 100 tabs
Month DD, 200Y
40 units x 100 tabs
Biostudy & Retained Samples
Month DD, 200Y
60 units x 100 tabs
Balance stored in
Pivotal Warehouse
[Active Material] TABLETS [USP] 40 mg - Batch No. Lot: [IA-00-00] (continued)
60cc HDPE Container
300cc HDPE Container
5 units x 180 tabs
Month DD, 200Y
15 units x 180 tabs
Month DD, 200Y
Balance stored in
Pivotal Warehouse
7 units x 1000 tabs
Month DD, 200Y
Month DD, 200Y
Balance stored in
Pivotal Warehouse
Stability (European Market)
Month DD, 200Y
SECTION XIII SECTION 13
Pac k agi ng and Label i ng Pr oc edur es
TABLE OF CONTENTS
This Section contains information on the container-closure systems, including type III
DMF authorization letters from the component manufacturers, as well as the
applicant's component specifications and component test data.
The container closure system for the drug product are described in detail in the
specifications and drawings included in this section.
13.1 Outlines for Packaging and Labeling Procedures
13.2 Blank Packaging Forms and Packaging reconciliation .
NOTE:
STANDARD OPERATION PROCEDURES - OUTLINES.
Actual Standard Operation Procedures should not generally be included in an ANDA
submission. For various reasons new editions or amendments to SOPs are
continually being development or new SOP procedure are introduced from time to
time.
The period between submission and pre-approval inspection or first commercial
production lots may well have resulted in a new SOP in use.
FDA's Published January 1999 ANDA Guideline Requirements:
(actual excerpt as published in agency guideline)
Section XIII.
Packaging Materials Controls
1. Summary of packaging system
2. Components specification and test data (Type III DMF references)
3. Packaging configuration and sizes
4. Container/closure testing (include ingress testing in Section XXII, as appropriate for
sterile processes only)
5. Vendor qualification specifications
6. Applicants acceptance criteria
7. Retest schedule
4 4
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.
A relatively standardized ANDA section
that emphasizes the intended commercial
production packaging procedures and
reconciliation controls in force.
Packaging and Labeling Procedures
PACKAGING AND LABELING PROCEDURES
Applicants Acceptance Criteria
The Acceptance criteria for new packaging components are detailed in the firms
appropriate SOPs required according to cGMP (21 CFR 211). Actual acceptance
activities are cross-checked by the firms QA department prior to manufacturer.
A narrative outline of the QA system is given.
1. The packaging work station is inspected prior to the start of work, for work
station and equipment cleanliness. The packaging station must be free of all
previous leftover work materials and the packaging line must be completely
clear.
2. The product and packaging materials are identified according to the Standard
Packaging Sheets printed with the required packaging specifications.
3. In-Process Control of the packaging procedure is carried out at the start of
packaging procedure, and then at approximately every hour during the
packaging process. When packaging machines are temporary stopped, the work
station is re-inspected and full In-Process Control checks are carried out prior to
restarting the cleared line.
4. At the end of packaging procedure, a material balance and a packaging
reconciliation is performed on the packed product and the unused printed
packaging materials that contain any overprinting (Lot number ; Expiry Date).
(Example of the material balance & packaging reconciliation sheet attached).
5. Any quantity absent during packaging reconciliation is resolved as an
unexplained loss. The limit for the unexplained loss may not exceed 2% of the
amount received.
6. A Packaging Department supervisor / representative and a QA representative
checks and approves that the entire packaging procedure was performed
according to required specifications, and signs the Packaging Work Sheet.
NOTE:
BLANK PACKAGING FORMS
Examples of Blank Packaging Forms are not given in this example. The critical
checks to proper packaging control forms are;
Identify and quantify - all incoming printed packaging material (including primary
and secondary packaging materials)
Identify and quantify - all incoming containers, closures and containers inserts
(including cotton wool etc.)
Perform a material balance check on all Packed Goods and a Packaging
Reconciliation on all printed materials and containers.
333
Packaging and Labeling Procedures
Packaging Material Balance and Reconciliation
Product & Strength: _______________________ Batch No:
Packaging Size ________________
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
Department Material Balance:
2.2 TOTAL Packs
rejected
100 x [Total no. of units] = _______%
Theoretical no. of units
2.3
TOTAL Packs
sampled
Compare to last production stage
(2%)
Signature
_______
Date
________
2.4 TOTAL PACKS
3. TOTAL BATCH RECONCILIATION (OF OVERALL PACKAGING PROCESS)
3.1 Material Rejected
______________________ units
3.2 Samples Taken
______________________ units
[2.1 + 3.1 + 3.2] _x _100 = % (Limits: 95.0% - 103.0%)
Theoretical no. of units
Signature: _______________________ Date: _______________
Quality Assurance Unit
TABLE OF CONTENTS
Glass
Thermoplastic Containers
Solid oral dosage forms.
Vendor qualification Specifications
Appropriate documentation from the packaging component manufacturer as
highlighted below is obtained for each component according to in-house SOPs,
including but not limited to, DMF reference authorization letters, cGMP compliance
certifications, manufacturers specifications and test results.
Furthermore samples of all materials with corresponding manufacturers Certificate of
Analysis are evaluated for QC and functionality testing as well as any compatibility
testing with the intended product.
FROM THE GENERIC FIRM'S QC LAB
1. General description (summary) of Container-closure-liner-seal-cotton
system used for each dosage strength
2. Description of Packaging Components of pack sizes used for each strength
3. Testing Specifications or protocol and test results (CoA) of Generic
packaging Lab.
4. CoAs of Containers from the QC Packaging Lab.
5. Batch Compliance Statement of applicants acceptance tests
FROM THE CONTAINER MANUFACTURER:-
6 Container Specifications:-name, product code and manufacturer (including)
- drawings / diagrams with annotated dimensions
- Tests performed on closure to include USP <661> and <671>
n Light transmission and n moisture vapor permeation
- Certificate of Conformance meeting all USP XXIII
- Complies to 21 CFR requirements / Food Additives Regulations
- Certificate of Analysis
- DSC thermal analysis (for thermoplastic containers only)
7 Brief description of manufacturing process (as appropriate)
Letters of Authorization - (LoA)
8 i. LoA from manufacturer referencing their facility DMF #.
ii. LoA from manufacturer referencing their container DMF #.
Note: Glass requires less tests and documentation
FROM THE RESIN MANUFACTURER:-
9 LoA from resin manufacturer referencing their resin DMF # as used in the
manufacture of the container
10 Obtain separate letters for each resin type used in different plastic
containers
4
Packaging Components Description
TABLE OF CONTENTS
Metal Caps or
Thermoplastic Closures
FROM THE GENERIC FIRM'S QC LAB:-
11 Testing Specifications or protocol and test results (CoA) of Generic
packaging Lab
12 CoA of closures from the QC Packaging Lab
13 Batch Compliance Statement of applicants acceptance tests
FROM THE CLOSURE MANUFACTURERS :-
14 Closure Specifications (including)
15 - drawings / diagrams with annotated dimensions
16 - Tests performed on closure system to include USP <661> and <671>
n moisture vapor permeation
17 - Certificate of Conformance meeting all USP XXIII
- Complies to 21 CFR requirements / Food Additives Regulations
18 - Certificate of Analysis
19 - DSC thermal analysis (for thermoplastic closure only)
Letters of Authorization
21 ii. LoA from closure manufacturer referencing DMF # of cap
Statement of GMP compliance of manufacturer
FROM THE RESIN MANUFACTURER:-
(Not required for metal closures)
22 i. LoA from (cap) resin manufacturer referring thermoplastic resin DMF #
and Statement of GMP compliance of manufacturer
23 Obtain separate letters for each resin type used in thermoplastic closures
Note:
Child Resistant Closures (CRCs) may consists of two parts made with different
HDPP/HDPE resins. Both inner (HDPP) and outer part (HDPE) resins need to be
treated separately in the documentation requirements.
4
TABLE OF CONTENTS
Inner closure liner
packaging Lab
25 CoA of liner from the QC Packaging Lab
FROM THE LINER MANUFACTURER:-
27 Liner Specifications (including);
28 - drawings / diagrams with annotated dimensions
29 - Tests performed on liner
30 - Certificate of Conformance meeting all current USP requirements and
complies to 21 CFR requirements
LETTERS OF AUTHORIZATION:-
33 ii. LoA from liner manufacturer referencing DMF # of liner
STATEMENTS OF COMPLIANCE
34 Statement of GMP compliance of liner manufacturer
35 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
TABLE OF CONTENTS
Foam Seals
Pressure sensitive, tamper resistant, adhesive seals
(data required for each container seal)
packaging Lab.
37 CoA of adhesive seal from the QC Packaging Lab.
FROM THE ADHESIVE SEAL MANUFACTURERS :-
39 Adhesive seal Specifications (including)
40 - Drawings / diagrams with annotated dimensions
41 - Tests performed on adhesive seal
42 - Complies to 21 CFR requirements
LETTERS OF AUTHORIZATION - (LOA)
44 LoA from seal manufacturer referencing their facility DMF #.
45 LoA from manufacturer referencing their seal DMF #.
46 Statement of GMP compliance of seal manufacturer
NOTE:
Moisture permeability - USP <661>: Max 10mg/day/Liter.
Container closing Torque - USP <671>: Should establish a good seal at target torque.
4
TABLE OF CONTENTS
Cotton Coil
(required for coiler )
FROM THE GENERIC FIRM:
packaging Lab.
49 CoA of Cotton Coil from the QC Packaging Lab
FROM THE COTTON COIL MANUFACTURERS :-
51 Purified Cotton Coil Specifications (including)
52 - Tests performed on Cotton Coil
53 - Partial Compliance to USP requirements
54 - Complies to 21 CFR requirements
55 - Certificate of Analysis (include moisture content)
LETTERS OF AUTHORIZATION - (LOA)
LoA from Cotton Coil manufacturer referencing their facility DMF #.
56 LoA from manufacturer referencing their Cotton Coil DMF #.
57 Cotton Coil manufacturer's: Statement of GMP Compliance
Note:
Fillers (cotton coil and rayon coil etc.) are Primary Packaging Material (in
immediate contact with dosage form). Specify coiler as 9g or 20g weight.
Desiccants (e.g. '2:1' silica gel) requires documentation similar to cotton or rayon
coilers. Desiccants should differ in size and shape from solid dosage form.
Cotton USP (as filler) - exempted from USP monograph sterility, absorbency and
fiber length tests
Rayon USP (as filler) - exempted from USP monograph absorbency and fiber
length tests
Rayon (Coiler as filler) - do not use for Hard Gelatin Capsules (impacts on
dissolution.)
Package Characteristics for container-liner-closure systems
Package Description concerning container-liner-closure systems
Technical Specifications (Diagrams &Drawings) of each component.
Certificates of Analysis of [Generic Company Name Inc./Ltd.] packages.
DMF Referral Letters
Statements of Compliance with applicable sections of the Indirect Food Additive
Regulations (21 CFR).
USP XXIV Testing Results of the closure system.
Documents for container-liner-closure system include the following:
Certificates of Analysis outlining the components used for packages containing;
