Professional Documents
Culture Documents
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
ORAL TABLETS DOSAGE FORM Dr ug Devel opment
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
Handbook of Pharmaceutical Generic Development
Part I (Development) & Part II (Development ANDA or EU Dossier)
Vol. 2 - Capsules
Handbook of Pharmaceutical Generic Development
Part I (Development) & Part II (Development ANDA or EU Dossier)
Vol. 3 - Semisolids
Handbook of Pharmaceutical Generic Development
Part I (Development) & Part II (Development ANDA or EU Dossier)
Vol. 4 - Liquids
Handbook of Pharmaceutical Generic Development
Part I (Development) & Part II (Development ANDA or EU Dossier)
Vol. 5 - SG Capsules
Handbook of Pharmaceutical Generic Development
Part I (Development Pharmaceutical Stability) & Part II (Analytical PAI)
Vol. 6 - e-SOPs / SOPs
Handbook of Pharmaceutical Generic Development
Part I (Development) & Part II (Development ANDA or EU Dossier)
Vol. 7 - Suspensions
Handbook of Pharmaceutical Generic Development
Part I (Development) & Part II (Development ANDA or EU Dossier)
Vol. 8 - Eye & Nose
Handbook of Pharmaceutical Generic Development
Part I (Development) & Part II (Development ANDA or EU Dossier)
Vol. 9 - Aerosols MDI
Handbook of Pharmaceutical Generic Development
Part I (Development) & Part II (Development ANDA or EU Dossier)
Vol. 10 - Tablets CR/MR
Handbook of Pharmaceutical Generic Development
Part I (Development) & Part II (Development ANDA or EU Dossier)
Vol. 11 - Capsules ER
Handbook of Pharmaceutical Generic Development
Part I (Development) & Part II (Development ANDA or EU Dossier)
Vol. 12 - Tablets Oral DR
Handbook of Pharmaceutical Generic Development
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
Handbook of Pharmaceutical Drug Development (6-10)
(Master Formula & Manufacturing Instructions Parts 6 - 10)
Vol. 18 - MF and MMI
Handbook of Pharmaceutical Drug Development (1-5)
(Part I, Part II & Part III.(Development, Manufacturing &
Engineering)
Vol. 19 - Validation
Protocols/PAI-Checklists
Handbook of Pharmaceutical Generic Development
Part I (Development) & Part II (Development ANDA or EU Dossier)
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
ORAL TABLETS DOSAGE FORM Dr ug Devel opment
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.
ORAL TABLETS DOSAGE FORM Dr ug Devel opment
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
h t t p : / / www. l o c u meur o. c o m
h t t p : / / www. l o c u mus a . c o m
handbooks@l o c u mus a . com
sales@l o c u mus a . com
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
ORAL TABLETS DOSAGE FORM Dr ug Devel opment
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
ORAL TABLETS DOSAGE FORM Dr ug Devel opment
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.
End of Section 1.
HANDBOOK OF GENERIC DRUG DEVELOPMENT info@iagim.org ANDA DEVELOPMENT
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
(Overall ANDA Guideline Requirements for this Section).
2.O Section Page and Title. The information in this section summarizes the four
critical structures supporting the legal basis for this abbreviated new drug application
2.1.0 Basis for ANDA Submission is submitted as follows and is;
2.1.1 Based on an Abbreviated New Drug Application
or
2.1.2 Based on an approved ANDA Suitability Petition
and
3.0 Based on Active Ingredient (same as RLD) and current approved labeling
and
4.0 Based on Route of Administration, Dosage Form and Strength
and
5.0 Based on Bioequivalency Data submitted (Applicant Generic Drug vs. RLD)
NOTE:-
MODEL Letters are provided in Section IV highlighting each of four critical structures
and supporting documentation stating the legal basis for this abbreviated new drug
application
4
HANDBOOK OF GENERIC DRUG DEVELOPMENT info@iagim.org ANDA DEVELOPMENT
24 V 24 Volume D Drug D Development S Ser ies Sect: 2 2.2 ANDA DEVELOPMENT
SECTION II SECTION 2
Basis for ANDA Submission
BASIS FOR ABBREVIATED NEW DRUG APPLICATION
[a] Listed Drug.
This applications refers to the Reference Listed Drug [NAME] 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])
HANDBOOK OF GENERIC DRUG DEVELOPMENT info@iagim.org ANDA DEVELOPMENT
24 V 24 Volume D Drug D Development S Ser ies Sect: 2 2.3 ANDA DEVELOPMENT
SECTION II SECTION 2
Basis for ANDA Submission
BASIS FOR ABBREVIATED NEW DRUG APPLICATION (continued)
ACTIVE INGREDIENT [00000]
21 CFR 314.94 [A][5][i]
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.]
[S i gnature of R esponsi bl e P erson]
[Two typical examples of this section are given below]
T
T
HANDBOOK OF GENERIC DRUG DEVELOPMENT info@iagim.org ANDA DEVELOPMENT
24 V 24 Volume D Drug D Development S Ser ies Sect: 2 2.4 ANDA DEVELOPMENT
SECTION II SECTION 2
Basis for ANDA Submission
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
[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.]
[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.]
1
INNOVATOR NAME COUNTRY US or EU
2
USA RLD 375 / 500 mg - Application Number 000000
3
INNOVATOR
HANDBOOK OF GENERIC DRUG DEVELOPMENT info@iagim.org ANDA DEVELOPMENT
24 V 24 Volume D Drug D Development S Ser ies Sect: 2 2.5 ANDA DEVELOPMENT
SECTION II SECTION 2
Basis for ANDA Submission
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
[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.]
[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.]
1 INNOVATOR
2 USA RLD IS REGISTERED AS STRENGTH 0 mg +00 mg
INNOVATOR Application Number [00000]
3 INNOVATOR
HANDBOOK OF GENERIC DRUG DEVELOPMENT info@iagim.org ANDA DEVELOPMENT
24 V 24 Volume D Drug D Development S Ser ies Sect: 2 2.6 ANDA DEVELOPMENT
SECTION II SECTION 2
Basis for ANDA Submission
ANDA SUITABILITY PETITION APPROVAL LETTER
Date:
Office of Generic Drugs
CDER, Food and Drug Administration
Document Control Room - No. 150
Metro Park North II
7500 Standish Place
ROCKVILLE MD 20855-2773.
ORIGINAL ABBREVIATED NEW DRUG APPLICATION
[Generic name] 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.
[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.]
[ANDA SUITABILITY PETITION APPROVAL LETTER
Attached in Section XXII]
4
End of Section 2.
HANDBOOK OF GENERIC DRUG DEVELOPMENT info@iagim.org ANDA DEVELOPMENT
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
(Overall ANDA Guideline Requirements for this Section).
ection Page (with Color Section TAG) and brief narrative of the section.
Enclosed in this sections is a statement of patent certification for [Applicant
Company Name Inc. / Ltd.]new drug application [Drug Name]. Also enclosed (if
applicable) are the statements concerning the required notices to the patent owners
and NDA holder. These statements are in accord with the FD&C Act as amended
September 24, 1984 and with the final regulations effective November 2 1994.
3.1 Patent Certification statement -
State Paragraph I
State Paragraph II
State Paragraph III
State Paragraph IV
3.2 Little VIII Patent Statement - i.e. no labeling claims on a new indication.
3.3 Exclusivity Statement with reference to the RLD.
3.4 Certification Pursuant to the Generic Drug Enforcement Act of 1992.
4
S
HANDBOOK OF GENERIC DRUG DEVELOPMENT info@iagim.org ANDA DEVELOPMENT
24 V 24 Volume D Drug D Development S Ser ies Sect: 3.2 ANDA DEVELOPMENT
SECTION III SECTION 3
Patent Certification / Exclusivity
Patent Certification Statement
Paragraph I Certification
[21 CFR 314.94(a)(12)(i)]
n accord with the Food, Drug and Cosmetic Act as amended September 24, 1984
and with the final regulations effective November 2 1994 Patent certification is
hereby provided for our Abbreviated New Drug Application for [Generic Drug
Name].
e the undersigned hereby certify to the best of our knowledge and in [Generic
Company Name Inc./Ltd.]s opinion patent information has not been submitted
to the FDA on Patent No [00-0000-00] which claims the reference listed drug [RLD]
DRUG Name [USP] [000.0] mg. NDA # 00-000
his certification is made in accordance with Section 505 (j)(2)(A)(vii)(I) of Title I
the Food, Drug and Cosmetic Act, as amended September 24, 1984 and
pursuant to 21 CFR 314.94 (a)(12)(i)(A)(1).
[S i gnature of R esponsi bl e P erson]
------------------------------------------------ -----------------------------------------
[ Name of Responsi bl e Per son] Date
Regul at or y Af f ai r s Di r ec t or
[Applicant Company Name Inc. / Ltd.]
I
W
T
HANDBOOK OF GENERIC DRUG DEVELOPMENT info@iagim.org ANDA DEVELOPMENT
24 V 24 Volume D Drug D Development S Ser ies Sect: 3.3 ANDA DEVELOPMENT
SECTION III SECTION 3
Patent Certification / Exclusivity
Patent Certification Statement
Paragraph II Certification
n accord with the Food, Drug and Cosmetic Act as amended September 24, 1984
and with the final regulations effective November 2 1994 Patent certification is
hereby provided for our Abbreviated New Drug Application for [Generic Drug
Name].
e the undersigned hereby certify that to the best of our knowledge and in
[Generic Company Name Inc./Ltd.]s opinion US Patent No [00-0000-00] held
by [Innovator/RLD Company Name Inc./Ltd.] which claimed the reference listed
drug [RLD] DRUG Name[USP] [000.0] mg. NDA # 00-000 expired on 31 December
1999
his certification is made in accordance with Section 505 (j)(2)(A)(vii)(I) of Title I
the Food, Drug and Cosmetic Act, as amended September 24, 1984 and
pursuant to 21 CFR 314.94 (a)(12)(i)(A)(1).
US. Patent No. 0-0000-0000 expiring Dec 31, 1999
US. Patent No. 0-0000-0000 expiring Dec 31, 1999
[S i gnature of R esponsi bl e P erson]
------------------------------------------------ -----------------------------------------
[ Name of Responsi bl e Per son] Date
Regul at or y Af f ai r s Di r ec t or
[Applicant Company Name Inc./Ltd.]
