What are generic drugs?

A generic drug is a copy

that is identical to a brand
name drug in dosage,
safety, strength, how it is
taken, quality, performance
and intended use.

Did you know that generic drugs...

Are safe and effective alternatives to brand name
prescriptions
Can help both consumers and the government reduce
the cost of prescription drugs
Are currently used in 44% of all prescriptions dispensed
Save an average of $45.50 for every prescription sold
Currently save consumers $56.7 billion/year
Can save consumers an additional $1.32 billion/year for
every 1% increase in the use of generic drugs

Generic drugs less expensive- Why?

The main reasons is :

Because generic manufacturers dont have the investment

costs of the developer of a new drug.
New drugs are developed under patent protection. The
patent protects the investmentincluding research,
development, marketing, and promotionby giving the
company the sole right to sell the drug while it is in effect.
As patents/Exclusivities near expiration, manufacturers can
apply to the FDA to sell generic versions. As those
manufacturers dont have the same development costs, they
can sell their product at substantial discounts.
Also, there is greater competition, which keeps the price
down. Today, almost half of all prescriptions are filled with
generic drugs

If brand-name drugs and generic drugs have the same

active ingredients, why do they look different?

In the United States, trademark laws do

not allow a generic drug to look exactly
like the brand-name drug. However, a
generic drug must duplicate the active
ingredient. Colours, flavours, and certain
other inactive ingredients may be
different.

Does every brand-name drug have a generic

counterpart?
No. When brand-name drugs are first introduced,
most are patent protected for 17 to 20 years. This
provides protection for the innovator who laid out
the initial costs (including research, development,
and marketing expenses) to develop the new drug.
However, when the patent expires, other drug
companies can introduce competitive generic
versions, but only after they have been thoroughly
tested by the manufacturer and approved by the
FDA.

How to assure the quality of generic drugs?

First 5 steps of review process are
identical to NDA process
Bioequivalence for complicated
products is discussed with the same
staff that reviewed the brand product
FDA has experience with the product
Scientific literature published
Product is known to be safe
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Hatch-Waxman Amendments to F&C Act - 1984

Considered one of the most successful pieces of legislation ever
passed
Created the generic drug industry
Compromise legislation to benefit both brand and generic firms
Allowed generic firms to rely on findings of safety and efficacy
of innovator drug after expiration of patents and exclusivities
(do not have to repeat expensive clinical and pre-clinical trials)
Allowed patent extensions and exclusivities to innovator firms

What are the requirements for a generic drug?

Same active ingredient(s)

Same route of administration
Same dosage form
Same strength
Same conditions of use
Compared to reference listed drug
(RLD) - (brand name product)
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NDA vs. ANDA Review Process

Brand Name Drug
NDA Requirements

Generic Drug
ANDA Requirements

1.
2.
3.
4.
5.
6.
7.
8.

1.
2.
3.
4.
5.

Chemistry
Manufacturing
Controls
Labeling
Testing
Animal Studies
Clinical Studies
Bioavailability

Chemistry
Manufacturing
Controls
Labeling
Testing

6. Bioequivalence

10

Orange Book
Book
All FDA approved drug products
listed
(NDAs, OTCs & ANDAs)
Therapeutic equivalence codes
A = Substitutable
B = Inequivalent, NOT Substitutable

Expiration dates: patent and exclusivity

Reference Listed Drugs/brand drugs
identified by FDA for generic companies
to compare with their proposed products

18

Generic
Drug
Review
Process

19

ANDA
Abbreviated New Drug Application

Organization of ANDA

20

Regulations to be referred
Content&Format of an Application -

21CFR314.50

Content & Format of ANDA Application-21CFR314.94

Address for Applications-

21CFR314.440

21

How to Organize application

A.
B.
C.
D.
E.
F.

Application copies and General Format

Cover Letter
Table of Contents
Tabs
Pagination
Field Copy- Additional Information

22

Application Copies and General Format

Applicants should submit
Archival Copy
Review Copy
Field Copy

23

Archival Copy
What does it mean:
A Complete copy of the abbreviated application intended to
serve as the official reference source for the Agency.
It is retained by the agency and serves as the sole file copy
of the approved application

Specifications for Archival Copy are

Poly vinyl 0.023 to 0.025 gauge
Front Cover (Flat Size):248X292 mm
Back Cover (Flat Size):248X305 mm
Colour of the Copy is Blue
Hidden reinforced one inch hinges for front
and back covers
Rounded outside covers for front and back
covers.