30 / 60 Tablets in HDPP with child-resistant cap
1000 Tablets in HDPP with metal screw cap.
4
PACKAGE CHARACTERISTICS
ORAL CAPSULES [00.0] mg LOT: IA00-00
Pivotal Lot
The container closure system used consists primarily of high density polyethylene
(HDPE) container using plastic or metal caps (child resistant where required), with
a non-reactive filler and an self adhesive internal tamper-evident seal covering the
opening of the container.
Amount 30 Units 60 Units 1000 Units 1000 Units
CONTAINER
manufacturer
Drug Plastics & Glass Drug Plastics & Glass Drug Plastics &
Glass
Drug Plastics &
Glass
CONTAINER
size
30 cc round, white
HDPE bottle
50 cc round, white
HDPE bottle
750 cc round, white
HDPE bottle
750 cc round, white
HDPE bottle
CONTAINER
composition
HDPE resin:
Quantum LR-7340-43
HDPE resin:
Quantum LR-7340-43
HDPE resin:
Quantum LR-7340-
43
HDPE resin:
Quantum LR-7340-
43
CONTAINER
color/pigment
Ampacet White 11078
PE,
DMF # 8354
Ampacet White 11078
PE,
DMF #4162
Ampacet White
11078 PE,
DMF # 8354
Ampacet White
11078 PE,
DMF #4162
Cap
manufacturer
Owens-Illinois U.S. CAN Owens-Illinois U.S. CAN
Cap type Child resistant cap Child resistant cap Metal screw cap Metal screw cap
Cap size 29 mm 33 mm 53 mm 53 mm
Closure liner
manufacturer
Tekni-Plex Inc. Tekni-Plex Inc. Tekni-Plex Inc. Tekni-Plex Inc.
Closure Liner
composition Foam seal PS 22 Foam seal PS 22
1.Tekniseal RVT+
LF 2.Foamseal PS
22
1.Tekniseal X-14
(p/poly)
2.Foamseal PS 22
Pharmaceutical
Cotton Coil
Manufacturer
American
White Cross
American
White Cross
American
White Cross
American
White Cross
Cotton
Coil
Snopure
Cotton Coil - 9 g
Snopure
Cotton Coil - 9 g
Snopure
Cotton Coil - 20 g
Snopure
Cotton Coil - 20 g
Desiccant
manufacturer
United Desiccant United Desiccant United Desiccant United Desiccant
Desiccant type Humi cap 0.75g
Silica gel
Humi cap 0.75g
Silica gel
Humi cap 0.75g
Silica gel
Humi cap 0.75g
Silica gel
PACKAGING COMPONENT DESCRIPTION FOR
THERMOPLASTIC CONTAINERS CONTAINING:
All container and closure systems are certified to comply with the indirect
food additive regulations (Parts 170-199) or are otherwise certified safe for
use in contact with a drug product - generally accepted as safe (Appear in
the 21 CFR GRAS List)
30 and 60 & 1000 Units
HDPE:
Description White, Round HDPE Bottle with 29/33/53 mm/400 Neck Finish
CODE & Size Code 000 - Size: 30, 50, 750 cc
Manufacturer Drug Plastics & Glass Company, Inc., DMF # 1933
Resin used QUANTUM DMF # 885
Color Batch AMPACET 11078 PE, DMF # 8354
DMF (MFG) DMF [0000]
DMF (Item) DMF [0000]
LoA Month DD, YYYY
21 CFR Complies with Food Additives Regulations Part 170 -199
Documentation Relevant data copies of the manufacturers current DMF #
[0000] (Type II) are attached for ease and simplicity of review.
General Tests &
Assays
All relevant tests applicable to the container closure system as
per table 14-A are performed by either the vendor or
applicant and supported in the documentation attached.
Stability Testing Where product stability testing is conducted referencing this
specific item's code then all above specifications shall apply to
the container-closure item.
4
CLOSURES OF CONTAINERS CONTAINING:
30 & 60 Units
CHILD RESISTANT - CLOSURE
Description
Child Resistant cap, 38 mm / 400 White, Unlined Polypropylene
Cap with Pressure Sensitive Inner Seal
CODE & Size Code 000 - 29/33 mm diameter
Fits Container Size 000 & 000 cc
Manufacturer Owens Brockway
Inner Liner None
Foam Seal
Foamseal PS 22 - Pressure Sensitive, adhesive
DMF (MFG) DMF [0000]
DMF (Item) DMF DMF # 2229
LoA
Month DD, YYYY
General Tests &
Assays
1000 Units
METAL SCREW CAP
Description
38/53 mm 400 White, Tin Plated Metal Screw Cap with Pressure
Sensitive Inner Seal
CODE & Size Code 000 - Size: [38/53] mm diameter
Fits Container Size 000 & 000 mL
Manufacturer: U.S. CAN [Full address]
DMF (MFG)
DMF #4162
DMF (Item)
DMF #4162
LoA
Month DD, YYYY
General Tests &
Assays
4
30 /60 / 1000 Units
INNER CAP LINER
Inner Liner Tekniseal X-14(Polyethylene)
CODE & Size Code 000 - Size: [00] mm diameter
Manufacturer
Tekni-Plex Inc.
DMF (MFG) DMF # 1378
DMF (Item) DMF # 1378
LoA Month DD, YYYY
CONTAINER FOAM SEAL
Foam Seal Foam seal PS 22 - Pressure Sensitive, adhesive
Manufacturer
US CAN.
Size [00] mm diameter
DMF (Mfg) DMF # 1378
DMF (Item) DMF # 1378
LoA Month DD, YYYY
General Tests &
Assays
INCLUSIONS USED IN ALL CONTAINER SYSTEMS
Description : : Snopure Cotton Coil
Type : : 9 or 20 grams
Manufacturer : : American White Cross
DMF of MNF : : American Fiber and Finishing, DMF # 4343
Product DMF : : DMF # 4164 / DMF # 4343
LoA : : Month DD, YYYY
American White Cross (formerly National Patent Medical), DMF # 4164 or American
Fiber and Finishing, DMF # 4343
DESICCANT USED IN ALL CONTAINER SYSTEMS
(where used)
Description : Humi cap 0.75 g silica gel.
Manufacturer : United Desiccant
DMF of MNF : : DMF [0000]
Product DMF : : DMF [0000]
LoA : Month DD, YYYY
4
U.S. Phar mac opoei a / Nat i onal For mul ar y
General Tests and Assays - Table 1
Ref.
No
USP
<No>
TITLE SUBTITLE
General Tests and Assays
1. <1> Injections
2. <87> In vitro Biological Reactivity Tests
3. <88> In vivo Biological Reactivity Tests
4. <161> Transfusion Transfusion and Infusion Assemblies
5. <381> Elastomeric closures for injections
6. n Biological Test Procedures
7. n Physiochemical Test Procedures
8. <601> Aerosols
9. <661> Containers
10. n Light transmission
11. n Chemical resistance - Glass Containers
12. n Biological Tests - Plastic and others
13. n Polymer
14. n Physiochemical Test - Plastics
15. n Polyethylene Containers
16. n Polyethylene Terephthalate / Terephthalate G Bottles
17. n Single Unit Containers & Unit Dose (Containers for
Non-sterile solid & liquids dosage forms )
18. n Customized Patient Medication Packages
19. <671> Containers Permeation - n Multiple unit containers for capsules
and tablets
20. n Permeation - n Single unit containers and Unit dose
for capsules and tablets
21. <691> Cotton Cotton or Purified Rayon Monograph (with
exclusions)
22. <771> Ophthalmic Ointments
23. <1151> Pharmaceutical Dosage Forms
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.
24 VOLUME DRUG DEVELOPMENT SERI ES: Sect: 14.1 Or al Or al TABLETS
SECTION XIV SECTION 14
Fi ni shed Dosage For m Cont r ol s
TABLE OF CONTENTS
State if drug product is:-
Compendial and test methods used are USP XXIV
Non-Compendial and test methods are validated in-house methods
Non-Compendial and test methods based on published analytical methods and
fully validated.
Certificate of Analysis and analytical spectra for the finished dosage form, representing
each container-closure system of the Pivotal Batch(es), including:
HPLC, TLC, GC, UV chromatograms and spectra for all pivotal strengths made.
Certificate of Analysis for each pivotal lot strength plus the corresponding HPLC
assay chromatogram of actual batch manufactured.
Stability Indicating Assay
Impurity Limit Tests
Dissolution Assay
USP Monograph tests
USPC Inc. Pharmacopeial Forum
Published Reference Works
Section XIV. Controls for the Finished Dosage Form
1. Test procedures
2. Testing specifications and data (COA)
Finished Dosage Form Controls
THE DRUG PRODUCT IS NON-COMPENDIAL.
Certificates of Analysis for the finished drug product [Generic name] TABLETS [0.00]
mg (all strengths).
Copies of the test methods and method validations are enclosed in Sections XVI, for
Analytical Methods.
These methods are used for release and stability purposes, assuring identity, strength,
quality and purity of the finished drug product.
Note:
Additionally, separately bound copies of all non-compendial methods have been
provided in accordance with 21 CFR 314.50(e)(2)(i).
or
THE DRUG PRODUCT IS COMPENDIAL.
Certificates of Analysis for the finished drug product [Generic name] TABLETS [0.00]
mg (all strengths).
The drug product is compendial. Copies of the stability indicating test methods and
method validations are enclosed in Sections XVI, under Analytical Methods.
Compendial methods are used for release, assuring identity, strength, quality and
purity of the finished drug product on batch release.
Stability indicating test methods are used for stability, assuring identity, strength,
dissolution and purity of the finished drug product during the entire shelf life period of
the drug.
Note:
Additionally, separately bound copies of all non-compendial methods have been
provided in accordance with 21 CFR 314.50(e)(2)(i).
RELEASE SPECIFICATION FOR FINISHED PRODUCT
SUMMARY
Product: [Generic name] TABLETS [000.0] mg
Labeled Amount: Each tablet contains [000.0] mg [Active Material]
Description [Color] white-to-off white [size in mm]
tablet printed/embossed with the number /
letters [000] on the face and [0000] on the
obverse.
Identification A: The Infra Red Absorption Spectrum conforms
to the Reference Standard
Identification B: The Chromatogram of the sample solution
Moisture (LOD / KF) Target 0.0 Limit: 0.0 - 0.0
Weight Individual (7.5%) Target 000 Limit: 000 - 000 mg
Weight Average (5.0%) Target 000 Limit: 000 - 000 mg
Uniformity of Dosage Units: Conforms to the current USP
Content Uniformity
Microbial Limit test Conforms to the current USP (where required)
Dissolution (Select Conditions) Equipment: USP App. No 1 or 2 (Paddle)
Media: 900 mL, 37 C.
pH 0.0 RPM 00
Tolerance: NLT [00]% of the labeled
is dissolved in [00] min.
- Each unknown: NMT 0.09% of the labeled amount
- Any identified: NMT 0.5% of the labeled amount
Residual Solvents
Isopropyl alcohol NMT 1.0 %
Acetone NMT 500 ppm
Ethanol NMT 1000 ppm
00.0] - [00.0] mg
Note:
IPC Limits
may be
tightened to
5.0%
The release Assay should allow for the
maximum degradation during the
entire product's shelf life. It may be
96% - 105% or even 97% - 105%.
All overages (5%) added must be
scientifically justified.
Total impurity profile should
not exceed 2% unless the
innovative brand leader
product exceeds the 2% limit
(i.e. the impurities are not
toxic or probably inert)
Assay decimals are
always reported as one
significant decimal place.
STABILITY SPECIFICATION FOR FINISHED PRODUCT
SUMMARY
Product: [Generic name] TABLETS [000.0] mg
Labeled Amount: Each tablet contains [000.0] mg [Active Material]
Description [Color] white to off-white [size in mm]
tablet printed / embossed with the number /
letters [000] on the face and [0000] on the
obverse.
Identification A: The Infra Red Absorption Spectrum conforms
to the Reference Standard
Identification B: The Chromatogram of the sample solution
Moisture (LOD / KF) Target 0.0 Limit: 0.0 - 0.0
Unit weight Individual (7.5%) Target 000 Limit: 000 - 000 mg
Unit weight Average (5.0%) Target 000 Limit: 000 - 000 mg
Uniformity of Dosage Units: Conforms to the current USP
Content Uniformity
Microbial Limit test Conforms to the current USP (where required)
Dissolution (Select Conditions) Equipment: USP App. No 1 or 2 (Paddle)
Media: 900 mL, 37 C.
pH 0.0 RPM 00
Tolerance: NLT [00]% of the labeled
is dissolved in [00] min.
- Each unknown: NMT 0.09% of the labeled amount
- Any identified: NMT 0.5% of the labeled amount
Residual Solvents
Isopropyl alcohol NMT 1.0 %
Acetone NMT 500 ppm
Ethanol NMT 1000 ppm
00.0] - [00.0] mg
Note:
Limits to official
parameters, which differ
may from the release QC
parameters
Select color to comply
with the full 2 -3 year
shelf life of the tablet
under market conditions
Total impurity profile should
not exceed 2% unless the
innovative brand leader
product exceeds the 2% limit
(i.e. the impurities are not
toxic or probably inert)
SUMMARY OF CERTI FI CATE OF ANALYSES AND
ANALYTI CAL SPECTRA :
Pivotal Batch C of A No.
Executed Lot
Pivotal Lot No: [000-01] [60.0] mg C 000-01
G C
SPECTRA
Pivotal Lot No: [000-01] [00.0] mg S 000-01
UV
SPECTRA