I
W
T
HANDBOOK OF GENERIC DRUG DEVELOPMENT info@iagim.org ANDA DEVELOPMENT
24 V 24 Volume D Drug D Development S Ser ies Sect: 3.4 ANDA DEVELOPMENT
SECTION III SECTION 3
Patent Certification / Exclusivity
Patent Certification Statement
Paragraph III Certification
n accord with the Food, Drug and Cosmetic Act as amended September 24, 1984
and with the final regulations effective November 2 1994 Patent certification is
hereby provided for our Abbreviated New Drug Application for [Generic Drug
Name].
e the undersigned hereby certify that to the best of our knowledge and in
[Generic Company Name Inc./Ltd.]s opinion US Patent No [00-0000-00] held
by [Innovator/RLD Company Name Inc./Ltd.] which claimed the reference listed
drug [RLD] DRUG Name [USP] [000.0] mg. NDA # 00-000 will expire on [31
December 1999.]
US. Patent No. 0-0000-0000 expiring MM DD, YYYY
US. Patent No. 0-0000-0000 expiring MM DD, YYYY
n accordance with Section 505 (j)(2)(A)(vii)(III) of the Food, Drug and Cosmetic
Act, as amended [Generic Company Name Inc./Ltd.] certifies that the Company
will not engage in the commercial manufacture, use or sale of the drug Product until
this aforementioned patent has expired.
[S i gnature of R esponsi bl e P erson]
------------------------------------------------ -----------------------------------------
[ Name of Responsi bl e Per son] Date
Regul at or y Af f ai r s Di r ec t or
[Applicant Company Name Inc. / Ltd.]
Note the Bolar amendment allows the sale of the bulk active material and the
development manufacture testing of the developed generic product SOLELY
for the purposes and under the condition of getting it approved as an ANDA
I
W
I
HANDBOOK OF GENERIC DRUG DEVELOPMENT info@iagim.org ANDA DEVELOPMENT
24 V 24 Volume D Drug D Development S Ser ies Sect: 3.5 ANDA DEVELOPMENT
SECTION III SECTION 3
Patent Certification / Exclusivity
Alternative Certification
Patent Certification Statement
Paragraph III Certification
he undersigned hereby certifies to the best of our knowledge and in [Generic
Company Name Inc./Ltd.]s opinion there is [one] patent which claims the listed
drug [RLD] DRUG Name [USP] [000.0] mg. NDA # 00-000.
US. Patent No. 0-0000-0000 expiring MM DD, YYYY
US. Patent No. 0-0000-0000 expiring MM DD, YYYY
I
n accordance with Section 505 (j)(2)(A)(vii)(III) of the Food, Drug and Cosmetic
Act, as amended [Generic Company Name Inc./Ltd.] certifies that the Company will
not engage in the commercial manufacture, use or sale of the drug Product until this
aforementioned patent has expired .
[S i gnature of R esponsi bl e P erson]
------------------------------------------------ -----------------------------------------
[ Name of Responsi bl e Per son] Date
Regul at or y Af f ai r s Di r ec t or
[Applicant Company Name Inc. / Ltd.]
Attached:
Page Number: [00]
The Prescription Drug Product List of the APPROVED DRUG PRODUCTS WITH
THERAPEUTIC EQUIVALENCE EVALUATIONS EDITION 20th - 2000 US
Department of Health and Human Sciences.
4
T
HANDBOOK OF GENERIC DRUG DEVELOPMENT info@iagim.org ANDA DEVELOPMENT
24 V 24 Volume D Drug D Development S Ser ies Sect: 3.6 ANDA DEVELOPMENT
SECTION III SECTION 3
Patent Certification / Exclusivity
Patent Certification Statement
Paragraph IV Certification
n accord with the Food, Drug and Cosmetic Act as amended September 24, 1984
and with the final regulations effective November 2 1994 Patent certification is
hereby provided for our Abbreviated New Drug Application for [Generic Drug
Name].
e the undersigned hereby certify that to the best of our knowledge and in
[Generic Company Name Inc./Ltd.]s opinion US Patent No [00-0000-00]
issued on MM DD, YYYY and will expire on 31 December 2004 [will not be
infringed] / [ is invalid] / [is unenforceable]
1
by the manufacturer [Generic Company
Name Inc./Ltd.] upon the manufacture use and sale by [Generic] DRUG Name
[USP] [000.0]mg. for which this application is submitted
NO INFRINGEMENT STATUS of the following patents.
US. Patent No. 0-0000-0000 expiring MM DD, YYYY
US. Patent No. 0-0000-0000 expiring MM DD, YYYY
[S i gnature of R esponsi bl e P erson]
------------------------------------------------ -----------------------------------------
[ Name of Responsi bl e Per son] Date
Regul at or y Af f ai r s Di r ec t or
[Applicant Company Name Inc./Ltd.]
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).
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HANDBOOK OF GENERIC DRUG DEVELOPMENT info@iagim.org ANDA DEVELOPMENT
24 V 24 Volume D Drug D Development S Ser ies Sect: 3.7 ANDA DEVELOPMENT
SECTION III SECTION 3
Patent Holder & NDA Holder
Statement Concerning Notice
To Patent Holder and NDA Holder
21 CFR 314.94(a)(12)(1)(A)(iv) & 21 CFR 314.95
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).
[S i gnature of R esponsi bl e P erson]
------------------------------------------------ -----------------------------------------
[ Name of Responsi bl e Per son] Date
Regul at or y Af f ai r s Di r ec t or
[Applicant Company Name Inc./Ltd.]
It has become standard practice for the large RLD (Innovative) Companies to delay for as long as
possible, by means of costly litigation action, the newly applied Generic registration, if submitted
under a Paragraph IV certification, whether or not there is any legal basis for the litigation suite.
The spirit and intention of the Act and law to provide suitable cheaper generic drugs for the
general public is overridden by the Innovative Companies desire to look for continued extra-legal
patent protection even thought the innovator has indeed received its fair and proper share of
protection under the law during its full marketing period. The branded RLD Company simply
immediately sues the generic applicant as a matter of routine practice, using its huge financial
leverage to suppress the potentially lesser generic company. (Quote Brussels Conference on Patent
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.
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HANDBOOK OF GENERIC DRUG DEVELOPMENT info@iagim.org ANDA DEVELOPMENT
24 V 24 Volume D Drug D Development S Ser ies Sect: 3.8 ANDA DEVELOPMENT
SECTION III SECTION 3
Patent Certification / Exclusivity
' No relevant Patent ' Statement
21 CFR 314.94(a)(12)(ii)
n accord with the Food, Drug and Cosmetic Act as amended September 24, 1984
and with the final regulations effective November 2, 1994. Patent certification
clarification is hereby provided for our submitted Abbreviated New Drug Application
for [Generic Drug Name].
his certification is made in accordance with Section 505 (j)(2)(A)(vii)(I) of Title I
the Food, Drug and Cosmetic Act, as amended, September 24, 1984 and
November 2, 1994 and pursuant to 21 CFR 314.94 (a)(12)(ii).
e the undersigned hereby certify to the best of our knowledge and in [Generic
Company Name Inc./Ltd.]s opinion there are no patent[s] which claim[s] the
Reference Listed Drug [RLD] DRUG Name [USP] [000.0]mg. NDA #[00-000-00]
referred to in this application or that claims a use of the Reference Listed Drug.
[S i gnature of R esponsi bl e P erson]
------------------------------------------------ -----------------------------------------
[ Name of Responsi bl e Per son] Date
Regul at or y Af f ai r s Di r ec t or
[Applicant Company Name Inc. / Ltd.]
Background
This specification is not specifically described under the FD&C Act but appears in the FDA final
regulations dated Nov 2, 1994. The purpose of the "No relevant Patents Statement " appears to be
designed to aid and help the internal FDA OGD reviewers to assure them that your firm's omission to
include a patent certification is a deliberate action and not simply a regulatory oversight.
Note: The intention of the regulations and the preamble to the regulations is to provide a positive
statement that the submitted ANDA should not contain any of the FOUR Patent Certification
Statements (i.e. No Paragraph I ; II ; III or IV statement) - Thus, it is necessary to submit a "No
relevant Patents Statement " if and only if, no patent(s) exist that should be the subject of a Patent
Certification - i.e. stating the negative condition and thus eradicating the element of an regulatory
oversight.
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HANDBOOK OF GENERIC DRUG DEVELOPMENT info@iagim.org ANDA DEVELOPMENT
24 V 24 Volume D Drug D Development S Ser ies Sect: 3.9 ANDA DEVELOPMENT
SECTION III SECTION 3
Patent Certification / Exclusivity
Method of Use Patent Statement
21 CFR 314.94(a)(12)(iii)
his certification is made in accordance with Section 505 (j)(2)(A)(vii)(I) of Title I
the Food, Drug and Cosmetic Act, as amended September 24, 1984 and
pursuant to 21 CFR 314.94 (a)(12)(i)(A)(1).
Method of Use Patent
n accord with the Section 505 (j)(2)(A)(viii) of Title I the Food, Drug and Cosmetic
Act, as amended September 24, 1984, [Generic Company Name Inc./Ltd.] hereby
states, with respect to method of Use Patent, US Patent No [000-000-00], submitted
by [RLD Company Name Inc./Ltd.] for listing in respect to [RLD Branded Drug
Name], that of Use Patent No [000-000-00] does not claim a use for which [Generic
Company Name Inc./Ltd.] is seeking approval for [Generic Drug Name]
e the undersigned hereby certify to the best of our knowledge that of Use
Patent No [000-000-00] is limited to the following claim (specific therapeutic
use), the use for which [Generic Company Name Inc./Ltd.] now seeks approval in
this ANDA, as evident by the attached proposed labeling (Refer to Page [00]), is for
use indication _________, which is beyond the reach of claims of Patent No [000-
000-00] .
[S i gnature of R esponsi bl e P erson]
------------------------------------------------ -----------------------------------------
[ Name of Responsi bl e Per son] Date
Regul at or y Af f ai r s Di r ec t or
[Applicant Company Name Inc. / Ltd.]
T
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HANDBOOK OF GENERIC DRUG DEVELOPMENT info@iagim.org ANDA DEVELOPMENT
24 V 24 Volume D Drug D Development S Ser ies Sect: 3.10 ANDA DEVELOPMENT
SECTION III SECTION 3
Patent Certification / Exclusivity
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.
[S i gnature of R esponsi bl e P erson]
------------------------------------------------ -----------------------------------------
[ Name of Responsi bl e Per son] Date
Regul at or y Af f ai r s Di r ec t or
[Applicant Company Name Inc./Ltd.]
Attached:
Page Number: [00]
The Prescription and OTC Drug Product Patent and Exclusivity Data of the
APPROVED DRUG PRODUCTS WITH THERAPEUTIC EQUIVALENCE
EVALUATIONS EDITION 20 (2000) - US Department of Health and Human
Sciences.
4
End Section III
T
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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
(Overall ANDA Guideline Requirements for this Section).
