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.

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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

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 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

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 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.

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 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.

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 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

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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 Generic Drug

NDA Requirements ANDA Requirements
1. Chemistry 1. Chemistry
2. Manufacturing 2. Manufacturing
3. Controls 3. Controls
4. Labeling 4. Labeling
5. Testing 5. Testing
6. Animal Studies
7. Clinical Studies 6. Bioequivalence
8. Bioavailability

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 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

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Generic
Drug
Review
Process

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 ANDA
Abbreviated New Drug Application

Organization of ANDA

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 Regulations to be referred

Content&Format of an Application - 21CFR314.50

Content & Format of ANDA Application-21CFR314.94

Address for Applications- 21CFR314.440

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How to Organize application

A. Application copies and General Format

B. Cover Letter
C. Table of Contents
D. Tabs
E. Pagination
F. Field Copy- Additional Information

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Application Copies and General Format

Applicants should submit

Archival Copy

Review Copy

Field Copy

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 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.

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 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.
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 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.

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 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
I Signed Application Form 21CFR314.94(a)(1)
(Recommended form FDA356h or FDA 3439)
II Basis for ANDA Submission 21CFR314.94(a)(3)
III Patent certification & 21CFR314.94(a)(12)
Exclusivity statement of drug 21CFR314.94(a)(3)
IV Comparison between Generic Drug and RLD
1.Conditions of Use 21CFR314.94(a)(4)
2. Active Ingredient(s) and supporting information 21CFR314.94(a)(5)
3.In active Ingredients as appropriate 21CFR314.94(a)(9)
4. Route of Administration, dosage form, and strength 21CFR314.94(a)(6)
5.Labeling comparison
V Labelling
Note: 4 copies of draft labelling or 12 copies of final 21CFR314.94(a)(8)
printed labelling should be submitted
VI Bioavailability/Bioequivalance
1.Financial Certification/disclosure statement
2.In vivo study protocols 21CFR314.94(a)(7)
3. .In vivo studies
4. Request for waiver of in vivo studies
5. In vitro dissolution data
6.Formulation Data (Comparison of all strengths)

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 Suggested Table of contents
ANDA application shall contain following sections
Section Content Reference
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 21CFR314.94(a)(9)
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
X Bioavailability/Bioequivalance
1.Financial Certification/disclosure statement
2.In vivo study protocols 21CFR314.94(a)(7)
3. .In vivo studies
4. Request for waiver of in vivo studies 30
 Suggested Table of contents
ANDA application shall contain following sections
Section Content Referen
ce
X Out side firms, including contract Testing Laboratories NIL
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 33
 Suggested Table of contents
ANDA application shall contain following sections
Section Content Reference
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

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 Suggested Table of contents
ANDA application shall contain following sections
Section Content Reference
XVIII Sample availability and identification of 21CFR314.94(a)
1. Drug Substance (10)
2.Finished dosage Form
XIX Environmental Consideration: Environmental assessment 21CFR314.94(a)
of claim of Categorical Exclusion (9)

XX Generic Drug Enforcement Act and U.S Agent letter of

Authorization
XXI Other
1. Reference to previously submitted information 21CFR314.94(a)
2. Literature publication for which English translation is (11)
submitted
3. Letter of authorization (two Copies)
4. Field Copy Certification
XXII Sterilization Assurance Information and Data

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 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.

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 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.

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 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

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 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..

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 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

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 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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