Pivotal Lot No: [000-01] [00.0] mg U 000-01
Pivotal Lot No: [000-02] [00.0] mg U 000-02
Pivotal Lot No: [000-03] [000.0] mg
U 000-03
U 000-04
HPLC
SPECTRA
Pivotal Lot No: [000-01] [00.0] mg H 000-01
Pivotal Lot No: [000-02] [00.0] mg H 000-02
H 000-03
H 000-04
TLC
Pivotal Lot No: [000-01] [00.0] mg T 000-01
Pivotal Lot No: [000-02] [00.0] mg T 000-02
T 000-03
T 000-04
(Labeled Photocopies of TLC plates provided)
NOTE: Attach summary and spectra for each of the pivotal lots and strengths
manufactured. Above table represents one pivotal lot of each dosage strength.
SUMMARY OF ANALYTI CAL METHODS
AND METHOD NUMBERS:
Table details the analytical Control Methods used :
Analytical Method Stability
PURPOSES
QC Release
PURPOSES
Method
Validation
Active Ingredient
Not Applicable QC-021-00 SI -V -021-00
Finished Product
Physical TESTS
SI-A22-00
Finished Product
Assay / Impurities
SI-A23-00
QC-025-00
SI -V -A23-00
Finished Product -
Dissolution Method
SI-D24-00 SI -V -D24-00
- -
KEY
QC = A Quality Control Method that has been validated and based on the R&D
validated method.
SI = A Stability Indicating Method that has been fully validated
A = An Assay Method
D = A Dissolution Method
V = The full validation procedure and test results of a corresponding stability
indicting method (Note: the same method number is used)
00 = The last two zeros (-00) indicated the editions number of the procedure - i.e.
edition number three is written as '-03.'
Test methods for release and for stability purposes. The R&D analytical methods 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.
Ed Number: 01 Effective Date
APPROVED
Ed. Status :
New
DD/MM/YY
_____________ __________ _______________ _________/________
24 VOLUME DRUG DEVELOPMENT SERI ES: Sect: 15.1 ANDA ANDA Development
SECTION XV SECTION 15
Anal yt i c al Met hods
TABLE OF CONTENTS
Included in his section are the analytical methods, method validations and test
specifications and data for the drug substance [Generic name] and the drug product
[Generic name] tablets [000]mg manufactured by the applicant. The methodology
includes validated stability indicating analytical assay methods
State if drug substance and drug product is:
q - Compendial and test methods used are USP XXIV
q - Non-Compendial and test methods in-house and validated.
q - US Non-Compendial test methods based on published reference works
and validated (e.g. Ph Eur / BP / Japan Pharm / DAB.)
Active material
15.1 Active Ingredient Test Method (QC Release method)
15.2 Active Ingredient Test Method Validation (Stability Check method)
In-process Material
15.3 Final Blend Test Methods
Finished Product
15.4 Finished Product Test Methods (QC Release method)
- physical tests
- Chemical tests
- microbiological tests - (where required)
[If compendial - methods are USP monograph]
15.5 Finished Product Test Methods (Stability Check method)
- stability Indicating Test Method
- impurity limit Test Method
- dissolution Test Method
15.6 Finished Product Analytical Validation methodology.
- Validation of Stability Indicating Assay
- Validation of impurity limits
- Validation of dissolution method.
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)
APPROVED
Ed. Status :
New
DD/MM/YY
_____________ __________ _______________ _________/________
Analytical Methods
Non Compendial USP materials.
The active drug substance, [Active Material], and the finished drug product
[Generic name] [USP] [000.0]mg., are both non-compendial in the 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 (ref. pages [00] to [00])
Final Blend Test Methods (ref. pages [00] to [00])
Finished Product Test Methods (Release) (ref. pages [00] to [00])
Finished Product Test Methods (Stability) (ref. pages [00] to [00])
Assay/Impurities
Degradation Products Determination
Dissolution Test
Test of Appearance
Finished Product Analytical Method Validation (ref. pages [00] to [00])
Note:
Additional separately bound copies are provided in accordance with 21 CFR
314.50(e)(2)(i).
APPROVED
Ed. Status :
New
DD/MM/YY
_____________ __________ _______________ _________/________
APPROVED
Ed. Status :
New
DD/MM/YY
_____________ __________ _______________ _________/________
Analytical Methods
SUMMARY OF ANALYTICAL METHODS AND METHOD NUMBERS:
Analytical Method Method No.
Active Material
Stability Indicating Assay SI-1000-01
Impurity Limit tests SI-1000-01
Validation of Stability Indicating Assay SI-1000-01
In-process Material
Content Uniformity SI-2000-01
Finished Product Release
QC Release Assay SI-4000-01
Content Uniformity SI-4000-01
Dissolution Assay SI-4000-01
Finished Product Stability Methods
Stability Indicating Assay SI-5000-01
Validation of Stability Indicating Assay SI-5000-01
Dissolution Assay SI-5000-01
Validation of Dissolution Assay method SI-5000-01
(All Analytical Methods Placed Here)
APPROVED
Ed. Status :
New
DD/MM/YY
_____________ __________ _______________ _________/________
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
Ed. Status :
New
DD/MM/YY
_____________ __________ _______________ _________/________
[c]. The stability of the Standard solution is assessed by re-injection of the
standard solution after 24 x n hours (where n = number of days the Standard will be
used).
Standard Preparation for Assay
Comparison of standard solutions for Assay of Active material, injected after one
month and freshly prepared demonstrate that the standard solutions are stable and
does not lose its quality after one month if refrigerated.
Standard Preparation for Impurity
Comparison of standard solutions of Guanine, injected after one month and freshly
prepared demonstrate that the standard solutions are stable and does not lose its
quality after 1 month if refrigerated.
Name of standards Storage conditions Difference. relative
to freshly prepared
standard
[Active] 100% 4C <2%
[Impurity] 100% 4C <2%
Standard Solutions are stored at controlled temperatures and light conditions as per
labeling.
[d]. Stability Indicating Procedures.
For the Stability Indicating Method, the product sample shall include forced
degradation by stressed analysis. Conditions of concentration and reaction time
may vary depending on the active drug substance and drug product e.g. :
Oxidation - (H
2
O
2
plus standing time).
Base Hydrolysis - (NaOH x N plus standing time).
Acid Hydrolysis - (HCl conc. plus standing time).
Sun light - (24 hours standing time).
Heat - (x degrees C).
Summary of Stability Indicating Results
Stressed Conditions Temp. Time Raw Material; Tablets
( C) (hr) Remaining
Substance.
(%)
Peak Purity,
(Figure)
Remaining
Substance
(%)
Peak
Purity,
(Figure)
Solution heating 90 12 100.2 pure 98 pure
Solid heating 160 2 101.3 pure 92 pure
Sunlight 765 w/m
2
40 14 101.1 pure 84.8 pure
3,3N Sodium Hydroxide 70 10 99.8 pure 100.2 pure
10%Hydrogen Peroxide 37 3 77.5 pure 90.5 pure
5% Hydrochloric Acid Room 20 79.7 pure 78.6 pure
APPROVED
Ed. Status :
New
DD/MM/YY
_____________ __________ _______________ _________/________
[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] =
2.65 = 0.31
RT
[Active]
8.45
2. Tailing factor for [Active] peak
T =
W
2
=
9
4.2
= 1.1
f
0.05
f
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
Ed. Status :
New
DD/MM/YY
_____________ __________ _______________ _________/________
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.
[f] Relative Retention Time of Main and Additional peaks.
Each stressed analysis shall indicate the percentage by which the Main peak is
decreased as well as the RRT for any other Additional peaks.
If the RRT of an Additional peak corresponds to a known degradant/impurity etc. it
shall be stated.
The peak purity of the main peak shall be given for each stressed analysis (where
possible).
[g]. Validation of limit testing for impurity methods shall include :
* Specificity
* Detection Limit (DL)
* Quantitation Limit (QL)
Detection Limit (DL)
The detection limit of an individual analytical procedure is the lowest amount of
analyte in a sample which can be detested but not necessary quantitated as an
exact value.
Quantitation Limit (QL)
The Quantitation limit of an individual analytical procedure is the lowest
amount of analyte in a sample which can be quantitatively determined with
suitable precision and accuracy. Used in the determination of impurities and or
degradation products.
[h]. Contents of a typical HPLC Analytical Validation Protocol
refer Method No. A-0340-01-1299
APPROVED
Ed. Status :
New
DD/MM/YY
_____________ __________ _______________ _________/________
Validation of HPLC Analytical Method
Method No: A-0340-01-1299
[1] Introduction - A brief description is given of the following parameters :
* Method and Edition # used
* Batch # of samples tested (test the lowest and the highest label strength)
* Type of detector used to analyze stressed samples
* Stress testing of Standard solution to determine origin of Additional peaks.
[2] Syst em Repr oduc i bi l i t y - Pr ec i si on
Ten replicate (single) injections of the standard solution at the nominal
concentration described in the method is performed and the RSD calculated. The
Results (sample # and peak areas) are tabulated. The Average Peak Area, SD and
RSD are shown in the table. Target values for RSD = 0.5 to 1.0
(Keep this standard solution for the stability of Standard Solutions - Point 9)
SYSTEM REPRODUCIBILITY
SAMPLE No. PEAK AREAS
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
Average Peak Area
Standard Deviation
Relative Standard
Deviation
=
=
= 0.5 - 1.0
APPROVED
Ed. Status :
New
DD/MM/YY
_____________ __________ _______________ _________/________
[3] Met hod Repr oduc i bi l i t y - Pr ec i si on
The full analytical method # is carried out and repeated Ten times on the finished
product (batch #) and the RSD is calculated. Two HPLC injections are performed
per method assay and the peak areas are averaged. The Results (assay %) are
tabulated. The Average Assay %, SD and RSD are calculated and shown in the
tabulations. Target values for RSD = 1.5 to 3.0.
METHOD REPRODUCIBILITY
SAMPLE No
Batch No:
ASSAY %
1
2
3
4
5
6
7
8
9
10
Average Assay %
Standard Deviation
Relative Standard
Deviation.
=
=
= 1.5 - 3.0
[4] Ac c ur ac y
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
Ed. Status :
New
DD/MM/YY
_____________ __________ _______________ _________/________
[4] Ac c ur ac y (continued).
A C C U R A C Y
INJECTION
No
PEAK
AREA
CALCULATED
CONC.
%
ACCURACY
1
2
3
4
5
6
7
8
9
10
Mean (% Accuracy) =
Standard Deviation =
% Coef. of Variation =
[5] Rec over y (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
Ed. Status :
New
DD/MM/YY
_____________ __________ _______________ _________/________
[5] Rec over y (Extraction time - tabulations continued).
The Results (Extraction time and Assay %) are tabulated as shown.
RECOVERY - EXTRACTION
TIME IN MINUTES
Batch No:
% ASSAY
0.5 T
T
1.5 T
[6] Rec over y (spiked placebo samples).
Five spiked admixtures of the active substance and the non-active vehicle (placebo)
at concentrations of about 50 % to 150 % of the stated concentration required by the
assay procedure is prepared and analyzed to show the percentage active recovery.
Two HPLC injections are performed per method assay and the peak areas are
averaged.
The Results (Theoretical conc. Actual conc. and % recovery ) are tabulated.
The Average Recovery, SD and the % Coefficient of Variation are given.
APPROVED
Ed. Status :
New
DD/MM/YY
_____________ __________ _______________ _________/________
[6] Rec over y (spiked placebo samples tables - continued).
The recovery results are shown graphically (peak area Vs conc. (mg/100 mL).
These results also show extraction method and detector linearity.
RECOVERY
Standard solution mg/100mL Peak Area =