4.1 Section Page (with Color Section TAG) and brief narrative of the section.
4.2 Comparison between Generic and Reference Listed Drug (RLD) / Innovator
Tabulate to show proposed product is the same as listed product namely: -
Conditions of Use
Active Ingredients
Inactive ingredients (OGD Interim Inactive ingredient Policy - 'Q&Q'
policy of Nov 17 1994 - does not apply to oral dosage forms i.e. tablets
[and suspensions])
Route of Administration & Dosage Form
Strength
Inactive Ingredients with supporting data
Labeling Comparison (Add section V data)
4.3 Rx or OTC Marketing Statement for proposed Generic Product.
FDA's Published January 1999 ANDA Guideline 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
HANDBOOK OF GENERIC DRUG DEVELOPMENT ANDA DEVELOPMENT
24 V 24 Volume D Dr ug D Development S Ser ies Sect: 4.2 DEVELOPMENT Or al Or al Tablets
SECTION IV SECTION 4
Generic and RLD Comparison
Information required under 314.94 (a)(4) through (6) of the ANDA Regulations final
rule issued April 28 1992.
[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.
HANDBOOK OF GENERIC DRUG DEVELOPMENT ANDA DEVELOPMENT
24 V 24 Volume D Dr ug D Development S Ser ies Sect: 4.3 DEVELOPMENT Or al Or al Tablets
SECTION IV SECTION 4
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.
[S i gnature of R esponsi bl e P erson]
------------------------------------------------ -----------------------------------------
[ Name of Responsi bl e Per son] Date
Regul at or y Af f ai r s Di r ec t or
[Applicant Company Name Inc. / Ltd.]
4
HANDBOOK OF GENERIC DRUG DEVELOPMENT ANDA DEVELOPMENT
24 V 24 Volume D Dr ug D Development S Ser ies Sect: 4.4 DEVELOPMENT Or al Or al Tablets
SECTION IV SECTION 4
Generic and RLD Comparison
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
Use point size 12 and highlight the
differences in the INNOVATIVE
CONTAINER LABEL - use line side bars
where differences appear.
NOTE:-
The differences in the CONTAINER
LABEL should be restricted to
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.
HANDBOOK OF GENERIC DRUG DEVELOPMENT ANDA DEVELOPMENT
24 V 24 Volume D Dr ug D Development S Ser ies Sect: 4.5 DEVELOPMENT Or al Or al Tablets
SECTION IV SECTION 4
Generic and RLD Comparison
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
Clinical to Administrative
Section
Differences are:- Differences are:-
Specific use patent indication excluded Specific use patent indication under
exclusivity rights
Similarities are:- Similarities are:-
Dosage Form Dosage Form
Strength Strength
How Supplied How Supplied
Differences are:- Differences are:-
Trade Name Trade Name
Addresses (Applicant & Distributing) Addresses
NDC # NDC #
Similarities are:- Similarities are:-
Dosage Form Dosage Form
Strength Strength
Quantities Quantities
HANDBOOK OF GENERIC DRUG DEVELOPMENT ANDA DEVELOPMENT
24 V 24 Volume D Dr ug D Development S Ser ies Sect: 4.6 DEVELOPMENT Or al Or al Tablets
SECTION IV SECTION 4
Generic and RLD Comparison
Labeling
ATTACHMENTS
HANDBOOK OF GENERIC DRUG DEVELOPMENT ANDA DEVELOPMENT
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
(Overall ANDA Guideline Requirements for this Section).
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
HANDBOOK OF GENERIC DRUG DEVELOPMENT ANDA DEVELOPMENT
24 Volume Dr ug Development Ser ies Sect: 5.2 DEVELOPMENT Or al Dosage For m
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]
[Applicant Company Name Inc. / Ltd.]
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]
HANDBOOK OF GENERIC DRUG DEVELOPMENT ANDA DEVELOPMENT
24 Volume Dr ug Development Ser ies Sect: 5.3 DEVELOPMENT Or al Dosage For m
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
_________________________
Each Tablet contains:
[Active Material] 000 mg
Caution: Federal law prohibits dispensing without prescription
000 TABLETS [USP]
[Applicant Company Name Inc. / Ltd.]
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
[Manufacturing Company Name Inc. / Ltd.].
[Short Address]
Distributed By:
[Distributing Company Name Inc. / Ltd.]
[Short Address]
HANDBOOK OF GENERIC DRUG DEVELOPMENT ANDA DEVELOPMENT
24 Volume Dr ug Development Ser ies Sect: 5.4 DEVELOPMENT Or al Dosage For m
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.
HANDBOOK OF GENERIC DRUG DEVELOPMENT ANDA DEVELOPMENT
24 Volume Dr ug Development Ser ies Sect: 5.5 DEVELOPMENT Or al Dosage For m
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
restrictions on indications still on patent
- these may not be included )
Use point size 7 and highlight the
differences in the GENERIC PACKAGE
INSERT - use line side bars where
differences appear as shown:
NOTE:-
The differences in the package insert
should be restricted to Generic product
name and different addresses for
Applicant Manufacturer, Distributor and
Product reference Numbers.
Present full Innovative package insert of
innovators (restrictions on indications
still on patent are included and shown
as a difference ) - latest edition of
package insert must be used - obtain
from FOI services
Use point size 7 and highlight the
differences in the INNOVATIVE
PACKAGE INSERT - use line side bars
where differences appear.
NOTE:-
The differences in the package insert
should be restricted to Innovative
product name and different addresses
for Applicant Manufacturer, Distributor
and Product reference Numbers
NOTE:
Examine innovators labeling carefully and reproduce wording meeting all regulatory
requirements. Note: the FDA provide a significant number of the latest package inserts
for Generics - on the Internet - See FDA Website. 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.
HANDBOOK OF GENERIC DRUG DEVELOPMENT ANDA DEVELOPMENT
24 Volume Dr ug Development Ser ies Sect: 5.6 DEVELOPMENT Or al Dosage For m
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
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
Use point size 12 and highlight the
differences in the INNOVATIVE
CONTAINER LABEL - use line side bars
where differences appear.
NOTE:-
The differences in the CONTAINER
LABEL should be restricted to
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
HANDBOOK OF GENERIC DRUG DEVELOPMENT ANDA DEVELOPMENT
24 Volume Dr ug Development Ser ies Sect: 5.7 DEVELOPMENT Or al Dosage For m
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
Each Tablet contains:
[Active Material] 000 mg
Caution: Federal law prohibits dispensing without prescription
000 TABLETS [USP]
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
[Applicant Company Name Inc. / Ltd.]
Distributed By:
[Distributing Company Name Inc. / Ltd.]
NOTE:
Examine innovator's labeling carefully and reproduce meeting all regulatory
requirements. Obtain the latest printing of the innovator's product labeling.
HANDBOOK OF GENERIC DRUG DEVELOPMENT ANDA DEVELOPMENT
24 Volume Dr ug Development Ser ies Sect: 5.8 DEVELOPMENT Or al Dosage For m
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
Each Tablet contains:
[Active Material] 000 mg
Caution: Federal law prohibits dispensing without prescription
000 Tablets [USP]
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
[Innovative (RLD) Company Name Inc. / Ltd.]
NOTE:
Examine innovators labeling carefully and reproduce meeting all regulatory
requirements
HANDBOOK OF GENERIC DRUG DEVELOPMENT ANDA DEVELOPMENT
24 Volume Dr ug Development Ser ies Sect: 5.9 DEVELOPMENT Or al Dosage For m
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.
[S i gnature of R esponsi bl e P erson]
------------------------------------------------ -----------------------------------------
[ Name of Responsi bl e Per son] Date
Regul at or y Af f ai r s Di r ec t or
[Applicant Company Name Inc. / Ltd.]
HANDBOOK OF GENERIC DRUG DEVELOPMENT ANDA DEVELOPMENT
24 Volume Dr ug Development Ser ies Sect: 5.10 DEVELOPMENT Or al Dosage For m
SECTION V SECTION 5
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
Clinical to Administrative
Section
Differences are:- Differences are:-
Specific use patent indication excluded Specific use patent indication under
exclusivity rights
Similarities are:- Similarities are:-
Dosage Form Dosage Form
Strength Strength
How Supplied How Supplied
Differences are:- Differences are:-
Trade Name Trade Name
Addresses (Applicant & Distributing) Addresses
NDC # NDC #
Similarities are:- Similarities are:-
Dosage Form Dosage Form
Strength Strength
Quantities Quantities
HANDBOOK OF GENERIC DRUG DEVELOPMENT ANDA DEVELOPMENT
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
(Overall ANDA Guideline Requirements for this Section).
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
HANDBOOK OF GENERIC DRUG DEVELOPMENT ANDA DEVELOPMENT
24 Volume Dr ug Development Ser ies Sect: 6.2 DEVELOPMENT Or al Tablets
SECTION VI SECTION 6
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
[Generic name] Tablets [USP] [000.0] mg. Lot: [000-00]
CoA No: [0000]
Packaging and Disbursement Summary for [Generic Company Name Inc./Ltd.]
pivotal Lot: [000-00]
HANDBOOK OF GENERIC DRUG DEVELOPMENT ANDA DEVELOPMENT
24 Volume Dr ug Development Ser ies Sect: 6.3 DEVELOPMENT Or al Tablets
SECTION VI SECTION 6
Bioavailability / Bioequivalenc e
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.
HANDBOOK OF GENERIC DRUG DEVELOPMENT ANDA DEVELOPMENT
24 Volume Dr ug Development Ser ies Sect: 6.4 DEVELOPMENT Or al Tablets
SECTION VI SECTION 6
Bioavailability / Bioequivalenc e
6.3 PERCENT COMPOSITION OF THE PRODUCT
[Generic name] Tablets [USP] [000.0] mg.
(equivalent to [000.0] mg [Active Material]
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.
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.
HANDBOOK OF GENERIC DRUG DEVELOPMENT ANDA DEVELOPMENT
24 Volume Dr ug Development Ser ies Sect: 6.5 DEVELOPMENT Or al Tablets
SECTION VI SECTION 6
Bioavailability / Bioequivalenc e
QUALITATIVE COMPARATIVE INGREDIENTS LIST
[Generic name] Tablets [USP] [00.0] mg.
[Active Material]
[Generic Company Name Inc. / Ltd.]
[RLD] Tablets [USP] [00.0] mg.
[Active Material]
[RLD Company Name Inc. / Ltd.]*
[Active Material] [Active Material]
Povidone USP Povidone
Colloidal Silicon Dioxide NF Colloidal Silicon Dioxide
Starch NF Starch
Starch NF (Re-dried) Lactose
Anhydrous Lactose NF Magnesium Stearate
Magnesium Stearate NF Another ingredient
* Reference Source - PDR 1998/200Y
HANDBOOK OF GENERIC DRUG DEVELOPMENT ANDA DEVELOPMENT
24 Volume Dr ug Development Ser ies Sect: 6.6 DEVELOPMENT Or al Tablets
SECTION VI SECTION 6
Bioavailability / Bioequivalenc e
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
HANDBOOK OF GENERIC DRUG DEVELOPMENT ANDA DEVELOPMENT
24 Volume Dr ug Development Ser ies Sect: 6.7 DEVELOPMENT Or al Tablets
SECTION VI SECTION 6
Bioavailability / Bioequivalenc e
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
HANDBOOK OF GENERIC DRUG DEVELOPMENT ANDA DEVELOPMENT
24 Volume Dr ug Development Ser ies Sect: 6.8 DEVELOPMENT Or al Tablets
SECTION VI SECTION 6
Bioavailability / Bioequivalenc e
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.
