ABBREVIATED NEW

DRUG APPLICATION
(ANDA) & PRESENTED BY :
SUPPLEMENTED NEW RUIANN FERNANDES
DRUG APPLICATION ROLL.NO: 03

(SNDA) M PHARM SEM I (MQA)

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ANDA INTRODUCTION
An abbreviated new drug application (ANDA): contains data which
is submitted to FDA for the review and potential approval of a
generic drug product.

Once approved, an applicant may manufacture and market the

generic drug product to provide a safe, effective, lower cost
alternative to the brand-name drug it references.

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 INTRODUCTION
Generic drug applications are termed "abbreviated" because they
are generally not required to include preclinical (animal) and
clinical (human) data to establish safety and effectiveness.

To be approved by FDA, the generic version must deliver the same
amount of active ingredients into a patient's bloodstream in the
same amount of time as the innovator drug.

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BASIC GENERIC DRUG REQIREMENTS
A generic drug is same as a reference-listed (i.e., brand name ) drug with respect to:
• Conditions of use.
• Active ingredient(s).
• Route of administration.
• Dosage form.
• Strength and
• Labelling.

In addition the generic drug must be bioequivalent to (i.e., perform in the same manner
as ) the brand name drug.

It should have the same clinical effect and safety profile as the brand name drug when
administered under the conditions specified in the labelling. 4
 BASIC GENERIC DRUG
REQIREMENTS
Sometimes generic versions of drug have different colours, flavours
or inactive ingredients and also do not look alike the branded ones
because of trade mark laws.

In such cases generics are available once the patent protection
available to the original developer expires.

When the patent expires, firms offering the generic substitutes may
enter the market and start selling the copies of original drug.

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BASIC GENERIC DRUG REQIREMENTS
The generics are cheaper because:
I. The generic manufacturers do not have to incur the cost of searching and
finding a new drug to treat a particular illness.

II. The generic mfg do not require to carry out clinical trials, only
bioequivalence is mandatory to prove their equivalency to the innovator.

III. These companies get the advantage of marketing established by

innovators, as the drug is usually in the market for a decade or so.

IV. They are also not required to spend much on the sales promotion.
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BASIC GENERIC DRUG
REQUIREMENTS
Same active ingredient(s)

Same route of administration

Same dosage form

Same strength

Same conditions of use

Inactive ingredients already approved in a similar NDA

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WHEN A
GENERIC
DRUG CAN Generic drugs
can be

BE
produced
when

PRODUCED ?
2)The generic
company certifies 3)In countries
the brand where the drug
1)The patent has does not have
company’s patents
expired are either invalid, current patent
unenforceable or protection
will not be infringed

4)For drugs
which have
never held
patents
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ANDA APPROVAL PROCESS

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 APPLICANT
 ANDA
APPROVAL ANDA
PROCESS
Acceptable & Complete Refuse to file – letter
issued
YES
REVIEW BY OGD / CDER

Bioequivalence Review Chemistry / Micro Review

Request for plant inspection Labelling review

Bioequivalence review YES

Chemistry / Micro /
acceptable
NO Labelling review
Bioequivalent deficiency acceptable
letter NO
Not approvable letter
Preapproval inspection
Approval differed pending
ANDA Approved satisfactory results
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HATCH-
WAXMAN ACT
The "Drug Price Competition and Patent Term
Restoration Act of 1984," also known as the
Hatch-Waxman Amendments, established
bioequivalence as the basis for approving
generic copies of drug products.

These act permit FDA to approve applications

to market generic versions of brand-name
drugs without repeating costly and duplicative
clinical trials to establish safety and efficacy.

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HATCH-WAXMAN ACT
The generic applicant is required to demonstrate therapeutic
equivalence to a specified previously approved “reference listed drug”
without submission of clinical studies and other data required in a full
NDA.

ANDA contains data that, when submitted to the FDA’s Centre for
Drug Evaluation and Research (CDER) and Office of Generic Drug
(OGD), provides for the review and approval of generic drug product.

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 SUBMISSION OF ANDA
APPLICATION
The application for the generic drug approval is needed to be
submitted in CTD format to the FDA.

The CTD format was developed by the International Council for

Harmonisation of Technical Requirements for Pharmaceuticals for
Human Use (ICH) in an attempt to streamline the submission
requirements for Japan, the European Union, and the United
States.