CONC.
Theoretical
(mg/100ml)
PEAK AREA
FOUND
CONC.
FOUND
(mg/100ml)
PERCENTAGE
RECOVERY
50
75
100
125
150
Mean (% Recovery) =
% Coef of Variation =
The Linear Regression value, Slope and Y-Intercept are shown in the GRAPH.
The placebo chromatogram (vehicle only) is shown to highlight the absence of
Additional Peaks
[7] Li near i t y and r ange.
The linearity on an analytical procedure is its ability (within a given range) to obtain
test results which are directly proportional to the concentration (amount) of the
analyte in the test sample.
Five Standard solutions in a concentration range of (about) 50 % to 150 % of the
stated concentration required by the assay procedure are prepared and analyzed by
the stated method.
Two HPLC injections are performed per method assay and the peak areas are
averaged.
APPROVED
Ed. Status :
New
DD/MM/YY
_____________ __________ _______________ _________/________
[7] Li near i t y and r ange - (continued).
The Area count and concentration range is plotted. Linear regression analysis will
demonstrate the acceptability of the method for quantitative analysis over the full
spectrum of the concentration range. Detector linearity is demonstrated.
The Results (Range conc. and peak areas ) are tabulated.
LINEARITY AND RANGE
CONC.
Batch No:
PEAK AREAS
50 %
75 %
100 %
125 %
150 %
Linear Regression
Y-Intercept
Slope
=
=
=
The results are shown graphically (peak area Vs range conc. (mg/100 mL).
GRAPH OF LINEARITY
Conc. mg/100mL
P
e
a
k