HANDBOOK OF GENERIC DRUG DEVELOPMENT ANDA DEVELOPMENT
24 Volume Dr ug Development Ser ies Sect: 6.9 DEVELOPMENT Or al Tablets
SECTION VI SECTION 6
Bioavailability / Bioequivalenc e
COMPARATIVE DISSOLUTION PROFILE FOR DRUG PRODUCT LOTS
USED IN BIOEQUIVALENCE STUDIES:
Tolerance: NLT 00 % (Q) in 00 mins.
12 Tablets [USP]
[Generic name] Tablets [USP] [000.0] mg. Lot: [000-00]
Figure No. 1. Comparative Dissolution Profile
Generic Tablets vs RLD 00mg
0
20
40
60
80
100
120
0 20 40 80
TIME (min)
% DISSOLVED
S-12345
RLD AA0000
0 20 40 80 0 20 40 80
Limits: NMT 5% variation between Generic and RLD data points.
HANDBOOK OF GENERIC DRUG DEVELOPMENT ANDA DEVELOPMENT
24 Volume Dr ug Development Ser ies Sect: 6.10 DEVELOPMENT Or al Tablets
SECTION VI SECTION 6
Bioavailability / Bioequivalenc e
COMPARATIVE DISSOLUTION PROFILE FOR DRUG PRODUCT LOTS
USED IN BIOEQUIVALENCE STUDIES:
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.
HANDBOOK OF GENERIC DRUG DEVELOPMENT ANDA DEVELOPMENT
24 Volume Dr ug Development Ser ies Sect: 6.11 DEVELOPMENT Or al Tablets
SECTION VI SECTION 6
Bioavailability / Bioequivalenc e
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.
HANDBOOK OF GENERIC DRUG DEVELOPMENT ANDA DEVELOPMENT
24 Volume Dr ug Development Ser ies Sect: 6.12 DEVELOPMENT Or al Tablets
SECTION VI SECTION 6
Bioavailability / Bioequivalenc e
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
HANDBOOK OF GENERIC DRUG DEVELOPMENT ANDA DEVELOPMENT
24 Volume Dr ug Development Ser ies Sect: 6.13 DEVELOPMENT Or al Tablets
SECTION VI SECTION 6
Bioavailability / Bioequivalenc e
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.
HANDBOOK OF GENERIC DRUG DEVELOPMENT ANDA DEVELOPMENT
24 Volume Dr ug Development Ser ies Sect: 6.14 DEVELOPMENT Or al Tablets
SECTION VI SECTION 6
Bioavailability / Bioequivalenc e
FORMULA COMPOSITION OF BIOSTUDY and PROPOSED WAIVER STRENGTH
[Generic name] Tablets [USP] [20.0] and [10.0] mg.
(equivalent to [00.0] mg [Active Material]
Ingredients Amount per Strength
per Tablet (in milligrams)
[Active Material BP / Ph. Eur]
20.00 10.00
(Biostudy) (Waiver)
[Active Material] 23.60 11.80
Povidone USP 9.00 4.50
Colloidal Silicon Dioxide NF 2.10
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
HANDBOOK OF GENERIC DRUG DEVELOPMENT ANDA DEVELOPMENT
24 Volume Dr ug Development Ser ies Sect: 6.15 DEVELOPMENT Or al Tablets
SECTION VI SECTION 6
Bioavailability / Bioequivalenc e
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
1004 units x 100 tablets = 100,400 tablets
Packaging date: Month DD, 200Y
Nov.28, 1996
9 units x 100 tabs
QC Testing & Reserve units
Month DD, 200Y
25 units x 100 tabs
Release & Stability Testing
Month DD, 200Y
40 units x 100 tabs
Biostudy & Retained Samples
Month DD, 200Y
60 units x 100 tabs
Balance stored in
Pivotal Warehouse
HANDBOOK OF GENERIC DRUG DEVELOPMENT ANDA DEVELOPMENT
24 Volume Dr ug Development Ser ies Sect: 6.16 DEVELOPMENT Or al Tablets
SECTION VI SECTION 6
Bioavailability / Bioequivalenc e
FINAL BIOEQUIVALENCE REPORT
(Summary Report Here)
FULL BIOEQUIVALENCE PRESENTED IN SEPARATE BINDINGS AS
STAND ALONE VOLUME(S) USING FDA BIO JACKET COVERS (RED).
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SECTION VI SECTION 6
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]
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SECTION VI SECTION 6
Bioavailability/ Bioequivalence
24 VOLUME DRUG DEVELOPMENT SERI ES Sect: 6.16 Oral Dosage Forms
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.
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SECTION VI SECTION 6
Bioavailability/ Bioequivalence
24 VOLUME DRUG DEVELOPMENT SERI ES Sect: 6.17 Oral Dosage 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
[S i gnature of R esponsi bl e P erson]
-----------------------------------------
[ Name of Pr i nc i pal I nvest i gat or ] Date
Pr i nc i pal I nvest i gat or
HANDBOOK OF GENERIC DRUG DEVELOPMENT info@iagim.org ANDA DEVELOPMENT
SECTION VI SECTION 6
Bioavailability/ Bioequivalence
24 VOLUME DRUG DEVELOPMENT SERI ES Sect: 6.18 Oral Dosage Forms
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.
[S i gnature of R esponsi bl e P erson]
------------------------------------------------ ---------------------------------
[ Name of CEO / Pr esi dent ] Date
CEO / President
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SECTION VI SECTION 6
Bioavailability/ Bioequivalence
24 VOLUME DRUG DEVELOPMENT SERI ES Sect: 6.19 Oral Dosage Forms
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
[S i gnature of R esponsi bl e P erson]
------------------------------------------------ - -----------------------------------------
[ Name of Pr i nc i pal I nvest i gat or ] Date
Pr i nc i pal Phar mac ok enet i c i st
T
HANDBOOK OF GENERIC DRUG DEVELOPMENT info@iagim.org ANDA DEVELOPMENT
SECTION VI SECTION 6
Bioavailability/ Bioequivalence
24 VOLUME DRUG DEVELOPMENT SERI ES Sect: 6.20 Oral Dosage Forms
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.
[S i gnature of R esponsi bl e P erson]
-----------------------------------------
[ Name of Pr i nc i pal I nvest i gat or ] Date
Pr i nc i pal I nvest i gat or
T
HANDBOOK OF GENERIC DRUG DEVELOPMENT info@iagim.org ANDA DEVELOPMENT
SECTION VI SECTION 6
Bioavailability/ Bioequivalence
24 VOLUME DRUG DEVELOPMENT SERI ES Sect: 6.21 Oral Dosage Forms
TITLE:
BIOEQUIVALENCE EVALUATION
of two Oral [Active Material] Preparations
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 : :
HANDBOOK OF GENERIC DRUG DEVELOPMENT info@iagim.org ANDA DEVELOPMENT
SECTION VI SECTION 6
Bioavailability/ Bioequivalence
24 VOLUME DRUG DEVELOPMENT SERI ES Sect: 6.22 Oral Dosage Forms
TITLE:
BIOEQUIVALENCE EVALUATION
of two Oral [Active Material] Preparations
in [00] Healthy Volunteers
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]
HANDBOOK OF GENERIC DRUG DEVELOPMENT info@iagim.org ANDA DEVELOPMENT
SECTION VI SECTION 6
Bioavailability/ Bioequivalence
24 VOLUME DRUG DEVELOPMENT SERI ES Sect: 6.23 Oral Dosage Forms
TITLE
BIOEQUIVALENCE EVALUATION
of two Oral [Active Material] Preparations
in [00] Healthy Volunteers
Vol ume Thr ee
Case Records Forms
Appendix : : Case Records Forms.
HANDBOOK OF GENERIC DRUG DEVELOPMENT info@iagim.org ANDA DEVELOPMENT
SECTION VI SECTION 6
Bioavailability/ Bioequivalence
24 VOLUME DRUG DEVELOPMENT SERI ES Sect: 6.24 Oral Dosage 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)
HANDBOOK OF GENERIC DRUG DEVELOPMENT ANDA DEVELOPMENT
24 Volume Dr ug Development Ser ies Sect: 7.1 DEVELOPMENT Or al Tablets
SECTION VII SECTION 7
Component s and Composi t i on
TABLE OF CONTENTS
(Overall ANDA Guideline Requirements for this Section).
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
HANDBOOK OF GENERIC DRUG DEVELOPMENT ANDA DEVELOPMENT
24 Volume Dr ug Development Ser ies Sect: 7.2 DEVELOPMENT Or al Tablets
SECTION VII SECTION 7
Components and Composition
LI ST OF COMPONENTS
Following is a full list of the articles used as components of the drug product:
[Generic name] Tablets [USP] [000.0] mg.
(equivalent to [000.0] mg [Active Material]
[Active Material] (Active Suppliers Name)
Povidone USP
Colloidal Silicon Dioxide NF
Starch NF
Starch NF (Re-dried)
Anhydrous Lactose NF
Magnesium Stearate NF
4
HANDBOOK OF GENERIC DRUG DEVELOPMENT ANDA DEVELOPMENT
24 Volume Dr ug Development Ser ies Sect: 7.3 DEVELOPMENT Or al Tablets
SECTION VII SECTION 7
Components and Composition
FORMULA COMPOSITION
Composition of the drug, stating the name and amount of each ingredient, whether active or
not, contained in a stated quantity of the drug in the form in which it is to be distributed.
[Generic name] Tablets [USP] [000.0] mg.
(equivalent to [000.0] mg [Active Material]
Formula
Ingredients
Amount in mg
per [00] mg Tablet
[Active Material] (Active Suppliers Name) 23.60
1
Povidone USP 9.00
Colloidal Silicon Dioxide NF 2.10
Starch NF 5.30
Starch NF (Re-dried) 27.00
Anhydrous Lactose NF 230.00
Magnesium Stearate NF 3.00
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 = 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
HANDBOOK OF GENERIC DRUG DEVELOPMENT ANDA DEVELOPMENT
24 Volume Dr ug Development Ser ies Sect: 7.4 DEVELOPMENT Or al Tablets
SECTION VII SECTION 7
Components and Composition
PERCENT COMPOSI TI ON OF THE PRODUCT
[Generic name] Tablets [USP] [000.0] mg.