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SUBMISSION OF ANDA
APPLICATION
The electronic CTD (eCTD) is the standard format for electronic
regulatory submissions for ANDAs.

As of May 5, 2017, ANDAs and submissions to ANDAs (which

includes amendments, supplements, and reports) must be
submitted to FDA electronically in eCTD format.

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CTD
TRIANGLE:

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SUBMISSION OF ANDA
APPLICATION
 CTD format for filling of ANAD application.

The CTD is comprised of the following modules:

• Module 1:Administrative Information and Prescribing Information
• Module 2: Summaries
• Module 3: Quality (CMC)
• Module 4: Nonclinical study reports
• Module 5: Clinical study reports

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SUBMISSION OF ANDA
APPLICATION
Module 1 : Administrative
• Required for Generic and New Drug Applications.
• Specific for the agency like FDA, UK MHRA, etc.
• Regulatory information.
• Forms and cover letters.
• Administrative information.
• References.
• Labelling information.

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SUBMISSION OF ANDA
APPLICATION
 Module 2: CTD Summaries
 CMC and Bioequivalence information.
• Quality overall summary.
• Clinical summary – Bioequivalence studies.

 Module 3: Quality
• Details of drug substance.
• Details of drug product.
• Product development.
• Regional information. 18
SUBMISSION OF ANDA
APPLICATION
 Module 4: Non-clinical data study reports
• Not required for generic applications.

 Module 5: clinical stud reports

• Tabular listing of all studies.
• Clinical study reports.
• Literature reports.
• SAS files in main folder of Module 5

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SUBMISSION OF ANDA
APPLICATION
Three copies of ANDA are required to be submitted: an archival copy,
a review copy and a field copy.
An archival copy shall include the following information:

• Patent certification
• Financial certification
• Application form
• Table of contents
• Basis for ANDA
ingredients
• •
Route of administration Labeling
• •
Dosage form and strength Chemistry
• Bioequivalence • Manufacturing
• Other information • Samples

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TYPES OF ANDA PATENT
CERTIFICATION
In ANDA application, a generic applicant must submit to FDA one out of
four certifications specified in Act regarding the patents for the RLD
(Reference Listed Drug ).

PARAGRAPH I:
• Is made when the innovator has not made the required
patent information in the Orange book.

PARAGRAPH II:
• Is made when the patent has expired i.e the drug is
already off patent.
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TYPES OF ANDA PATENT CERTIFICATION

PARAGRAPH III:
• When the applicant does not have any plans to
sell the generic drug until the generic drug is off
patent.

PARAGRAPH IV:
• Is made when the applicant believes its product or the use
of its product does not infringe on the innovator’s patents
or where the applicant believes such patents are not valid
or enforceable.

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REVIEW AND APPROVAL/
DISAPPROVAL OF ANDA

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REVIEW AND APPROVAL OF
ANDA
• Three divisions within FDA’s Centre for Drug Evaluation and Research
(CDER), and Office of Generic Drugs (OGD), review all ANDAs.

• On receipt of the application, a pre-filling assessment of its

completeness and its acceptability is performed by a project
manager within the regulatory support branch.

• If the initial REVIEW is found in order, then acceptability letter is sent

to the applicant.

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REVIEW AND APPROVAL OF
ANDA
• The application is reviewed at Bioequivalence division, microbiology
and division of labelling and program support.

• The applicant is intimated to provide information or data if any

deficiency is found at any review division to address the deficiency.

• After all components of the application are found to be acceptable, an

APPROVAL or tentative letter is issued to the applicant.

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SUPPLEMENTAL NEW
DRUG APPLICATION

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INTRODUCTION
Supplement :
• A supplement is an application to allow a company to make changes
in a product that already has an approved new drug application
(NDA).

• CDER must approve all important NDA changes (in packaging or

ingredients, etc..) to ensure the conditions originally set for the
product are still met.