A
r
e
a
0
20000
40000
60000
80000
100000
120000
0 25 50 75 100 125 150
APPROVED
Ed. Status :
New
DD/MM/YY
_____________ __________ _______________ _________/________
[8] RUGGEDNESS & Robust ness.
Ruggedness measures the lack of external influence on the test results whereas
robustness measures the lack of internal influences on the test results.
The Robustness of an analytical procedure is a measure of its capacity to remain
unaffected by small but deliberate variations in method parameters and thus
providing an indication of its reliability normal usage.
The method may be evaluated for specificity using two different columns.
No differences in specificity, selectivity or column performance should be observed.
Robust ness
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)
C O N D I T I O N R E S U L T S
Condition
No.
Column Flow Rate
mL/min
Buffer
Conc. (%)
RRT T
f
RSD
bet. LOQ of
[Active]
RSD
bet. LOQ of
[Impurity]
1 1 2.5 0.1 0.3 1.1 <10 <10
2 1 2.2 0.1 0.3 1.1 <10 <10
3 1 2.8 0.1 0.3 1.1 <10 <10
4 1 2.5 0.15 0.3 1.1 <10 <10
5 2 2.5 0.1 0.3 1.1 <10 <10
Notes on different terms frequently used:
INTERMEDIATE PRECISION
The analytical variation expressed between laboratories on different days; 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
Ed. Status :
New
DD/MM/YY
_____________ __________ _______________ _________/________
[8] RUGGEDNESS & Robust ness - (Tabulations - continued).
The Results (Average assay % for Analyst 1 and 2 ) are tabulated.
RUGGEDNESS
ANALYST
No 1
%
ASSAY
Column I
ANALYST
No 2
%
ASSAY
Column 2
1
2
3
4
5
6
7
8
9
10
Mean (% Accuracy) =
% Coef of Variation =
Robust ness.
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
Ed. Status :
New
DD/MM/YY
_____________ __________ _______________ _________/________
[9] St abi l i t y of St andar d sol ut i ons
Re-chromatography of ten replicate single injections of the same standard solution
(which have been allowed to stand for x hours ) against freshly prepared Standards
showed no significant differences from the original results.
STABILITY OF STANDARD SOLUTIONS
mg/100mL
Initial Analysis
(Date)
mg/100mL
Repeat Analysis
2nd (Date)
1 injection
2 injection
3 injection
4 injection
5 injection
6 injection
7 injection
8 injection
9 injection
10 injection
1 injection
2 injection
3 injection
4 injection
5 injection
6 injection
7 injection
8 injection
9 injection
10 injection
Mean
Standard Deviation
Relative Standard Dev.
=
=
= NMT 2.0 %
[10] Typi c al Chr omat ogr ams.
Representative chromatograms of the following traces are routinely provided:-
System Suitability
Standard Solution
Drug Product
placebo
APPROVED
Ed. Status :
New
DD/MM/YY
_____________ __________ _______________ _________/________
Typi c al Chr omat ogr ams
When Representative Chromatograms are displayed - all peaks are LABELED with
the peak name and RRT.
Representative chromatogram
Drug Product
[11] Conc l usi on.
(Closing Statement)
An appropriate conclusion should be given stating clearly that:
The method # IAG00-005 Ed. No [00] is shown to be accurate and precise for
carrying out assay analysis as part of the Assay and Stability Studies for the Drug
Product conforming to the formula as shown in Appendix 1
[ 12] Ref er enc es and Appendi x es.
Acknowledgment to references as well as attachments such as the drug product
formula are attached at the end of the validation protocol.
It is important to emphasize that analytical validation applies to a drug formula and
a set manufacturing procedure. Extraneous peaks and processing stresses are
specific to a manufacturing procedure, equipment used and the nature of the
excipients.
References:
1. "Validation of compendial methods" USP 23 <1225> USPC Rockville Maryland USA 1994.
2. USP/NF XXIII USPC Rockville Maryland USA 1994.
3. Scale up and Post approval Changes Manufacturing and Controls In vitro Dissolution and In Vivo
Bioequivalence Documentation CEDER 1995 (SUPAC)
4. International Conference on Harmonization "Guidelines on validation of Analytical Procedures:
Definitions and Terminology; Federal Register (March 1, 1995.)
5. ASTM Standard Guide For Conducting Ruggedness Tests E1169 American Society for testing
Materials Philadelphia 1989.
6. G. Kateman and L. Buydens, The Ruggedness Test Quality Control in the Analytical chemistry
John Wiley and Sons NY 2nd Edition 1993, pp118 125.
Label the peak
clearly
Name and Retention
time (8.78 min)
.
24 V 24 Volume D Dr ug D Development S Ser ies Sect: 16.1 Or al Or al TABLETS
SECTION XVI SECTION 16
St abi l i t y of Fi ni shed Dosage For m
TABLE OF CONTENTS
Section Page and Title.
Expiration Dating Period Statement
Stability Protocol for Post Approval Production Batches (ANDA commitment)
Stability Reports indicating results of Pivotal lot from 3 months accelerated
and controlled room temperature studies
Package Configuration and sizes (largest and smallest) used in stability
studies.
Stability Protocol used for Pivotal lot
Stability Data Summary Report (plus graphs).
4
Proposed expiration date and stability commitment
Stability protocol for post-approval production batches
Summary of Stability summary
Stability reports containing data from 3 month accelerated and 6 months controlled
room temperature studies
Package Characteristic of pivotal batch
OVERVIEW
Stability testing is performed on the largest and smallest container-closure systems
proposed for marketing; i.e. in each material type, namely plastic (HDPE/HDPP), glass, or
push-through blister packs.
When more than one closure for the same container material type (e.g. glass bottle) is
used in the proposed marketing containers, the largest and smallest container-closure
configuration is tested, - for both accelerated and long term studies.
In cases where plastic bottles of the same size range and shape are manufactured from
different thermoplastic resins, they exhibition different storage characteristics and thus are
considered as completely separate container-closure systems.
The number of stability tests conducted can be quite large in such cases. The example
below for the following packaging configuration highlights the number of stability tests
needed. Tests can be reduced using a matrix stability protocol.
1. Glass bottle with plastic Child Resistant Cap (CRC) and metal-screw cap
2. HDPP (1) container with plastic Child Resistant Cap and a HDPE screw-on cap
3. HDPP (2) container with plastic Child Resistant Cap and a HDPE screw-on cap
when tested in the largest and smallest container-closure configuration at accelerated and
long term testing will produce 24 separate stability protocols.
Calculation.
(3 containers x [largest & smallest size] x 2 closures x [25 C+40 C] = 24 studies).
4
Proposed Expiration Date
and Stability Commitment
ll stability data support the proposed expiration period of 2 years when the product is
stored at room temperatures.
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 annual ANDA Reports filed on the anniversary
date of the submitted product.
[Generic Company Name Inc. / Ltd.] commits to remove any batch promptly from the
market place any material falling outside the products check specifications.
Extensions to the expiration date will be made via the annual ANDA Reports as
acceptable long term stability data is obtained,
------------------------------------------------ -----------------------------------------
4
A
Stability Protocol for Post-approval Production Batches
[Generic name] TABLETS [USP] [000.0] mg. [Batch No: [IA00-00-00]
FINISHED PRODUCT STABILITY PROTOCOL
Package sizes: Smallest and largest containers
Storage Conditions
Controlled Room Temperature: 25-30C.
Test Intervals: 0,3,6,9,12,18,24 and 36 months.
Samples: First three marketable production batches and annual batch thereafter.
Storage Conditions
Accelerated Temperature: 40C / 75%RH.
Test Intervals: 1, 2, 3 months.
Samples: To be submitted as appropriate in supplements to the approved application
Stability Testing.
All test results will be subjected to compliance with current official requirements of the
approved applications and all supplements approved thereafter.
Test parameters will include:
TEST PROCEDURE TEST METHOD
& ED. NUMBER
SPECIFICATION
1 Appearance SI-P-000-01 Conforms
2 Assay SI-A-000-01 90.0 - 110.0% of labeled amount
IMPURITIES / DEGRADATION PRODUCTS
3 - Each Individual
- Any other Individual
- Total:
SI-A-000-01
SI-A-000-01
SI-A-000-01
NMT 0.5% of the labeled amount
4 Dissolution SI-D-000-01 NLT 00% (Q) in 00 min.
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) Stability Start Date
10) Manufacturing Site
11) Manufacturer of Bulk Drug
12) Inventory Control Number of (11)
13) Manufacturer of Container/Closure
14) Formulation
15) Data profile
16) Methodology and Specifications
SUMMARY OF STABILITY STUDIES
The 3 months accelerated (40 2C / 75 RH 5% ) and 6 months room temperature (25
2C / 60 RH 5%) stability data were examined for [Generic name] TABLETS [USP]
[000.0] mg.
The data indicate that the formulation is stable, with no observed degradation, under test
conditions. No significant change in either chemical or physical attributes was noted in
any sample under any of the storage conditions.
The attached tables and graphs are summaries of the results for the parameters used to
establish the stability profile of [Generic name] TABLETS [USP] [000.0] mg.
[Generic name] TABLETS [USP] [000.0] mg. were stored at accelerated conditions (40
2C / 75% RH 5%) and at room temperature (25 2C/ 60% RH 5%) in the proposed
market container/closure system.
All stability data support the proposed expiration period of 2 years when the product is
stored at room temperatures.
SUMMARY OF STABILITY STUDY RESULTS.
HDPE Container Closure liner system
25C 60%RH 40C 75%RH
Small Large Small Large
30cc HDPE Metal Screw Cap q q
30cc Child Resistant Closure (CRC Cap) q q
300cc Child Resistant Closure (CRC Cap) q q
300cc HDPE Metal Screw Cap q q
GLASS CONTAINER CLOSURE LINER SYSTEM