(equivalent to [000.0] mg [Active Material]
Formula
Ingredients
Each 00 mg Tablet
contains (Percentage)
[Active Material] (Active Suppliers Name) 7.87
1
Povidone USP 3.00
Colloidal Silicon Dioxide NF 0.70
Starch NF 1.76
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
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 = 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
HANDBOOK OF GENERIC DRUG DEVELOPMENT ANDA DEVELOPMENT
24 Volume Dr ug Development Ser ies Sect: 8.1 DEVELOPMENT Or al Tablets
SECTION VIII SECTION 8
Raw Mat er i al Cont r ol
TABLE OF CONTENTS
(Overall ANDA Guideline Requirements for this Section).
Active Ingredient(s)
8.1 Title Page and brief summary statement of what this section contains
8.2 Outlines of SOPs for handling Raw Materials (Retest procedure max. 12
months)
- Outlines of SOP for Qualification of Vendors
- Outlines of SOP for Acceptance Criteria
- Outlines of SOP for Retesting Schedules
- Outlines of SOP for Raw Materials storage
8.3 Disclosure of Active ingredients Source
8.4 DMF of Manufacturer via Letter of Access from Active Manufacturer (Type II)
8.5 Active Monograph supplied by QC laboratory
8.6 CoA from Generic Firms QC laboratory, plus supporting
- Identification IR or UV spectra of Active
- HPLC chromatograms (Assay - Impurities) - label peaks
- Photocopy of TLC chromatograms (Assay - Impurities)
8.7 CoA from Active Manufacturer, - plus supporting
- Identification IR or UV spectra of Active
- HPLC chromatograms (Assay - Impurities) - label peaks
- Photocopy of TLC chromatograms (Assay - Impurities)
8.9 IR Identification Spectra of Reference Standard (Pharmacopoeial)
8.10 Physical Specifications from Active Manufacturer
- Bulk Density,
- Particle Size (note: water insoluble material)
- Physical and analytical test methods
8.11 Outline of Material Data Safety Sheet (MDSS)
(source of data for manufacturing instructions precautions).
9.0 Inactive Ingredients
9.1 Testing Specifications (ID and characterization)
9.2 Suppliers Certificate of Analysis (Specifications and Test Results)
4
13 of 13
HANDBOOK OF GENERIC DRUG DEVELOPMENT ANDA DEVELOPMENT
24 Volume Dr ug Development Ser ies Sect: 8.2 DEVELOPMENT Or al Tablets
SECTION VIII SECTION 8
Raw Material Control
This section contains:
Outline of the Standard Operating Procedures for Raw Materials
Summary of Lot Numbers of Active and Inactive Ingredients
Disclosure of Active Ingredient Source (approved supplier)
Active Ingredient DMF Authorization Letter
Active Ingredient Certificates of Analysis
Active Ingredient Supporting Data (Spectra)
Outline of Material Data Safety Sheet (MDSS)
Inactive Ingredient Certificates of Analysis
Inactive Ingredient Testing Monographs/Test Procedures
Routine Testing Protocols
4
HANDBOOK OF GENERIC DRUG DEVELOPMENT ANDA DEVELOPMENT
24 Volume Dr ug Development Ser ies Sect: 8.3 DEVELOPMENT Or al Tablets
SECTION VIII SECTION 8
Raw Material Control
OUTLINE OF STANDARD OPERATING PROCEDURES FOR
HANDLING RAW MATERIALS AND PACKAGING MATERIALS
1. Vendors Approval
All chemical raw materials used in the manufacturing of commercial products and
primary stability batches, must be supplied by approved vendors.
The approval of vendors is a shared responsibility of the QA Department of the plant
and the Purchasing Department. For pilot batches, the R&D Department is
responsible.
The Purchasing Dept. submits an application to approve a vendor to the QA
Department, specifying the full details of the vendor and samples identified by the
manufacturer, including the Certificates of Analysis of the manufacturer. The
manufacturer must have a DMF (Drug Master File) submitted to the FDA.
The QC Laboratory tests must confirm that the Certificate of Analysis, which must
accompany the raw material, meets the raw material requirements.
In the absence of a pharmacopoeia monograph, compliance to an approved 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.
HANDBOOK OF GENERIC DRUG DEVELOPMENT ANDA DEVELOPMENT
24 Volume Dr ug Development Ser ies Sect: 8.4 DEVELOPMENT Or al Tablets
SECTION VIII SECTION 8
Raw Material Control
Rejected Batches:
Raw materials samples not approved for use by the laboratory will be marked by a
laboratory issued red Rejected label, affixed to the sample by a quality assurance
unit, and transferred to the Rejected area of the warehouse.
Rejected materials will remain in the Rejected area until a final decision is reached
whether to return them to the supplier or to destroy them.
3. Retest Schedule
Each lot of raw material remaining in the inventory is retested based on the previous
date of analysis.
Retest period for highly sensitive materials (actives and excipients) and materials
requiring microbiological testing, is 12 months.
All other active and excipient materials are retested after 24 months, or as stipulated in
the laboratory documents. [Active Material] (Approved Supplier) will be retested
after 12 months.
4. Storage
Quarantine Storage
1. Raw materials shall be stored in controlled environmental areas under monitored
environmental storage temperatures, held between 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
HANDBOOK OF GENERIC DRUG DEVELOPMENT ANDA DEVELOPMENT
24 Volume Dr ug Development Ser ies Sect: 8.5 DEVELOPMENT Or al Tablets
SECTION VIII SECTION 8
Raw Material Control
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.
HANDBOOK OF GENERIC DRUG DEVELOPMENT ANDA DEVELOPMENT
24 Volume Dr ug Development Ser ies Sect: 8.6 DEVELOPMENT Or al Tablets
SECTION VIII SECTION 8
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
HANDBOOK OF GENERIC DRUG DEVELOPMENT ANDA DEVELOPMENT
24 Volume Dr ug Development Ser ies Sect: 8.7 DEVELOPMENT Or al Tablets
SECTION VIII SECTION 8
Active Material Control
P h y s i c a l S p e c i f i c a t i o n s
of Active Materials
TEST
METHODS
PHYSICAL SPECIFICATIONS
[ACTIVE MATERIAL]
SPECIFICATIONS
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.
HANDBOOK OF GENERIC DRUG DEVELOPMENT ANDA DEVELOPMENT
24 Volume Dr ug Development Ser ies Sect: 8.8 DEVELOPMENT Or al Tablets
SECTION VIII SECTION 8
Active Material Control
Certificate of Analysis and Spectra of Active and Reference Materials
Active Material Certificate of Analysis and Spectra Numbers.
Document Material
Supplied by:
Certificate
number
Remarks
[Active Material]
CoA
Approved
Supplier
# [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]
Typical HPLC Spectra
Approved
Supplier
# [C076-98] Suppliers HPLC
[Active Material]
Typical HPLC Spectra
In-house Ref.
material
Ref. G
In-house HPLC
[Active Material]
Typical TLC Photocopy
Approved
Supplier
# [C076-98] In-house TLC
[Active Material]
Typical TLC Photocopy
Approved
Supplier
# [C076-98] Suppliers TLC
[Active Material]
Typical TLC Photocopy
In-house Ref.
material
Ref. G
In-house TLC
HANDBOOK OF GENERIC DRUG DEVELOPMENT ANDA DEVELOPMENT
24 Volume Dr ug Development Ser ies Sect: 8.9 DEVELOPMENT Or al Tablets
SECTION VIII SECTION 8
Active Material Control
Attachments.
Page No. ___ to Page No: ___ .
Active Ingredients:
CoA and supporting graphs/Spectra
Three (3) active material Certificates of Analysis attached as per table.
Three (3) active material - I R Spectra - as per table.
Three (3) active material - Typical UV Spectra - as per table.
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)
HANDBOOK OF GENERIC DRUG DEVELOPMENT ANDA DEVELOPMENT
24 Volume Dr ug Development Ser ies Sect: 8.10 DEVELOPMENT Or al Tablets
SECTION VIII SECTION 8
Raw Material Control
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
HANDBOOK OF GENERIC DRUG DEVELOPMENT ANDA DEVELOPMENT
24 Volume Dr ug Development Ser ies Sect: 8.11 DEVELOPMENT Or al Tablets
SECTION VIII SECTION 8
Raw Material Control
Summary of Certificate of Analysis Numbers of Non-active Raw Materials
Used in the Executed (Pivotal) Batch.
Raw Material Certificate of Analysis (CoA) Numbers.
Approved
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)
HANDBOOK OF GENERIC DRUG DEVELOPMENT ANDA DEVELOPMENT
24 Volume Dr ug Development Ser ies Sect: 8.12 DEVELOPMENT Or al Tablets
SECTION VIII SECTION 8
Raw Material Control -
Non active Ingredients
Attachments.
CoAs
Twelve (12) Certificates of Analysis attached as per table.
(Presented in the order of tabulation).
Supporting Documentation
Seven (7) Testing Monographs of non-active materials
Seven (7) Routine Testing Protocols
(List of Routine tests Performed on non-active materials)
Page 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: ___ .
HANDBOOK OF GENERIC DRUG DEVELOPMENT ANDA DEVELOPMENT
24 Volume Dr ug Development Ser ies Sect: 8.13 DEVELOPMENT Or al Tablets
SECTION VIII SECTION 8
Raw Material Control
Non active Ingredients
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
Magnesium Stearate NF
(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
HANDBOOK OF GENERIC DRUG DEVELOPMENT info@iagim.org ANDA DEVELOPMENT
24 V 24 Volume D Drug D Development S Ser ies Sect: 9.1 ANDA DEVELOPMENT
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
(Overall ANDA Guideline Requirements for this Section).
Section Page (with Color Section TAG) and brief descriptor of the section. The
manufacturer of the final dosage form of the new drug for which this application is
submitted is [Generic Company Name Inc. / Ltd.]. The applicant performs all of the
manufacturing, packaging, testing and stability test functions of the submitted drug
product.
[Generic Company Name Inc. / Ltd.] does not manufacturer the active drug
substance, the excipients or the container closure system used in the manufacturing
and packing operations for the finished dosage forms. Details concerning the bulk
active drug substance appears in section VIII as those of the excipients while details
for the container closure system appear in section XIII.
No / [One / Two] contract firms are involved in the finished [product testing],
[packaging components] or [stability testing] requirements as filed in this ANDA
(Delete where required)
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
HANDBOOK OF GENERIC DRUG DEVELOPMENT info@iagim.org ANDA DEVELOPMENT
24 V 24 Volume D Drug D Development S Ser ies Sect: 9.2 ANDA DEVELOPMENT
SECTION IX SECTION 9
Description of Manufacturing Facility
This section contains:-
Addresses of RESEARCH Facilities
[Generic Company Name Inc. / Ltd.]