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INTRODUCTION
Supplement Number:
• A supplement number is associated with an existing FDA New Drug
Application (NDA) number.
• Companies are allowed to make changes to drugs or their labels after
they have been approved.
• To change a label, market a new dosage or strength of a drug, or
change the way it manufactures a drug, a company must submit a
supplemental new drug application (sNDA).
• Each sNDA is assigned a number which is usually, but not always,
sequential, starting with 001.
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INTRODUCTION
Supplement Type :
• The supplement type refers to the kind of change that was approved
by FDA.
• This includes changes in:

manufacturing
patient population
formulation
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Why change is required :
To alter / improve the product or to introduce
additional safeguard.

To meet the market requirements-- scale up, add

manufacturing site.

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Post approval changes include:
(1) Components and composition.
(2) Manufacturing sites.
(3) Manufacturing process.
(4) Specifications.
(5) Container closure system and labelling.
(6) Miscellaneous changes and multiple related changes.

An applicant should consider all relevant CDER guidance

documents &submit all necessary information to support a given
change.
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CONDITION
Changes may have potential impact on the quality,
safety or efficacy of products.

Any change to prequalified products are subject to

approval by FDA & CDER.

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GUIDANCE ON VARIATION AS
PER US FDA
There are three categories of variations according to their potential
impact on pharmaceutical quality, they are Major, Moderate and
Minor Changes.

Major changes : substantial potential to have an adverse effect on

the;
• identity, strength, quality, purity, or potency of a drug product as
these factors may relate to the safety or effectiveness of the drug
product.
• These are labelled as Prior Approval Supplement.
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GUIDANCE ON VARIATION AS
PER US FDA
Moderate changes: moderate potential to have an adverse effect.
• 2 types:
• 1 requires the submission of a supplement to FDA at least 30 days
before the distribution of drug product. labelled as: Supplement -
Changes Being Effected in 30 Days.

• 2 for which distribution can occur when FDA receives the

supplement. labelled as: Supplement - Changes Being Effected.

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GUIDANCE ON VARIATION AS
PER US FDA
• If FDA disapproves may cease distribution.
• FDA say prior approval supplement is required.
• If information is missing: distribution is delayed untill amendment is
made.

Minor changes: has minimal potential to have an adverse effect.

• The applicant must describe minor changes in its next Annual
Report.

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GUIDANCE ON VARIATION TO A
PREQUALIFIED PRODUCT
To facilitate classification of various types of changes.
The variation guide is composed of 4 Appendixes :-

Appendix IV:
Appendix III: stability
Appendix I:
Appendix II: changes that requirements
lists minor
definition and make a new for variations
changes,
examples of application and changes to
including
major /extension Pre-qualified
notification
changes. application FPPs (Finished
(N).
necessary. Pharmaceutica
l Products).
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APPENDIX I – MINOR CHANGES
Only few types of variation predominantly occur.

Change in batch size of FPP:

 Additional new API source.
Extension shelf life of FPP.
Addition of FPP manufacturing .

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APPENDIX II – MAJOR CHANGES
Major changes Exceed the scope of minor changes which
doesn't fulfil the conditions.

Do not yet reach the scope of Appendix III, hence new
application is necessary.
• Examples:
Change in the manufacturing process of the API.
Change in the composition of the FPP.
Change to the immediate primary packaging of the FPP.

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 APPENDIX II – MAJOR CHANGES

Applicants responsibility to provide the relevant

documentation to prove that the intended change will
not affect the quality of the prequalified product
negatively.

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APPENDIX III – CHANGES
MAKING A NEW APPLICATION
/EXTENSION APPLICATION
NECESSARY
Changes to the API:
Change of the API to a different API, e.g. different
salt/ester/derivative, different isomer
Changes to the pharmaceutical form/ dosage form:
 Change from an immediate-release product to a modified release
dosage form or vice versa.
Change from a liquid to a powder for reconstitution, or vice versa.
Change or addition of a new route of administration.

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APPENDIX IV - STABILITY
REQUIREMENTS FOR
VARIATIONS TO PRE-QUALIFIED
FPPS
Responsibility of the pre-qualified supplier: to investigate whether
or not the intended change will have an impact on the quality
characteristics of APIs and /or FPPs and consequently on their
stability.
Base on the knowledge and experience acquired on APIs and FPPs
(Stress testing, supportive data, accelerated and long- term testing).
At the time of submission, 3 or 6 months stability data should be
provided according to the nature of the change, stability of the API,
dosage form of the FPP, etc.