Blister packaging

BULK PACKAGING
Bulk Packaging
Number of Studies Performed 10
Number of resins used in the HDPE containers = one resin from same supplier.
STABILITY REPORT
1 Product name, dosage form and strength. Generic name] [000.0] mg.
2 Fill size 100 Tablets [USP]
3 Site of Manufacture NJ MNF SITE
4 Batch or lot number [IA-0000-00]
5 Batch size (type) 200 000 Tablets [USP]
6 Batch manufacturing Date and Packaging Date Month DD, 200Y / Month DD, 200Y
7 Manufacturer of Active Material (approved supplier) LEK Chemical Co. dd
8 Date placed on stability Month DD, 199Y
9 Batch number or receiving number of Active Material LK 2323
10 Full details of container/closure system (type, material, resin) 100cc HDPP (LR-7340-43) Screw-on
HDPP white cap (resin LR-7340-43)
11 Goods Receiving number of container-liner GRN 96-2-02234 (body)
Goods Receiving number of closure GRN 96-2-02237 (cap)
12 Manufacturer of container/closure Wheeler Cap Co PA USA.
13 Objective of the stability program Pivotal Batch
14 Site where stability test conducted US PA MAN Site
15 Number of units to be sent for testing in each time interval 2 x 100
16 Analytical method number and Edition Number for each stability indicating testS-I A00-22-24 / S-I A0023 Ed . 01
17 Stability specifications indicating names of test required. Tabulated
18 Number of packages placed on stability 70
19 Testing intervals required 0, 1, 2, 3 months
20 Stability storage conditions 40 degrees C / 75% RH
Stability
Parameters
Storage
Period
Date of
Analysis
Appearance ASSAY
Percentage
D I S S O L U T I O N
Percentage of label claim dissolved in 45 minutes
SPECIFIC-
ATIONS
Months White to
Off-White
90.0 % -
110.0%
NLT 80% (Q) in 45 minutes

Method # S-I 551 -02 S-I 555 -03 S-I 1234 Ed. 03 Mean C.V.
0 1/6/96 conforms 100.3 98.2 99.8 95.2 98.2 99.5 98.3
95.2 94.2 96.2 98.3 99.1 99.8 96.4 2.1
1 15/7/96 conforms 99.8 95.2 94.2 99.2 98.3 99.1 99.8
95.9 94.2 99.0 96.2 98.3 99.1 97.5 2.4
2 16/8/96 conforms 101.3 95.7 94.2 99.2 96.2 98.3 99.1
97.2 94.2 99.2 96.8 98.3 99.1 98.1 1.7
3 15/9/96 conforms 101.4 95.6 94.2 96.2 98.3 99.1 99.2
94.2 99.2 96.5 99.1 99.8 101.5 99.0 2.2
21. Product Formula On Stability (Formula N
o:
S000).
Active material 23.60

Povidone USP 9.00
Starch NF 5.30

Starch NF (Redried) 27.00
Purified Water USP (Processing Solvent Only)
STABILITY REPORT
1 Product name, dosage form and strength. [Generic name] [000.0] mg.
2 Fill size 100 Tablets [USP]
3 Site of Manufacture NJ MNF SITE
4 Batch or lot number P-5432
5 Batch size (type) 200 000 Tablets [USP]
6 Batch manufacturing Date and Packaging Date DD/MM/YY / May 28, 200Y
7 Manufacturer of Active Material (approved supplier) LEK Chemical Co. dd
8 Date placed on stability June DD, 200Y
9 Batch number or receiving number of Active Material LK 2323
10 Full details of container/closure system (type, material, resin) 100cc HDPP (LR-7340-43) Screw-on
HDPP white cap (resin LR-7340-43)
11 Goods Receiving number of container-liner GRN 96-2-02234 (body)
Goods Receiving number of closure GRN 96-2-02237 (cap)
12 Manufacturer of container/closure Wheeler Cap Co PA USA.
13 Objective of the stability program Pivotal Batch
14 Site where stability test conducted US PA MNF Site
15 Number of units to be sent for testing in each time interval 2 x 100
16 Analytical method number and Edition Number for each stability indicating testS-I A-0323/34/35 / S-I 0024 Ed . 01
17 Stability specifications indicating names of test required. Tabulated
18 Number of packages placed on stability 70
19 Testing intervals required 0, 1, 2, 3 6months
20 Stability storage conditions 25degreesC/60% RH
Stability
Parameters
Storage
Period
Date of
Analysis
Appearance ASSAY
Percentage
D I S S O L U T I O N
Percentage of label claim dissolved in 45 minutes
SPECIFIC-
ATIONS
Months White to
Off-White
90.0 % -
110.0%
NLT 80% (Q) in 45 minutes
Method # S-I P022 -02 S-I A024 -03 S-I D024 Ed. 03 Mean C.V.
0 1/6/96 conforms 100.3 98.2 99.2 95.2 98.2 99.5 98.3
95.2 94.2 99.0 98.3 99.1 99.8 96.4 2.1
3 15/8/96 conforms 99.8 95.2 94.2 99.2 96.2 98.3 99.1
95.9 94.2 99.0 96.2 98.3 99.1 97.5 2.4
6 6/11/96 conforms 101.3 95.7 94.2 99.2 96.2 98.3 99.1
97.2 94.2 99.2 96.8 98.3 99.1 98.1 1.7
9 15/2/97 conforms 101.4 95.6 94.2 99.3 96.2 98.3 99.1
94.2 99.2 98.0 99.1 99.8 101.5 99.0 2.2
12 5/5/97 conforms 100.4 98.2 95.2 96.2 98.3 99.1 99.2
99.0 96.2 98.3 99.1 99.8 101.5 99.0 1.2
18 5/1197
24 5/5/98
21. Product Formula On Stability (Formula N
o:
S000).
Active material 23.60