Description of Facility
Responsible Personnel (Key Staff)
List of Production Equipment
Blueprint of Facility
GMP Certification Statement
Addresses of Scale-up Facilities
[Generic Company Name Inc. / Ltd.]
Description of Facility
Responsible Personnel (Key Staff)
List of Production Equipment
Blueprint of Facility
Addresses of Manufacturing Facilities
[Generic Company Name Inc. / Ltd.]
List of Responsible Personnel (Key Staff)
Blueprint of Facilities
GMP Certification Statement
Drug Establishment Registration No [#00-00-00-00]
NOTE:
Applicant facilities with more than one site who perform special functions at the
specific site (such as analytical or stability testing) need to describe these facilities in
section VIII and X. A separate GMP certificate for that specific site needs to be
included in the application.
4
HANDBOOK OF GENERIC DRUG DEVELOPMENT info@iagim.org ANDA DEVELOPMENT
24 V 24 Volume D Drug D Development S Ser ies Sect: 9.3 ANDA DEVELOPMENT
SECTION IX SECTION 9
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
HANDBOOK OF GENERIC DRUG DEVELOPMENT info@iagim.org ANDA DEVELOPMENT
24 V 24 Volume D Drug D Development S Ser ies Sect: 9.4 ANDA DEVELOPMENT
SECTION IX SECTION 9
Description of Manufacturing Facility
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
HANDBOOK OF GENERIC DRUG DEVELOPMENT info@iagim.org ANDA DEVELOPMENT
24 V 24 Volume D Drug D Development S Ser ies Sect: 9.5 ANDA DEVELOPMENT
SECTION IX SECTION 9
Description of Manufacturing Facility
BLUEPRINT OF MNF FACILITY
Manufacturing, Testing and Storage Areas blueprints - showing facilities layout.
ADDRESSES OF FACILITIES
Manufacturing, processing, bulk packaging, bulk labeling, handling and storage of
the bulk [Generic name] DRUG [USP] [000.0] mg. will take place at the
pharmaceutical manufacturing facility identified below:
[Generic Company Name Inc. / Ltd.]
Pharmaceutical Manufacturing Division
Industrial Area [Street]
[Town] [State] [Zip Code] [Country]. and/or
Unit packaging, labeling and handling of all packed [Generic name] DRUG[USP]
[000.0] mg. will take place at the manufacturing and packaging facility identified
below:
[Generic Company Name Inc. / Ltd.]
Pharmaceutical Packaging Division
Industrial Area [Street]
[Town] [State] [Zip Code] [Country].
The packaged and labeled product will be distributed through the [Address]
warehouse located at:
[Generic Company Name Inc. / Ltd.]
Pharmaceutical Warehouse Division
Industrial Area [Street]
[Town] [State] [Zip Code] [Country].
Finished product release testing and annual stability testing is performed by
[Generic Company Name Inc./Ltd.] Analytical Research / QC Laboratories in
accord with the Division of Generic Drugs Policy and Procedure Guide
at:
[Generic Company Name Inc. / Ltd.]
Analytical Research / QC Laboratories
Industrial Area [Street]
[Town] [State] [Zip Code] [Country].
(Additional information on these sites is provided herein.)
4
HANDBOOK OF GENERIC DRUG DEVELOPMENT info@iagim.org ANDA DEVELOPMENT
24 V 24 Volume D Drug D Development S Ser ies Sect: 9.6 ANDA DEVELOPMENT
SECTION IX SECTION 9
Description of Manufacturing Facility
STATEMENT OF GMP
[Generic Company Name Inc. / Ltd.]
[Generic Company Name Inc. / Ltd.] certifies that the methods used in, and the
facilities and controls used for, the manufacture, processing, packaging and storage
of drugs at our [Generic Company Name Inc./Ltd.] manufacturing plant conform to
Current Good Manufacturing Practice in accord with 21 CFR Parts 210 and 211.
Central File Numbers (CFN) for all facilities used in the manufacture, processing,
labeling and packaging and quality control are CFN [00-0000-00]
and/or
[Third Party Company Name Inc. / Ltd.] certifies that the methods used in, and the
facilities and controls used for, the manufacture, processing, packaging and storage
of drugs at our [Third Party Company Name Inc. / Ltd.] plant conform to Current
Good Manufacturing Practice in accord with 21 CFR Parts 210 and 211.
Central File Numbers (CFN) for all facilities used in the manufacture, processing,
labeling and packaging and quality control are CFN [00-0000-00]
[S i gnature of R esponsi bl e P erson]
------------------------------------------------ -----------------------------------------
[ Name of Responsi bl e Per son] Date
Plant General Manager
Pharmaceutical Manufacturing Division
[Generic Company Name Inc. / Ltd.]
[S i gnature of R esponsi bl e P erson]
------------------------------------------------ -----------------------------------------
[ Name of Responsi bl e Per son] Date
QA Manager
Pharmaceutical Manufacturing Division
[Generic Company Name Inc. / Ltd.]
(Signed GMP statement required for all processing, warehousing and testing sites.)
HANDBOOK OF GENERIC DRUG DEVELOPMENT info@iagim.org ANDA DEVELOPMENT
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
(Overall ANDA Guideline Requirements for this Section).
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
HANDBOOK OF GENERIC DRUG DEVELOPMENT info@iagim.org ANDA DEVELOPMENT
24 V 24 Volume D Dr ug D Development S Ser ies Sect: 10.2 ANDA DEVELOPMENT
SECTION X SECTION 10
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.
[S i gnature of R esponsi bl e P erson]
------------------------------------------------ -----------------------------------------
[ Name of Responsi bl e Per son] Date
QA Manager
Pharmaceutical Quality Assurance Unit
[Generic Company Name Inc./Ltd.]
[S i gnature of R esponsi bl e P erson]
------------------------------------------------ -----------------------------------------
[ Name of Responsi bl e Per son] Date
Production Manager
Pharmaceutical Manufacturing Division
[Generic Company Name Inc./Ltd.]
4
HANDBOOK OF GENERIC DRUG DEVELOPMENT info@iagim.org ANDA DEVELOPMENT
24 V 24 Volume D Dr ug D Development S Ser ies Sect: 10.3 ANDA DEVELOPMENT
SECTION X SECTION 10
Outside firms and Contract Facilities
(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.
[S i gnature of R esponsi bl e P erson]
------------------------------------------------ -----------------------------------------
[ Name of Responsi bl e Per son] Date
QA Manager
Pharmaceutical Manufacturing Division
[Generic Company Name Inc./Ltd.]
[S i gnature of R esponsi bl e P erson]
------------------------------------------------ -----------------------------------------
[ Name of Responsi bl e Per son] Date
Production Manager
Pharmaceutical Manufacturing Division
[Generic Company Name Inc./Ltd.]
4
HANDBOOK OF GENERIC DRUG DEVELOPMENT info@iagim.org ANDA DEVELOPMENT
24 V 24 Volume D Dr ug D Development S Ser ies Sect: 10.4 ANDA DEVELOPMENT
SECTION X SECTION 10
Outside firms and Contract Facilities
ADDRESSES OF FACILITIES
Manufacturing, processing, bulk packaging, bulk labeling, handling and storage of the
bulk [Generic name] Drug [000.0]mg [USP]. will take place at the pharmaceutical
manufacturing facility identified below:
[Third Parties Company Name Inc. / Ltd.]
Pharmaceutical Manufacturing Division
Industrial Area [Street]
[Town] [State] [Zip Code] [Country]
(and / or)
Unit packaging, Labeling and handling of all packed [Generic name] Drug [USP]
[000.0] mg. will take place at the manufacturing and packaging facility identified
below:
[Third Parties Company Name Inc. / Ltd.]
Pharmaceutical Packaging Division
Industrial Area [Street]
[Town] [State] [Zip Code] [Country]
(and / or)
The packaged and labeled product will be distributed through the [Address]
warehouse located at:
[Third Parties Company Name Inc. / Ltd.]
Pharmaceutical Warehouse Division
Industrial Area [Street]
[Town] [State] [Zip Code] [Country]
Finished product release testing and annual stability testing is performed by [Generic
Company Name Inc./Ltd.] Analytical Research / QC Laboratories in accord with the
Division of Generic Drugs Policy and current Procedure Guides
[Third Parties Company Name Inc. / Ltd.]
Analytical Research / QC Laboratories
Industrial Area [Street]
[Town] [State] [Zip Code] [Country]
HANDBOOK OF GENERIC DRUG DEVELOPMENT info@iagim.org ANDA DEVELOPMENT
24 V 24 Volume D Dr ug D Development S Ser ies Sect: 10.5 ANDA DEVELOPMENT
SECTION X SECTION 10
Outside firms and Contract Facilities
STATEMENT OF GMP OF
[Third Parties Company Name Inc. / Ltd.]
[Third Parties Company Name Inc. / Ltd.] certifies that the methods used in,
and the facilities and controls used for, the manufacture, processing, packaging and
storage of drugs at our [Third Parties Company Name Inc. / Ltd.] plant conform to
Current Good Manufacturing Practice in accord with 21 CFR Parts 210 and 211.
[S i gnature of R esponsi bl e P erson]
------------------------------------------------ -----------------------------------------
[ Name of Responsi bl e Per son] Date
General Manager
Pharmaceutical Division
[Third Parties Company Name Inc. / Ltd.]
[S i gnature of R esponsi bl e P erson]
------------------------------------------------ -----------------------------------------
[ Name of Responsi bl e Per son] Date
QA Manager
Pharmaceutical Division
[Third Parties Company Name Inc. / Ltd.]
Note: Current cGMP or if applicable CGLP certification statement(s) are required for
EACH of the third party firms (outside firms) listed in this section
HANDBOOK OF GENERIC DRUG DEVELOPMENT info@iagim.org ANDA DEVELOPMENT
24 V 24 Volume D Dr ug D Development S Ser ies Sect: 10.6 ANDA DEVELOPMENT
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.
[S i gnature of R esponsi bl e P erson]
------------------------------------------------ -----------------------------------------
[ Name of Responsi bl e Per son] Date
Regul at or y Af f ai r s Di r ec t or
[3rd Party Company Name Inc. / Ltd.]
[S i gnature of R esponsi bl e P erson]
__________________________ ______________________
[ Name of Responsi bl e Per son] Date
Di r ec t or Qual i t y Assur anc e Uni t
Pharmaceutical Manufacturing Division
[3rd Party Company Name Inc. / Ltd.]