24

Review Copy
What does it mean:
A duplicate of the archival copy for use of Agency
reviewers. It is destroyed after the approval of
application.
Specifications for Review Copy are
Extra-Heavy paper (or Poly vinyl)
Front Cover (Flat Size):267X292 mm
Back Cover (Flat Size):267X305 mm
Colour of the Copy is Red and Orange
Red Copy-Chemistry, Manufacturing and
Controls
Orange Copy- Bioavaliability/Bioequivalance
Hidden reinforced one inch hinges for front
and back covers
Rounded outside covers for front and back
covers.

25

Field Copy

What does it mean:

A duplicate of the archival copy to be submitted for
use by FDA Investigators
Specifications for field Copy are
Extra-heavy paper (or polyvinyl)
Front Cover (Flat Size):248X292 mm
Back Cover (Flat Size):248X305 mm
Colour of the Copy is Burgundy

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Cover Letter
Each submission should be accompanied by a dated
cover letter with a clear, brief introductory statement.
The cover letter should contain
Purpose of submission

Type of Submission
Name, title, signature, and address of the applicant
Proprietary name (if any) and established name of the drug
Number of Volumes Submitted
Commitment to resolution of any issues identified in the
methods of validation process after approval.
Statement that the application
Clearly identify submissions that contain
sterility assurance data
In case of SUPAC only the following things to be addressed:
A brief description of the change addressed by the
submission
An indication of which SUPAC guidance is referenced
A statement identifying the specific section of that guidance.

27

Table of Contents21CFR314.50(b)
Each original application must include a table of contents.
If a section of the table of contents does not apply to a
particular application,this should be stated in the table
of contents, and a page should be inserted behind a tab
for that section, stating Not Applicable
If the archival copy or review copy of the application
results in more than one volume, the table of contents
should be duplicated and a copy placed in each volume.

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Suggested Table of contents

ANDA application shall contain following sections
Section

Content

Reference

Signed Application Form

(Recommended form FDA356h or FDA 3439)

21CFR314.94(a)(1)

II

Basis for ANDA Submission

21CFR314.94(a)(3)

III

Patent certification &

Exclusivity statement of drug

IV

Comparison between Generic Drug and RLD

1.Conditions of Use
2. Active Ingredient(s) and supporting information
3.In active Ingredients as appropriate
4. Route of Administration, dosage form, and strength
5.Labeling comparison

21CFR314.94(a)(4)
21CFR314.94(a)(5)
21CFR314.94(a)(9)
21CFR314.94(a)(6)

Labelling
Note: 4 copies of draft labelling or 12 copies of final
printed labelling should be submitted

21CFR314.94(a)(8)

VI

Bioavailability/Bioequivalance
1.Financial Certification/disclosure statement
2.In vivo study protocols
3. .In vivo studies
4. Request for waiver of in vivo studies
5. In vitro dissolution data
6.Formulation Data (Comparison of all strengths)

21CFR314.94(a)(12)
21CFR314.94(a)(3)

21CFR314.94(a)(7)

29

Suggested Table of contents

ANDA application shall contain following sections
Section

Content

VII

Components and Composition Statements

VIII

1.Active Ingredient(s)
CofA specs and test results from Vendor
a.
Testing Specs &data from Vendor
b.
Spectra&Chromatograms for RS and Testing
Samples
c.
Retesting Period
2.Inactive Ingredients
a.
Synthesis listing manufacturer/Supplier(Type II
DMF Letters)
b.
Suppliers C of As
c.
Retest Schedule

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.
cGMP certification
4.
Central File Numbers

Bioavailability/Bioequivalance
1.Financial Certification/disclosure statement
2.In vivo study protocols
3. .In vivo studies
4. Request for waiver of in vivo studies

Reference

21CFR314.94(a)(9)

21CFR314.94(a)(7)

30

Suggested Table of contents

ANDA application shall contain following sections
Section

Content

Out side firms, including contract Testing Laboratories

1.Full Address
2.Functions
3.cGMP certification/GLP

XI

Manufacturing and Processing Instructions

1.Description of Manufacturing
(Including Microbiological verification in Section XIV, as appropriate)
2.Blank Batch records for largest intended commercial production runs with
equipment specified
3.Reprocessing Statement

XII

In-Process Information
1.
Copy of executed batch record with equipment specified, including
packaging records, and batch reconciliation
2.
In-Process controls
a) Test Procedures
b) Specifications and data