Povidone USP 9.00
Starch NF 5.30

Starch NF (Redried) 27.00
Purified Water USP (Processing Solvent Only)
PACKAGE CHARACTERISTICS
[Generic name] TABLETS [USP] [000.0] mg. [Batch No: [IA00-0000]
Pivotal Lot Packaging Characteristics
Amount 30 Tablets 100 tablets 30 tablets 100 tablets
Container
manufacturer
Drug Plastics & Glass
Co Inc.
Drug Plastics & Glass
Co Inc.
BROCKWAY Glass BROCKWAY Glass
Container
size
60 cc round, White
HDPE container
60 cc round, White
HDPE container
50 cc amber glass
bottle
50 cc amber glass
bottle
Resin Type
HDPE
Quantum LR-7340-43
HDPE
Quantum LR-7340-43
--- ---
11087 PE
White
Masterbatch
White Ampacet 11078
Polyethylene
White Ampacet 11078
Polyethylene
Amber Glass Amber Glass
Cap
Manufacturer
Owens-Illinois U.S. CAN
(Penn-Wheeling
Closure Corp.)
Owens-Illinois U.S. CAN
(Penn-Wheeling
Closure Corp.)
Cap Type
Child Resistant Cap Metal Screw Cap Child Resistant Cap Metal Screw Cap
Cap Size
31 mm 31 mm 31 mm 31 mm
Closure Liner
Manufacturer
Tekni-Plex Inc. Tekni-Plex Inc. Tekni-Plex Inc. Tekni-Plex Inc.
Inner liner
composition
TEKNISEAL RVT
+ LF
TEKNISEAL X-14
(polyethylene/Kraft
Paper laminate)
- -
Adhesive Foam
Seal - Tamper
Evident

Foamseal PS 22 Foamseal PS 22 Foamseal PS 22 Foamseal PS 22
Pharmaceutical
Cotton coil
Manufacturer
American White
Cross* or American
Fiber and Finishing
American White
Cross* or American
Fiber & Finishing
American White
Cross* or American
Fiber & Finishing
American White
Cross* or American
Fiber and Finishing
Cotton Coil
Snopure cotton coil
(9 or 20 g)
Snopure cotton coil
(9 or 20 g)
Snopure cotton coil
(9 or 20 g)
Snopure cotton coil
(9 or 20 g)
PACKAGE CHARACTERISTICS - BULK
[Generic name] TABLETS [USP] [000.0] mg. [Batch No: [IA00-000]
Pivotal Lot Packaging Characteristics
Fill size [00] kg Bulk
Polyethylene
bag
manufacturer
(Transparent)
[Manufacturing Company Name Inc. / Ltd.]
[Address]
Size Ht [00] x Wt [000] cm, [0.0] mm thickness
Composition Low Density Polyethylene [Name]:
Resin [000], Transparent
Polyethylene
bag
manufacturer
(Black)
[Manufacturing Company Name Inc. / Ltd.]
[Address]
Size Ht [00] x Wt [000] cm, [0.0] mm thickness
Composition Low Density Polyethylene [name]:
Resin PE [000]
24 VOLUME DRUG DEVELOPMENT SERI ES: Sect: 17.1 Drug Development
SECTION XVII SECTION 17
Reser ved
TABLE OF CONTENTS
17.1 RESERVED
This section is reserved:
ELECTRONIC FORMATTED ANDAs
Proposed use is anticipated for electronic formatted ANDAs
4
SECTION XVII SECTION 17
RESERVED
THIS SECTION HAS BEEN RESERVED FOR FUTURE USE.
ELECTRONIC FORMATTED ANDAs
Proposed use is anticipated for electronic formatted ANDAs
4
SECTION XVIII SECTION 18
Sampl es of Dr ug/Ar t i c l e Component s
TABLE OF CONTENTS
18.1 Section Page and Title
18.2 Statement on Sample Submission Procedures to FDA on request
18.3 Drug substance
18.4 Finished drug product
18.5 Reference Standards with appropriate identification, graphs and
spectra
Section XVIII.
Samples ( 3l4.94(a)(l0)). Sample availability and identification of:
1. Drug substance
2. Finished dosage form
4
SECTION XVIII SECTION 18
Samples of Drug/ Article Components
SAMPLES OF THE
DRUG AND ARTICLES
USED AS COMPONENTS
21 CFR Section 314.50 (e) (1).
[Generic Company Name Inc./Ltd.] shall submit samples of the drug
substance or the finished drug product or otherwise make such samples FDA,
in accordance with their instructions and requirements pertaining to 21 CFR
Section: 314.50 (e) (1).
Furthermore the [Generic Company Name Inc./Ltd.] shall submit appropriate
REFERENCE STANDARDS with appropriate identification, graphs and spectra
as required.
__________________________ ___________________
[ Gener i c Company Name I nc . Lt d.]
4
24 VOLUME DRUG DEVELOPMENT SERI ES: Sect: 19.1 ANDA ANDA DEVELOPMENT
SECTION XIX SECTION 19
Envi r onment al I mpac t Anal ysi s Repor t s
TABLE OF CONTENTS
19.1 Section Page and Title
19.2 Environmental Exclusion Assessment
- Development Site
19.3 Applicable Environmental Laws (National / State / Local /Foreign)
- Development Site
19.4 Site Environmental Certification
- Development Site
19.5 Statement on Environmental Compliance
- Development Site
19.6 Commercial Plant Manager and QA Director Signatures.
FDA's Published January 1999 ANDA Guideline requirements:-
1. Environmental Consideration: Environmental Assessment (EA)
or
2. Claim of Categorical Exclusion ( 3l4.94(a)(9))
4
Environmental Impact Analysis Reports
Requests for Categorical Exclusion
Environmental Regulations Compliance Certification
Environmental Regulations Compliance Certification (Foreign Firms)
Site Environmental Certification (USA)
OVERVIEW
This section is used for clarifying the various ENVIRONMENTAL PROTECTION
REQUIREMENTS that apply to the development and the manufacturing environment.
Note:-
Where the development and/or the manufacturing of the drug product is performed in
a foreign country, the applicable National Environmental laws of the country need to
be closely observed. Statements of Environmental Compliance with respect to:-
1. Toxic waste
2. Waste disposal
3. Environmental Compliance Laws
need to be addressed with appropriate signed certification by senior responsible
personnel.
The FDA needs to see that there was no infringement of the local countries
Environment and Waste Management laws in BOTH the development and
manufacture of the drug product or the drug's Active Ingredient.
4
REQUEST FOR CATEGORICAL EXCLUSION
FROM REQUIREMENTS OF AN
ENVIRONMENTAL ASSESSMENT,
21 CFR 25.31(a).
[Generic Company Name Inc./Ltd.] hereby requests a categorical exclusion [in
accord with 21 CFR 25.23(c) and 21 CFR 25.24(c)(1)] from the requirement of
an Environmental Assessment Statement [21 CFR 25.31(a)].
This request is based on two facts:
1. The finished drug product which is the subject of the Abbreviated New Drug
Application will not be administered at higher dosage levels, for longer duration,
or for different indications than previously in effect for the listed drug product
(RLD) as stated more fully in section IV of this application.
2. Data available to the Agency does not establish that, at the expected level of
exposure, the substance may be toxic to organisms in the environment.
On the basis of the forgoing statements [Generic Company Name Inc./Ltd.]
submits that an Environmental Impact Analysis Statement is not required
with this application and, therefore requests that it be categorically
excluded from the requirements to submit an Environmental Impact
Analysis.
___________________________________ _________________
Director Pharmaceutical Research & Development
[ Generic Company Name Inc./Ltd.]
STATEMENT OF ENVIRONMENTAL
COMPLIANCE
The undersigned hereby certifies that [Generic Company Name Inc./Ltd.] operates
its [Address] manufacturing facility in compliance with all local and national
environmental laws and with the emission requirements set forth in all permits. The
undersigned further certifies that the approval and subsequent increase in production
at the facility is not expected to affect compliance with current emission requirements
or compliance with environmental laws.
__________________________ ___________________
Pl ant Manager
__________________________ ___________________
STATEMENT OF ENVIRONMENTAL
COMPLIANCE
FOREIGN SITE
Development and manufacturing
The undersigned hereby certifies that [Generic Company Name Inc./Ltd.] operates
a certified waste disposal program its [Address] manufacturing facility which is in full
compliance with all Local, State and National environmental laws and with the
emission requirements set forth in all required permits.
The undersigned further certifies that the approval and subsequent increase in
production at the facility is not expected to affect compliance with current emission
requirements or compliance with environmental laws.
__________________________ ___________________
Pl ant Manager
__________________________ ___________________
[ Gener i c Company Name I nc . Lt d. ]
Site Environmental
Certification
The undersigned hereby certifies that [Generic Company Name Inc. / Ltd.].
maintains compliance with all appropriate Federal, Sate and Local environmental
laws and regulations in the distribution of [Generic name] Dosage Form [USP]
[000.0] mg.
__________________________ ___________________
Pl ant Manager
__________________________ ___________________
333
SECTION XX SECTION 20
Gener i c Dr ug Enf or c ement Ac t
TABLE OF CONTENTS
20.1 Section Page and Title and Color Tag
20.2 Generic Drug Enforcement Act
20.3 U.S. Agent Letter of Authorization
1. Generic Drug Enforcement Act
2. U.S. Agent - Letter of Authorization
4
Applicant or Agent Letterhead
STATEMENT
Where Company has NO previous convictions
AND does not use a debarred person in connection with the ANDA
to the
n behalf of [Generic Company Name's Inc. / Ltd.], the applicant, I hereby
certify, pursuant to Section 2(k) Generic Drug Enforcement Act of 1992, 21 USC
335a (k), that the applicant has not used, is not using and will not in the future use in
any capacity the services of any person who has been debarred pursuant to Section
2 (a) and or Section 2 (b) Generic Drug Enforcement Act of 1992, 21 USC 335a (a)
and/or (b), in connection with this application.
Applicant further certifies that there have been no conviction of applicant for any of
the types of crimes set forth in Section 2(a) and Section 2(b) of the Generic Drug
Enforcement Act of 1992, 21 USC 335a (a) and/or (b), within the five years prior to
the date of this certification, nor has any person affiliated with the applicant, who is
responsible in whole or in part, for the development or the submission of this
application been convicted of any crime of the type listed in Section 2(a) and Section
within the five years prior to the date of this certification.
------------------------------------------------ ---------------------------------------
--
__________________________ ______________________
[ Gener i c Company Name I nc . Lt d. ]
O
STATEMENT
Where Company has a previous conviction
but does not use a debarred person in connection with the ANDA.
to the
n behalf of [Generic Company Name's Inc. / Ltd.], the applicant, I hereby
certify, pursuant to Section 2(k) Generic Drug Enforcement Act of 1992, 21 USC
335a (k), that the applicant has not used, is not using and will not in the future use in
any capacity the services of any person who has been debarred pursuant to Section
2 (a) and or Section 2 (b) Generic Drug Enforcement Act of 1992, 21 USC 335a (a)
and/or (b), in connection with this application.
Applicant further certifies that during the previous five years it has sustained the
following conviction for the types of offenses as set forth in Section 2(a) and Section
Date of Conviction MM/DD/YY
Nature of Conviction Conviction on six counts of fraudulent documentation
pertaining to stability reports.
To the best of [Generic Company Name's Inc. / Ltd.] knowledge no 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
certification.
------------------------------------------------ -----------------------------------------
O
Let t er of Aut hor i zat i on - US Agent
[ PRI NTED ON US APPOI NTED AGENTS LETTERHEAD]
n behalf of [Generic Company Name's Inc. / Ltd.], I, [ US APPOI NTED
Appl i c ant ' 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 APPOI NTED APPLI CANT
[Applicant Company Site Address]
Full Site Address
[Applicant Company Contact Numbers]
Contact Person. Responsibility. Tel. Fax.
Director of
Registration
Quality Assurance
Director
4
O
SECTION XXI SECTION 21
Addi t i onal I nf or mat i on
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 as well as the following four categories
1. References to information that has been previously submitted by applicant
2. English translations of literature publications
3. Letters of Authorization (when referring to third party data (e.g. DMF) on file with
the FDA) - Always provide TWO copies of actual LOA
4. Field Copy Certification (+proof of delivery - i.e. photocopy of courier Fedex / DHL
delivery Form and date of Fedex / DHL pick-up. Avoid where possible registered mail
and postal return (red) cards)
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.
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.
Do not use this section for manufacturing steps that do not require support data and
are classified as minor procedures such as fluid bed drying operations that may
require additional drying to reach the required target moisture content (LOD %) of the
granule. These conditional procedures are highlighted as standard instructions in the
manufacturing method or manufacturing instructions.
1. Reference to previously submitted information ( 3l4.94(a)(11))
2. Literature publication for which English translation is submitted ( 3l4.94(a)(11))
3. Letters of authorization (two copies)
4. Field Copy Certification.
T
Addi t i onal I nf or mat i on
REFERENCING PREVIOUS SUBMITTED INFORMATION
References to information that has been previously submitted to the FDA by applicant
under 21CFR 314.94 [a][11]
Applicants need to provide precise and detailed Reference Data to the FDA in order
to clearly identify the previously submitted file. Remember any referrals to a
previously submitted file or data will marginally slow down the approval process (refer
to thirteen commandments Section XXII)
1. Date supplied to FDA MM/DD/YY
2. File Name at FDA
3. Volume Number of File at FDA
4. Reference Number of File at FDA
5. Actual Document Name of File at FDA
6. Page Number where reference data is available
Additional Information
TABLE OF CONTENTS
21.1 Outline of manufacturing re-work study
21.2 Table of DMF Numbers (with LOA dates)
Special Note:
DMF numbers are required for active / excipient materials.
Active material
Specific Excipients
Capsules
Colors/dyes
Film coating color premixes
DMF numbers are required for container/closure materials.
Primary Material in direct contact with the drug product e.g.
Plastic containers
Plastic caps
Plastic closures
Plastic liners
Plastic seals
Plastic application nozzles
(Glass bottles are exempt from a DMF number)
Product DMF numbers are required for container closure material that is a;
Secondary Material in indirect contact or during use of the drug product e.g.
Inner Liners
Closure seals
Epoxy Coated Liners (tubes)
Foam Seals
Cotton Wool
Silica gel drying agent in plastic containers
Measuring caps as an integral part of closure system.
MNF DMFs
Manufacturing DMF numbers are required for the manufacturing facility supplying the
raw material.
LOAs
Letters of Access (recent date is essential) are required for all referenced DMF
numbers.
SUMMARY OF DMF NUMBERS USED IN THIS APPLICATION:
Raw Material / Component
DMF No.
Active Material(s)
Active material for Biostudy and Pivotal DMF
Alternative Supplier DMF
Alternative Supplier DMF
Non active Materials
Non-compendial Excipient I DMF
Non-compendial Excipient II DMF
Color / Pigment (US Certification) Yes
Color / Pigment (US Certification) Yes
Coating material / Premix DMF
Capsules DMF
Container-closures
HDPE Container DMF
HDPE Container DMF
HDPE Cap DMF
Metal Cap DMF
Cap liner DMF
Adhesive Tamper evident inner-seal DMF
Silica Gel /Other DMF
Cotton Coil DMF
Thermoplastic Resins and Master Batch Dyes
Resin No [A000] DMF
Resin No [B000] DMF
Resin No [C000] DMF
Master Batch White DMF
Master Batch color DMF
SUMMARY OF LOA LETTERS BY DATE AS USED IN THIS APPLICATION:
Raw Material / Component
LOA date.
Active Material(s)
Active material for Biostudy and Pivotal LOA
Alternative Supplier LOA
Non active Materials
Capsules LOA
Color / Pigment (US Certification) Cert.
Coating materials LOA
Container-closures
HDPE Container DMF
HDPE Container DMF
HDPE Cap DMF
Metal Cap DMF
Cap liner DMF
Adhesive Tamper evident inner-seal DMF
Silica Gel /Other DMF
Cotton Coil DMF
Thermoplastic Resins and Master Batch Dyes
Resin No [A0000] of THERMOPLASTIC container DMF
Resin No [B0000] of Cap DMF
Resin No [C0000] of CRC OUTER component DMF
Resin No [D0000] of CRC INNER component DMF
Master Batch White DMF
Master Batch color DMF
Resin No [E0000] LOA
Resin No [F0000] LOA
Resin No [G0000] LOA
Master Batch White LOA
Master Batch color LOA
No LOA date greater than two years. Change in Ownership show new DMF Holder.
FIELD COPY
Date:
District Director
District OFFICE ADDRESS
District ZIP CODE
State