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 CHANGES IN MANUFACTURING
SITE
Major changes, eg:-

 Move to new site never inspected by FDA or cGMP.

Transfer of aseptically processed sterile drug substance eg, lyophilized
drug.
Finished drug product sterilized by terminal process.
Manufacture of primary package eg, aerosols.

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CHANGES IN MANUFACTURING SITE
Moderate changes eg:-
Manufacture of drug product that is not otherwise provided for in
this guidance.

Minor changes eg:-

for secondary packaging.
For labelling.
Manufacture of drug substance intermediate other then the final
intermediate.
Ink imprinting of solid oral dosage form drug product.
Sterilization site for packaging component when process is same.
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 CHANGES IN MANUFACTURING
PROCESS
Major changes eg:-

When it effect release of drug eg modified release or controlled

release.
Change in sterility method.
Addition or deletion of sterilization procedure.
Replacing sterilizer with other of different principle.
Addition of new equipment.

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CHANGES IN MANUFACTURING PROCESS
Replace Class 100 aseptic fill area with barrier system.

Change to aseptic process method beyond 50%.

Replacing lyophilisation equipment of different size.

Change in sterilizer load limit from pre validated load limit.

Change in pore size of filter.

For natural product:-change in source material eg microbe, cell, plant.

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CHANGES IN MANUFACTURING
PROCESS
Change in process:-
 from dry to wet granulation.
 One type of drying to another.
 Change in route of synthesis of drug substance.
 Synthesis of drug substance that may effect impurity.
 Addition of ink cod imprint not currently used in CDER.

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CHANGES IN MANUFACTURING
PROCESS
Moderate changes:
• In drug substance or product except as otherwise provided for in this
guidance.
• Change in filtration parameters flow rate, pressure, time.
• Change from single to dual sterilizing filters.
• Increase the bulk solution storage time by more than 50%
• Supplement - Changes Being Effected.
• A change in methods that provides increased assurance that the drug
substance will have the characteristics of identity, strength, quality,
purity.
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CHANGES IN MANUFACTURING
PROCESS
Minor changes:
• Changes to equipment of the same design.
• Minor change in an existing code imprint.
• Addition or change in ink imprint when the ink is currently used on
CDER- approved drug product.
• Change in the order of addition of ingredients.
• Increase the bulk solution storage time by NMT 50 percent.
• For natural increase or decrease in production.
• Replacement with equipment of the same design.
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CONTAINER CLOSURE SYSTEM
Major Changes:-
Change from ampule to vial.
Change that may effect drug product sterility assurance.
From single dose to multiple dose.
Change to a flexible container system.
Change to a prefilled syringe dosage.
Change in size of sterile container.
Deletion of secondary package when it provide light , moisture protection.
Addition of secondary package when it may effect impurity.

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CONTAINER CLOSURE SYSTEM
Moderate changes:-
Change in container size no of units in unit dosage form.
Change in label amount.
Addition/deletion of desiccant.

Minor changes:-
Change from metal to plastic.
Change in child resistant pack.
Increasing the wall thickness.
Change in/addition of a cap liner.
Change in antioxidant, colorant, stabilizer.
Change to new container already in NDA.
A change in/addition of a seal. 50
 LABELING
Major Changes:-
Changes based on data from preclinical studies.
Changes to the clinical pharmacology.
Claims of superiority to another drug product.
Changes based on post-marketing study results with new indication
use.
Revision of population based on data.
Change in the labelled storage conditions.

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 LABELING
Moderate Changes:-
Addition of an adverse event.
Addition of a precaution, warning, contraindication arising out of a
post-marketing study,
Adds about drug abuse, dependence, psychological effect.

 Minor Changes:-
Editorial changes eg distributer name add.
Foreign language versions of the labelling.
Changes in the layout of the package label.
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  CONCLUSION
Any change to the content of the pre-qualified dossier should be
reported.
The change should not adversely affect the quality, safety and
efficacy of the pre-qualified product.
Position correctly the variation and submit necessary data.
Contact prequalification for assistance in classifying an unforeseen
change pre-submission.

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 REFERENCE:
• www.fda.gov/cder/ord.
• www.worldtradelaw.net/uragreements/tripsagreement.pdf.
• www.usfda.gov.com.

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THANK YOU
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