XIII

Packaging Materials Controls

1.Summary of Packaging System
2.Components Specification and Test Data (Type III DMF references)
3.Packaging Configuration and sizes
4.Container/Closure testing(include ingress testing in Section XXII, as
appropriate)
5.Vendor Qualification Specifications

Referen
ce
NIL

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Suggested Table of contents

ANDA application shall contain following sections
Section

Content

XIV

Controls for the Finished Dosage Form

1.Test Procedures
2.Testing specifications and Data (COA)

XV

Analytical Methods
(Two additional separately bound copies if the drug
substance and/or drug product are not USP
article)
1.Methods for drug substance
a) Method Validation
b) Test Specification & Data
2.Methods of Drug product
a) Method Validation
b) Test Specification & Data

XVI

Stability of Finished Dosage Form

1.
stability testing protocol
2.
Post Approval Commitments
3.
Expiration dating period
4.
Stability Data submitted
5.
Stability- indicating test data of samples under
various stress conditions

XVII

RESERVED

Reference

34

Suggested Table of contents

ANDA application shall contain following sections
Section

Content

Reference

XVIII

Sample availability and identification of

1. Drug Substance
2.Finished dosage Form

21CFR314.94(a)
(10)

XIX

Environmental Consideration: Environmental assessment

of claim of Categorical Exclusion

21CFR314.94(a)
(9)

XX

Generic Drug Enforcement Act and U.S Agent letter of

Authorization

XXI

Other
1.
Reference to previously submitted information
2.
Literature publication for which English translation is
submitted
3.
Letter of authorization (two Copies)
4.
Field Copy Certification

XXII

21CFR314.94(a)
(11)

Sterilization Assurance Information and Data

35

Tabs
The contents of sections should be organized by sections
Each section should be identified by a tab that corresponds
to the section
The tab should show the section number and brief descriptor
of the section
(e.g. Section VI- Bioavailability/Bio equivalence).
Applicants can also use tabs for subsections within a
section. In this event, use of a different colour tab for the
subsection would be helpful.

36

Pagination

All Pages of the application should be numbered in sequence.(Except

the tabs
The sequence should begin with page number one for the front side of
the Application Form and continue to the end of the document without
any breaks in numbering sequence.
Correct pagination is essential to the reviewer for locating the
material in application
If the Review Copy is in two sections to provide BA/BE data separate
form CMC, for each discipline will contain the common information and
the data for review.
The page numbers should be consistent with those sections in the
archival copy.

37

Refusal to approve ANDA (By FDA)

FDA refuses the submitted applications under following conditions,
but not limited to (Under 21CFR314.125)

The methods used in, or the facilities & controls used for, the
manufacture,processing, and packing of the drug product are
inadequate to ensure and preserve its identity, strength, purity and
quality.
Insufficient information submission
Improper labeling
If RLD has more than one active ingredient, the active ingredients
are the same as the active ingredients of the RLD
Different route of administration when compared with RLD
Different strength when compared with RLD
A change in an inactive ingredient so that the product does not
comply with an official compendium

38

Effective date of approved application

After releasing the Date of approval letter by

FDA(Under21CFR314.105)
After the patent expiration certification-(Under21CFR314.105)
After the disposition of patent litigation{Under21CFR314.94(a)(12)}
Effective date will delayed by the agency..
a)Delay due to exclusivity
b)court actions etc..

39

Time frames for Reviewing ANDAs

Within 60 days after FDA receives an application, the agency will

determine whether the application may be filed.
Within 180 days of receipt of an application, FDA will review it and
send the applicant either an approval letter (Under21CFR314.105)
or a not approvable letter (Under21CFR314.120). This 180-day
period is called the review clock
During the review period an application may withdraw an
application(Under21CFR314.99) and later resubmit it. But FDA will
treat the resubmission as a new application

40

Recommended Specifications (&) Mailing Address

The Volumes of an application should not be more than 3 inches

thick
The name&address of the applicant, the name of the drug, dosage
form, and strength of the drug should be displayed on the Front of
the binder of each volume
The volumes should not be numbered. The Agency will number
the volumes.
All Original abbreviated applications should be submitted in
binders
Small amendments or supplements not contained within binders
should be bound with fasteners and without staples.
Mailing Address:

Office of Generic Drugs,(HFD-600)

Center for Drug Evaluation and Research,

Food & Drug Administration,5600
Fishers Lane Rockville, MD 20857
United States of America.

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Thank You

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