O
HANDBOOK OF GENERIC DRUG DEVELOPMENT info@iagim.org ANDA DEVELOPMENT
24 V 24 Volume D Dr ug D Development S Ser ies Sect: 10.7 ANDA DEVELOPMENT
Gener i c Dr ug Enf or c ement Ac t - 1992
Third Party Letterhead
STATEMENT
Where Company has a previous conviction
but 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
undersigned firm has not used, is not using and will not in the future use in any
capacity the services of any person who has been debarred pursuant to Section 2 (a)
and or Section 2 (b) Generic Drug Enforcement Act of 1992, 21 USC 335a (a) and/or
(b), in connection with this application.
Wet further certify that during the previous five years our firm has sustained the
following conviction for the types of offenses as set forth in Section 2(a) and Section
2(b) of the Generic Drug Enforcement Act of 1992, 21 USC 335a (a) and/or (b),
Date of Conviction MM/DD/YY
Nature of Conviction Conviction on two counts of fraudulent documentation
pertaining to analytical reports
To the best of [3rd Party Company Name Inc. / Ltd.], knowledge no person
affiliated with the applicant, who is responsible in whole or in part, for the
development or the submission of this application has been convicted of any offense
of the type listed in Section 2(a) and Section 2(b) of the Generic Drug Enforcement
Act of 1992, 21 USC 335a (a) and/or (b), within the five years prior to the date of this
certification.
[S i gnature of R esponsi bl e P erson]
------------------------------------------------ -----------------------------------------
[ Name of Responsi bl e Per son] Date
Regul at or y Af f ai r s Di r ec t or
[3rd Party Company Name Inc. / Ltd.]
4
End of Section 10.
O
HANDBOOK OF GENERIC DRUG DEVELOPMENT info@iagim.org ANDA DEVELOPMENT
24 V 24 Volume D Dr ug D Development S Ser ies Sect: 10.8 ANDA DEVELOPMENT
SECTION X SECTION 10
Outside firms and Contract Facilities
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.
[S i gnature of R esponsi bl e P erson]
------------------------------------------------ -----------------------------------------
[ Name of Responsi bl e Per son] Date
QA Manager
Pharmaceutical Manufacturing Division
[Generic Company Name Inc./Ltd.]
[S i gnature of R esponsi bl e P erson]
------------------------------------------------ -----------------------------------------
[ Name of Responsi bl e Per son] Date
Production Manager
Pharmaceutical Manufacturing Division
[Generic Company Name Inc./Ltd.]
HANDBOOK of GENERIC DRUG DEVELOPMENT ANDA Development
24 Volume Dr ug Development Ser ies Sect: 11.1 DEVELOPMENT Or al Tablets
SECTION XI SECTION 11
Pr oposed Manuf ac t ur i ng I nst r uc t i ons
TABLE OF CONTENTS
(Overall ANDA Guideline Requirements for this Section).
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
HANDBOOK of GENERIC DRUG DEVELOPMENT ANDA Development
24 Volume Dr ug Development Ser ies Sect: 11.2 DEVELOPMENT Or al Tablets
SECTION XI SECTION 11
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.
HANDBOOK of GENERIC DRUG DEVELOPMENT ANDA Development
24 Volume Dr ug Development Ser ies Sect: 11.3 DEVELOPMENT Or al Tablets
SECTION XI SECTION 11
Proposed Manufacturing Instructions
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.
HANDBOOK of GENERIC DRUG DEVELOPMENT ANDA Development
24 Volume Dr ug Development Ser ies Sect: 11.4 DEVELOPMENT Or al Tablets
SECTION XI SECTION 11
Proposed Manufacturing Instructions
PROPOSED COMMERCIAL BATCH MASTER FORMULA
[Generic name] Tablets [USP] [000.0] mg. Lot: [0000-00]
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
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
PART ONE - GRANULATION
SUBLOT TWO
[Active Ingredient] 00 000
00.0 [Intra-granular excipient NF] 00 000
00.0 [Intra-granular excipient NF] 00 000
GRANULATI NG SOLUTI ON 2
- [Purified Water USP] 00 000
- [Purified Water USP] q.s. 00 000
00.0 [Granulating Agent NF] 00 000
- [Alcohol USP 95%] 00 000
- [Alcohol USP 95%] q.s. 00 000
000.0 Theoretical End Weight. 00 000
PART 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
000.0 Theoretical End Weight. 00 000
Edition Number:
01
Effective Date:
APPROVED
Ed. Status:
New
DD/MM/200Y _____________ __________ _______________ _________/________
Department R &D RA QC / QA
HANDBOOK of GENERIC DRUG DEVELOPMENT ANDA Development
24 Volume Dr ug Development Ser ies Sect: 11.5 DEVELOPMENT Or al Tablets
SECTION XI SECTION 11
Proposed Manufacturing Instructions
PROPOSED COMMERCIAL BATCH MASTER FORMULA
[Generic name] Tablets [USP] [000.0 ] mg. Lot: [ 0000-00]
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 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
Name] Tablets [000] mg CORES
Aqueous Film Coating Suspension
000
000.0 Theoretical End Weight. 000
PART SIX - FILM COATING,
SUBLOT 3 3
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
Edition Number:
01
Effective Date:
APPROVED
Ed. Status:
New
DD/MM/200Y _____________ __________ _______________ _________/________
Department R &D RA QC / QA
Aqueous film coat suspension contains 00.% solids
Solids remaining in film coat. Each strength has a full set of manufacturing instructions.
HANDBOOK of GENERIC DRUG DEVELOPMENT ANDA Development
24 Volume Dr ug Development Ser ies Sect: 11.6 DEVELOPMENT Or al Tablets
SECTION XI SECTION 11
Proposed Manufacturing Instructions
MANUFACTURING INSTRUCTIONS FOR COMMERCIAL PRODUCTION
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.
HANDBOOK of GENERIC DRUG DEVELOPMENT ANDA Development
24 Volume Dr ug Development Ser ies Sect: 11.7 DEVELOPMENT Or al Tablets
SECTION XI SECTION 11
Proposed Manufacturing Instructions
MANUFACTURING INSTRUCTIONS FOR COMMERCIAL PRODUCTION
MANUFACTURING INSTRUCTIONS
Machine Sign Date
7b. Check the milled granulate portion for Loss on Drying (LOD).
Use (Type & No) IR machine with temperature set at temperature 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).
HANDBOOK of GENERIC DRUG DEVELOPMENT ANDA Development
24 Volume Dr ug Development Ser ies Sect: 11.8 DEVELOPMENT Or al Tablets
SECTION XI SECTION 11
Proposed Manufacturing Instructions
MANUFACTURING INSTRUCTIONS FOR COMMERCIAL PRODUCTION
MANUFACTURING INSTRUCTIONS
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
fitted with a roller mixer. (#0)
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 _____________ __________ _______________ _________/________
Department R &D RA QC / QA
HANDBOOK of GENERIC DRUG DEVELOPMENT ANDA Development
24 Volume Dr ug Development Ser ies Sect: 11.9 DEVELOPMENT Or al Tablets
SECTION XI SECTION 11
Proposed Manufacturing Instructions
MANUFACTURING INSTRUCTIONS FOR COMMERCIAL PRODUCTION
MANUFACTURING INSTRUCTIONS
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 _____________ __________ _______________ _________/________
Department R &D RA QC / QA
HANDBOOK of GENERIC DRUG DEVELOPMENT ANDA Development
24 Volume Dr ug Development Ser ies Sect: 11.10 DEVELOPMENT Or al Tablets
SECTION XI SECTION 11
Proposed Manufacturing Instructions
MANUFACTURING INSTRUCTIONS FOR COMMERCIAL PRODUCTION
MANUFACTURING INSTRUCTIONS
Machine Sign Date
PART FIVE
Coating Procedure:
25. Identify and verify the cleanliness of the coating equipment in use
Sublot Size ________ Kg. Equal to ___________ tablets.
SUB LOT No 2.
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 _____________ __________ _______________ _________/________
Department R &D RA QC / QA
HANDBOOK of GENERIC DRUG DEVELOPMENT ANDA Development
24 Volume Dr ug Development Ser ies Sect: 11.11 DEVELOPMENT Or al Tablets
SECTION XI SECTION 11
Proposed Manufacturing Instructions
MANUFACTURING INSTRUCTIONS FOR COMMERCIAL PRODUCTION
MANUFACTURING INSTRUCTIONS
Machine Sign Date
PART SIX
Coating Procedure:
25. Identify and verify the cleanliness of the coating equipment in use
Sublot Size ________ Kg. Equal to ___________ tablets.
SUB LOT No 3.
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 _____________ __________ _______________ _________/________
Department R &D RA QC / QA
HANDBOOK of GENERIC DRUG DEVELOPMENT ANDA Development
24 Volume Dr ug Development Ser ies Sect: 11.12 DEVELOPMENT Or al Tablets
SECTION XI SECTION 11
Proposed Manufacturing Instructions
MANUFACTURING INSTRUCTIONS FOR COMMERCIAL PRODUCTION
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
HANDBOOK of GENERIC DRUG DEVELOPMENT ANDA Development
24 Volume Dr ug Development Ser ies Sect: 11.13 DEVELOPMENT Or al Tablets
SECTION XI SECTION 11
Proposed Manufacturing Instructions
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.
HANDBOOK of GENERIC DRUG DEVELOPMENT ANDA Development
24 Volume Dr ug Development Ser ies Sect: 11.14 DEVELOPMENT Or al Tablets
SECTION XI SECTION 11
Proposed Manufacturing Instructions
IN-PROCESS CONTROL SPECIFICATION - TABLET
CORES
SUMMARY
PROPOSED FULL SIZE COMMERCIAL BATCH
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 %
HANDBOOK of GENERIC DRUG DEVELOPMENT ANDA Development
24 Volume Dr ug Development Ser ies Sect: 11.15 DEVELOPMENT Or al Tablets
SECTION XI SECTION 11
Proposed Manufacturing Instructions
IN-PROCESS CONTROL SPECIFICATION - COATING PROCESS
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
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
Weight of 100 tablets #2 (g) 000.0 000.0
Weight of 100 tablets #3 (g) 000.0 000.0
Weight of 100 tablets #4 (g) 000.0 000.0
Weight of 100 tablets #5 (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.
HANDBOOK of GENERIC DRUG DEVELOPMENT ANDA Development
24 Volume Dr ug Development Ser ies Sect: 11.16 DEVELOPMENT Or al Tablets
Difference
in dissolution profile
for controlled release
dosage forms
SECTION XI SECTION 11
Proposed Manufacturing Instructions
RELEASE SPECIFICATION FOR COATED CR/MR TABLETS [USP]
SUMMARY
PROPOSED FULL SIZE COMMERCIAL BATCH
Product: [Generic name] Tablets [USP] [000.0] mg.
Labeled Amount: Each tablet contains: [Active Material] [000.0] mg.