FI ELD COPY CERTI FI CATI ON
US Appl i cant s:
Dear District Director,
1. [Applicant Company Name Inc. / Ltd.] has submitted on the MM/DD/YY by
courier an original abbreviated New Drug Application (ANDA) seeking approval to the
US market of the drug product [NAME] Drug Strength [00.0] and [00.0]mg.
2. The [Generic NAME] Drug Strength [00.0]mg are bioequivalent to the Reference
Listed Drug [RLD] as manufactured by [RLD's Inc. Address] pursuant to NDA #00-
0000.
3. This FIELD COPY which is a true field copy of the same technical sections
(chemistry, manufacturing and controls and including a copy of the 356h form) of the
application is identical to the original copy that has been submitted to the appropriate
Office of Generic Drugs FDA Maryland. The field copy is submitted in the standard
burgundy colored folder.
Please be so kind as to direct written correspondence with regard to this submission
to the undersigned writer. Please direct calls or facsimiles directly to me as per
contact numbers shown in the signature line.
S i gnature
Tel (Di r ec t ) 202-000-000
Fax 202-000-001
Note Difference
Address is to District Director
District Office
(e.g. NJ)
FIELD COPY
[Field is sent to FDA Headquarters OGD and may be forwarded tot the Office of
Compliance used for overseas PAI foreign inspections]
Date:
Metro Park North II
7500 Standish Place
Dear Office of Generic Drugs
For ei gn Appl i cant s:
1. [Applicant Company Name Inc. / Ltd.] has submitted on the MM/DD/YY by
courier an original abbreviated New Drug Application (ANDA) seeking approval to the
US market of the drug product [NAME] Drug Strength [00.0] and [00.0] mg.
2. The [Generic NAME] Drug Strength 00.0 mg are bioequivalent to the Reference
Listed Drug [RLD] as manufactured by [RLD's Inc. Address] pursuant to NDA # [00-
0000].
3. This FIELD COPY which is a true field copy of the same technical sections
(chemistry, manufacturing and controls and including a copy of the 356h form) of the
application is identical to the original copy that has been submitted to the appropriate
Office of Generic Drugs FDA Maryland. The field copy is submitted in the standard
burgundy colored folder.
Please be so kind as to direct written correspondence with regard to this submission
to the undersigned writer. Please direct telephone calls or facsimiles directly to me as
per contact numbers shown in the signature line.
S i gnature
Tel (Di r ec t ) +972-97-494-965
Fax +972-97-494-532
Note Difference
Address is FDA Headquarters
Maryland and not one of the FDA
District Office (e.g. NJ)
LETTERS OF AUTHORIZATION
Date:
Metro Park North II
7500 Standish Place
US Appl i cant s:
Certified copies of the relevant LETTERS OF AUTHORIZATION as referenced in
this applications are herewith attached:
TABLE OF LOAs ATTACHED
Letter of authorization Company Referenced LOA Item LOA Date
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
S i gnature
4
End of Section 21.
SECTION XXII SECTION 22
St er i l i zat i on Assur anc e
TABLE OF CONTENTS
This section applies to sterile processes:
Sterile Manufacturing Processes Only
Copies of the original batch manufacturing instructions in the language of origin
q Chinese q Dutch q French q Hebrew q Italian q Polish q Portuguese
q Spanish q _________
Section XXII.
Sterilization Assurance Information and Data
Note: This section can be provided as a separate volume for ease of review. If the
microbiology section is in a separate volume, please provide copies of the indicated
information that may be in other sections of the application instead of page
references.
1. General Information
a. Copy of cover letter (or page reference)
b. Label/package insert copy (or page reference)
c. Summary of manufacturing process including components and composition
statement (or page reference)
d. Copies of pages from completed batch production record containing
holding times,
filtration integrity testing
sterilization records (or page reference)
NOTE:-
Follow the portions of guidance for industry on Submission of Documentation for
Sterilization Process Validation in Applications for Human and Veterinary Drug
Products that apply to the process in the application.
4
24 VOLUME DRUG DEVELOPMENT SERI ES CMC DEVELOPMENT
Do's and Don'ts
13 Commandments
when Preparing an Application.
1. The less you make the reviewer work the sooner you get the application!
2. Make it really easy for agency reviewers to review your work.
3. Prepare the applications so that you drag the reviewer through it.
4. Don't challenge the FDA reviewer to think deeply.
5. Don't make them look for a copy of the Orange Book.
6. Don't make them go and find the suitability petition letter.
7. Do include every DMF # and GMP certification that you refer to.
8. Do prepare a detailed narrative where ever possible to give a quick
overview of what they can expect. Write confirmation narrative letters on all
protocol discussions.
9. Do make your narratives reader friendly - take your time writing them.
10. Don't exclude and executive summary just because its not a statutory
requirement - they really help to get the message across.
11. Do layout and assemble your application so that the reviewer can cruise
though it by making it a real joy to read.
12. Supply a PDF copy on CD ROM of the full application.
13. Do use the KISS principle - ' Keep it Simple Scientist '.
I n t e r n a t i o n a l A s s o c i a t i o n
Drug 2001 Manufacturers
High Quality Low Cost Drug Development & Manufacturing Excellence World Wide
I n n o v a t i v e & G e n e r i c
HANDBOOK OF
DRUG DEVELOPMENT
Series
Par t I - Dr ug Devel opment Par t I - Dr ug Devel opment
Par t I I - US Type Par t I I - US Type CMCs & EC DOSSI ERS CMCs & EC DOSSI ERS
US US
CHEMI STRY MANUFACTURI NG CONTROL CHEMI STRY MANUFACTURI NG CONTROL
Know How Technol ogy Know How Technol ogy
& &
EU EU
DOSSI ERS DOSSI ERS
Know How Technol ogy Know How Technol ogy
I n t e r n a t i o n a l A s s o c i a t i o n
Drug 2001 Manufacturers
High Quality Cost Effective Drug Development & Manufacturing Excellence World Wide
I n n o v a t i v e & G e n e r i c
HANDBOOK of DRUG DEVELOPMENT
+120 Title Specific Series
Par t I - Dr ug Devel opment Par t I - Dr ug Devel opment
Par t I I - US Type Par t I I - US Type CMCs or EC DOSSI ERS CMCs or EC DOSSI ERS
Generic Development ISSN Series number 0793 7407
Generic Development ISSN Series number 0793 7792 - Electronic Issue (Disk/CD ROM)
The follow HBGD HANDBOOKS KNOW-HOW SERIES are available in the most
common dosage forms namely solid, semisolid and liquid dosage forms. The
presentation of the actual data is based on manufactured production batches and
the format of all sections is similar to the data in the standard ANDA.
Drug Development Series Form Strength
Volume Part
Alendronate Sodium Tablets 5 - 10 mg Volume II 1 & 2
Alendronate Sodium Tablets 40 mg Volume II 1 & 2
Amitriphyline HCl Tablets 10 mg Volume II 1 & 2
Azithromycin Suspension 200 mg Volume II 1 & 2
Azithromycin Capsules 250 /600 mg Volume II 1 & 2
Azithromycin Tablets 600 mg Volume II 1 & 2
Atenolol EU Tablets 50 /100 mg Volume II 1 & 2
Atenolol US Tablets 50 /100 mg Volume II 1 & 2
Amoxicillin Capsules 250/500mg Volume II 1 & 2
Bromhexine Hydrochloride Tablets 8mg Volume II 1 & 2
Bromhexine Hydrochloride Syrup 8mg Volume II 1 & 2
Bromocriptine Mesylate Tablets 2.5mg Volume II 1 & 2
Bupropion Tablets 75.0/100 mg Volume II 1 & 2
Buspirone HCl Tablets 5 mg /10 mg Volume II 1 & 2
Carbamazepine (EU + US) Tablets 200mg Volume II 1 & 2
Carbamazepine (Chewable) Chewable Tab 100 mg Volume II 1 & 2
Carbamazepine (Extented Release)
Geigy TEGRATOL XR
Coated Tab 400 mg Volume II 1 & 2
Carbidopa/Levodopa Tablets 10/100 mg Volume II 1 & 2
Carbidopa/Levodopa Tablets 25/100 mg Volume II 1 & 2
Carbidopa/Levodopa Tablets 25/250mg Volume II 1 & 2
Carbidopa/Levodopa ER Tablets 50/200mg Volume II 1 & 2
Cefaclor Oral Suspension USP Suspension 125 /187 mg/5mL
Volume II 1 & 2
Cefaclor Oral Suspension USP Suspension 250/375 mg/5mL Volume II 1 & 2
Cefaclor Oral Suspension EU Suspension 250 mg/5mL Volume II 1 & 2
Cefaclor Capsules 250/500mg Volume II 1 & 2
Cefuroxime Sodium USP Vials 750-1500mg Volume II 1 & 2
Clonazepam Tablets USP Tablets USP 0.5/1.0/ 2.0mg
Volume II 1 & 2
Lat est Li st s ar e vi ew abl e on w eb ht t p://l oc umusa.c om/2go
+120 Series
Clomiphene Citrate Tablets USP 50mg Volume II 1 & 2
Clomipramine HCl Capsules 25/50 mg 1 & 2
Clomipramine HCl Capsules 75 mg Volume II 1 & 2
Diclofenac Potassium Tablets 50 mg Volume II 1 & 2
Diclofenac Sodium Tablets 50 / 75 mg Volume II 1 & 2
Diclofenac Sodium Tablets 100 mg Volume II 1 & 2
Diclofenac Sodium Clear Gel 10 mg/g Volume II 1 & 2
Dorzolamide HCL Ophthalmic Solution 2% Volume II 1 & 2
Etodolac Capsules 200/300mg Volume II 1 & 2
Etodolac Wyeth Lodine Tablets 400 mg Volume II 1 & 2
Etodolac Wyeth Lodine Tablets 500 mg Volume II 1 & 2
Enalapril Maleate Tablets 40 mg Volume II 1 & 2
Etidronate Disodium Tablets 0 mg Volume II 1 & 2
Famotidine Tablets 10 mg Volume II 1 & 2
Felodipine Tablets 5 mg Volume II 1 & 2
Felodipine Tablets 10 mg Volume II 1 & 2
Felodipine Extended Release Tablets 2.5 mg Volume II 1 & 2
Felodipine Extended Release Tablets 5 mg Volume II 1 & 2
Felodipine Extended Release Tablets 10 mg Volume II 1 & 2
Flunisolide Hemihydrate solution Nasal solution 1mg/5mL Volume II 1 & 2
Flunitazapam Tablets 2 mg Volume II 1 & 2
Fluoxetine Capsules 10 / 20 mg Volume II 1 & 2
Fusemide Capsules 40 mg Volume II 1 & 2
Gabapentin (=Neurontin-Park Davis) Capsules 100/200 mg Volume II 1 & 2
Gabapentin (=Neurontin-Park Davis) Capsules 300 /400 mg Volume II 1 & 2
Gemfibrosil Tablets 450 mg Volume II 1 & 2
Gemfibrosil Extended Release Tablets 600 mg Volume II 1 & 2
Glibenclamide Tablets 5 mg Volume II 1 & 2
Glipizide Extended Release Tablets 2.5 mg Volume II 1 & 2
Ibuprofen Tablets 200-800mg Volume II 1 & 2
Isosorbide Mononitrate Tablets 20 mg Volume II 1 & 2
Ketorolac Tromethamine Tablets 10 mg Volume II 1 & 2
Levodopa/ Benserazide HCl Tablets 200/50 mg Volume II 1 & 2
Labetalol HCL Tablets 100 +200mg Volume II 1 & 2
Labetalol HCL Tablets 300mg Volume II 1 & 2
Loperimide Tablets Volume II 1 & 2
Mesalamine (Enteric Coated) Tablets 400mg Volume II 1 & 2
Metformin HCl (Coated) Tablets 500 mg Volume II 1 & 2
Metformin HCl (Coated) Tablets 850 mg Volume II 1 & 2
Miconazole/Hydrocortazone Cream 2% + 1% Volume II 1 & 2
Miconazole Nitrate Cream 2% Volume II 1 & 2
Nabumatone Tablets 500 mg Volume II 1 & 2
Nabumatone Tablets 750mg Volume II 1 & 2
Copyright 1995-9 by Locum Publishing House Inc. All Rights Reserved. Neither this book nor any part may be reproduced 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
+120 Series
Naproxen (Enteric Coated) Tablets 250mg Volume II 1 & 2
Naproxen DR Tablets 375/500mg Volume II 1 & 2
Naproxen Sodium Tablets 220 mg Volume II 1 & 2
Naproxen Sodium Tablets 275/550 mg Volume II 1 & 2
Norfloxacin USP Tablets 400 mg Volume II 1 & 2
Ofloxacin Tablets
100/200/
400 mg Volume II 1 & 2
Oxolamine Syrup 10 mg/mL Volume II 1 & 2
Paracetamol - sugar/dye-free Syrup 125 mg Volume II 1 & 2
Paracetamol Chewable Fruit Flavors Tablets 160 mg Volume II 1 & 2
Pentoxifylline ER Tablets 400 mg Volume II 1 & 2
Penfluridol Capsules 10 mg Volume II 1 & 2
Piroxicam Capsules 20 mg Volume II 1 & 2
Quinidine Bisulphate Tetrahydrate Tablets 250 mg Volume II 1 & 2
Ranitidine HCl Tablets 150 mg Volume II 1 & 2
Ranitidine HCl Tablets 300 mg Volume II 1 & 2
Simvastatin Tablets 5/10mg 20 / 40 mg Volume II 1 & 2
Scopolamine Butylbromide Tablets 10 mg Volume II 1 & 2
Selegiline Tablets 5 /10 mg Volume II 1 & 2
Sotalol (=Betapace/Berlex) Tablets 80 /120mg Volume II 1 & 2
Sotalol (=Betapace/Berlex) Tablets 160 /240mg Volume II 1 & 2
Silver Sulphadiazine Cream 1% Volume II 1 & 2
Tamoxifen EU Tablets 10 / 20 mg Volume II 1 & 2
Tamoxifen EU Tablets 30 / 40mg Volume II 1 & 2
Tamoxifen US Tablets 10/20/40mg Volume II 1 & 2
Terbutaline Sulfate Syrup 0.3 mg/mL Volume II 1 & 2
Terazosin Tablets 1mg / 2mg Volume II 1 & 2
Terazosin Tablets 5mg / 10mg Volume II 1 & 2
Terfenadine Tablets 60 mg Volume II 1 & 2
Tetrahydrozoline HCl USP Eye Drops 2,5mg/5mL Volume II 1 & 2
Ticlopidine Tablets 250 mg Volume II 1 & 2
Timolol maleate Drops USP Eye Drops 0.25 / 0.5% Volume II 1 & 2
Tolmetin Sod. Capsules 400 mg Volume II 1 & 2
Tolmetin Sod. Tablets 600 mg Volume II 1 & 2
Trazodone Tablets 50/100 mg Volume II 1 & 2
Trazodone Tablets 150 mg Volume II 1 & 2
Tretinoin Cream USP 0.025% Volume II 1 & 2
Sulfamethoxazole Trimethoprim Tablets USP 80/400mg Volume II 1 & 2
Sulfamethoxazole Trimethoprim Tablets USP 160/800mg Volume II 1 & 2
Sulfamethoxazole Trimethoprim Suspension 80/400mg Volume II 1 & 2
Sodium Valproate Syrup 200mg/5mL Volume II 1 & 2
Verapamil Hydrochloride Tablets 40 mg Volume II 1 & 2
AN ONGOING SERIES - NEW ADDITIONS ADDED TO SERIES
Second International Edition - 02 (First to Fourth Print). Fourth printing published and distributed in UK, US, EU, Israel, Asia, and Japan in 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

Handbook of Pharma Generic Develop. - Part II (2000)

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Handbook of Pharma Generic Develop. - Part II (2000)

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ORAL TABLETS DOSAGE FORM Dr ug Devel opment

Third International Edition

ISSN 0793 8632

HDPE Container Cleaning

Tablet Count & Fill

Closure Torque Test

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