Description [Color] (white to off-white) shaped (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
HANDBOOK of GENERIC DRUG DEVELOPMENT ANDA Development
24 Volume Dr ug Development Ser ies Sect: 11.17 DEVELOPMENT Or al Tablets
SECTION XI SECTION 11
Proposed Manufacturing Instructions
RELEASE SPECIFICATION FOR COATED IR TABLETS [USP]
SUMMARY
PROPOSED FULL SI ZE COMMERCI AL BATCH
Product: [Generic name] Tablets [USP] [000.0] mg.
Labeled Amount: Each tablet contains: [Active Material] [000.0] mg.
Description [Color] (white to off-white) shaped (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)
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.
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
IR = IMMEDIATE RELEASE ER = EXTENDED RELEASE
CR = CONTROLLED RELEASE DR = DELAYED RELEASE (ENTERIC COATED)
HANDBOOK of GENERIC DRUG DEVELOPMENT ANDA Development
24 Volume Dr ug Development Ser ies Sect: 11.18 DEVELOPMENT Or al Tablets
SECTION XI SECTION 11
Proposed Manufacturing Instructions
COMPARISON OF EXECUTED (PIVOTAL) AND PRODUCTION FORMULAE
[Generic name] Tablets [USP] [000.0] mg. Lot: [00-0000]
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
Magnesium Stearate NF
Total
140.000
28.000
98.000
Adjust where applicable (i.e. if moisture content of active is greater than 0.5-1.0%):
Weight Adjustment Calculation:
1
Note: [00.0] mg for [Active Salt] is equivalent to [00.0] mg of [Active] base.
Quantity of [Active Salt] to be weighed = Batch Size x [00.0] x 100
100 - LOD
Where LOD = Loss on Drying of for [Active Salt] =
2
The actual quantity of a non active ingredient such as Starch NF used in the formula will
depend on the WEIGHT for [Active Salt] used.
HANDBOOK of GENERIC DRUG DEVELOPMENT ANDA Development
24 Volume Dr ug Development Ser ies Sect: 11.19 DEVELOPMENT Or al Tablets
SECTION XI SECTION 11
Proposed Manufacturing Instructions
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
HANDBOOK of GENERIC DRUG DEVELOPMENT ANDA Development
24 Volume Dr ug Development Ser ies Sect: 11.20 DEVELOPMENT Or al Tablets
DIRECT COMPRESSION
MODEL
ALENDRONATE TABLETS
5.0 AND 10 mg
DC TABLETS
HANDBOOK of GENERIC DRUG DEVELOPMENT ANDA Development
24 Volume Dr ug Development Ser ies Sect: 11.21 DEVELOPMENT Or al Tablets
SECTION XI SECTION 11
Proposed Manufacturing Instructions
MANUFACTURING INSTRUCTIONS FOR COMMERCIAL PRODUCTION
Identification of Batch Parameters.
Product name: Alendronate Tablets 5.0 and 10 mg.
Batch Number: IA97-06
Department: ______________ Batch Size: 1000 000 units
Precautions: Sub-lot No: 1 2 3
Caution: Manufacture Date: 200Y
Cat./Formula No: # MF-104 Cores : Coated Tablets
Based on PQ: Batch # PQ106 PIVOTAL BATCH
Validation Lot Commercial Lot
Change Control for this document: Original - No Change : Change
Change made: - none
KEY t o :
Precautions: Wear Mask and Gloves
Wear disposable overalls
Use air stream face visor with AIR filter
Use Mask, Gloves and Safety glasses
Material causes extreme irritation to skin and eyes
Do not expose to skin or exposed areas.
Caution: Avoid exposure to light / Protect form light
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%
HANDBOOK of GENERIC DRUG DEVELOPMENT ANDA Development
24 Volume Dr ug Development Ser ies Sect: 11.22 DEVELOPMENT Or al Tablets
SECTION XI SECTION 11
Proposed Manufacturing Instructions
MANUFACTURING INSTRUCTIONS FOR COMMERCIAL PRODUCTION
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
Magnesium Stearate NF
0 750
100.00 Theoretical End Weight. 100 000
100 Tablet weight 5 mg
200 Tablet weight 10mg
Edition Number:
02
Effective Date:
APPROVED
Ed. Status:
SPDS 01
DD/MM/200Y _____________ __________ _______________ _________/________
Department R &D RA QC / QA
* 13.05 mg of sodium salt is equivalent to free acid
HANDBOOK of GENERIC DRUG DEVELOPMENT ANDA Development
24 Volume Dr ug Development Ser ies Sect: 11.23 DEVELOPMENT Or al Tablets
SECTION XI SECTION 11
Proposed Manufacturing Instructions
MANUFACTURING INSTRUCTIONS FOR COMMERCIAL PRODUCTION
ALENDRONATE TABLETS 5.0 /10 MG LOT: IA97-06
MANUFACTURING INSTRUCTIONS
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
Mixing time - Start _______
Mixing time - Stop _______
Total Mixing Time is 23 minutes.
Edition Number:
02
Effective Date:
APPROVED
Ed. Status:
SPDS 01
DD/MM/200Y _____________ __________ _______________ _________/________
Department R &D RA QC / QA
HANDBOOK of GENERIC DRUG DEVELOPMENT ANDA Development
24 Volume Dr ug Development Ser ies Sect: 11.24 DEVELOPMENT Or al Tablets
SECTION XI SECTION 11
Proposed Manufacturing Instructions
MANUFACTURING INSTRUCTIONS FOR COMMERCIAL PRODUCTION
ALENDRONATE TABLETS 5.0 /10 MG LOT: IA97-06
MANUFACTURING INSTRUCTIONS
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
Mixing time - Start _______
Mixing time - Stop _______
Total blending Time is 15 minutes.
Step 5.
SIFT the Magnesium Stearate NF through a vibrating sieve (Type
& No) fitted with a 100.0 mesh screen.
Step 6.
ADD the sieved material Magnesium Stearate 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.
Theoretical Weight [100.0] Kg. Yield ___________ %
(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 _____________ __________ _______________ _________/________
Department R &D RA QC / QA
HANDBOOK of GENERIC DRUG DEVELOPMENT ANDA Development
24 Volume Dr ug Development Ser ies Sect: 11.25 DEVELOPMENT Or al Tablets
SECTION XI SECTION 11
Proposed Manufacturing Instructions
MANUFACTURING INSTRUCTIONS FOR COMMERCIAL PRODUCTION
MANUFACTURING INSTRUCTIONS
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
Tabletting machine: (Type & No).
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 _____________ __________ _______________ _________/________
Department R &D RA QC / QA
HANDBOOK of GENERIC DRUG DEVELOPMENT ANDA DEVELOPMENT
24 Volume Dr ug Development Ser ies Sect: 11.26 DEVELOPMENT Or al Tablets
SECTION XI SECTION 11
Proposed Manufacturing Instructions
MANUFACTURING INSTRUCTIONS FOR COMMERCIAL PRODUCTION
ALENDRONATE TABLETS 5.0 /10 MG LOT: IA97-06
ATTACHMENTS:
THE FOLLOWING ATTACHMENTS ARE PLACED HERE:
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
HANDBOOK of GENERIC DRUG DEVELOPMENT ANDA Development
24 Volume Dr ug Development Ser ies Sect: 11.27 DEVELOPMENT Or al Tablets
SECTION XI SECTION 11
Proposed Manufacturing Instructions
IN-PROCESS CONTROL SPECIFICATION - BLENDED MATERIAL
SUMMARY OF YIELD AND LIMIT VALUES FOR
ALENDRONATE TABLETS 5.0 /10 mg LOT: IA97-06
MANUFACTURING INSTRUCTIONS FOR COMMERCIAL PRODUCTION
Product: ALENDRONATE TABLETS 5.0 /10mg LOT: IA97-06
Quantity 1000 000
Yields
Final Blend 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.
HANDBOOK of GENERIC DRUG DEVELOPMENT ANDA Development
24 Volume Dr ug Development Ser ies Sect: 11.28 DEVELOPMENT Or al Tablets
SECTION XI SECTION 11
Proposed Manufacturing Instructions
IN-PROCESS CONTROL SPECIFICATION
TABLET / CORES
MANUFACTURING INSTRUCTIONS FOR COMMERCIAL PRODUCTION
Product: ALENDRONATE TABLETS 5.0 /10 mg LOT: IA97-06
Labeled Amount: Each tablet contains ALENDRONATE 5.0 or 10.0 mg.
In-process tablet specifications
Punch Diameter 5.0mg 6.5 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
Individual core weight (7.5%) Nominal 100.0 Limit: 92.5 - 107.5 mg:
Average core weight (5.0%) Nominal 100.0 Limit: 95.0 - 105.0 mg:
10 mg 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.
Friability NMT 1.0 %
HANDBOOK of GENERIC DRUG DEVELOPMENT ANDA Development
24 Volume Dr ug Development Ser ies Sect: 11.29 DEVELOPMENT Or al Tablets
SECTION XI SECTION 11
Proposed Manufacturing Instructions
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
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.
5 mg TABLET
Individual weight (7.5%) Nominal 100.0 Limit: 92.5 - 107.5 mg:
Average weight (5.0%) Nominal 100.0 Limit: 95.0 - 105.0 mg:
10 mg 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:
Uniformity of Dosage Units Conforms to the current USP
Content Uniformity
Dissolution Equipment: USP App. 2 (Paddle)
Media: 900 mL, 37 C. Deaerated Water
pH 6.8 RPM 100
Tolerance: NLT [80]% (Q) of the labeled
is dissolved in [30] minutes.
Impurities /Degradation
(1)
Products determination
- Each Individual: NMT 0.5% of the labeled amount
- Any other Individual: NMT 0.5% of the labeled amount
- Total: NMT 2.0% of the labeled amount
Assay Limit: 95.0 - 105.0% of labeled amount
5mg Equal to [4.75] - [5.25] mg / Tablet.
Assay Limit: 95.0 - 105.0% of labeled amount
10 mg Equal to [9.5] - [10.5] mg / Tablet.
(1)
Vendor or approved supplier dependent.
HANDBOOK of GENERIC DRUG DEVELOPMENT ANDA Development
24 Volume Dr ug Development Ser ies Sect: 11.30 DEVELOPMENT Or al Tablets
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
HANDBOOK of GENERIC DRUG DEVELOPMENT ANDA Development
24 Volume Dr ug Development Ser ies Sect: 11.31 DEVELOPMENT Or al Tablets
SECTION XI SECTION 11
Proposed Manufacturing Instructions
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
HANDBOOK of GENERIC DRUG DEVELOPMENT ANDA Development
24 Volume Dr ug Development Ser ies Sect: 11.32 DEVELOPMENT Or al Tablets
SECTION XI SECTION 11
Proposed Manufacturing Instructions
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
Cotton Coil
Insert / Leaflet
Capping (Screw or CRC)
or Outsert Attaching
Container Label