ANDA REGULATORY APPROVAL PROCESS & IN-VITRO STUDIES BY MS PYNSKHEMLIN SYIEMLIEH 1ST SEM M.PHARM

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DEPARTMENT OF PHARMACEUTICS
ANDA REGULATORY APPROVAL PROCESS & IN-VITRO STUDIES
R R COLLEGE OF PHARMACY
BY
MS PYNSKHEMLIN SYIEMLIEH
1ST SEM M.PHARM
SUBMITTED TO
MRS SRILATHA K S
ASST PROF DEPARTMENT OF PHARMACEUTICS

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CONTENTS
1. INTRODUCTION
2. TYPES OF ANDA FILLING
3. FLOW CHART
4. ANDA REQUIREMENT
5. CHANGES TO AN APPROVED ANDA
6. IN-VITRO STUDIES
7. REFERENCE

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INTRODUCTION
• An Abbreviated New Drug Application (ANDA) is an application for a US generic drug approval for an
existing licensed medication or approved drug.
• A generic drug is one that is comparable to a patented drug product in dosage form, strength,route of
administration,quality,performance,characteristics and intended use.
• ANDA filing is possible only when the patent of innovator drug is expired or is scheduled to expire.
• All approved products, both innovator and generic, are listed in FDAApproved Drug Product with Therapeutic
Equivalence Evaluations ( Orange Book).
• The ANDA is submitted to FDA’s Centre For Drug Evaluation And Research, Office of Generic Drugs, which
provides for the review and ultimate approval of a generic drug product.
• Once approved an applicant may manufacture and market the generic drug product to provide a safe , effective,
low cost alternative to the American public.

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INTRODUCTION contd..
• Using bioequivalence as the basis for approving generic copies of the drug products was established by the
‘Drug Price Competition & Patent Term Restoration Act of 1984’, also known as the Waxman-Hatch Act.
• Generic product must meet bioavailability-bioequivalence standard of innovator product.
• Generic products are termed as ‘abbreviated’ because they are generally not required to include preclinical and
clinical data to establish safety and effectiveness.
• As per US-FDA ,generic drugs are identical or within an acceptable bioequivalence range to branded product.
• Availability of generic products increases market competition and substantially lowers price of branded product
upto 90%.

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TYPES OF ANDA FILLING
Option Specification Acceptance of ANDA
Para I The drug has not been patented If application is complete then
immediately
Para II Patent has already expired If application is complete then
immediately
Para III Patent is exist but company want to launch product
after expiry of patent
After expiry of patent
Para IV Patent is infringed or is invalid After proving that either patent is
invalid or not infringed

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FLOW CHART

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ANDA REQUIREMENT
1. Signed FDA form 356h : Provides information regarding the applicants name and address, name of the drug
prroduct , thre product strength and route of administration, indication of drug master files cited, proposed
indications, a statement regarding whether the product is for prescription or over the counter.
2. The index should specify volume and page number for each complete and detailed item.
3. Information on the basis for which the ANDA is being submitted: a) Name of the reference drug, its dosage
form and strength . b) Information on exclusively for the listed drug. c) If a suitability petition is approved a
reference to the FDA number that was assigned to that suitability petition.
4. Conditon for use : Including, a) A statement regarding the condition for which the drug will be used. b) A
reference to the annoted labelling for the product and the currently approved labelling for the listed drug
product.
5. A statement that active ingeredient is the same as for that of the reference drug : For the combination product
this must be shown for both active ingredients.
6. Route of administration,dosage form and strength are same as the reference drug.
Bioequivalence: This should include information to demonstrate that the proposed drug is bioequivalence to
the listed drug product.
7. Labelling: Include a copy of currently approved labeling for the listed drug as well as the proposed labeling
for the drug being provided for in the ANDA . A side by side comparison of two sets of labeling is also
necessary.

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8. Chemistry, Manufacturing and Controls : Describe the composition , manufacture, specifications and analytical
procedures for the drug substance and drug product.
9. Human pharmacokinetics and Bioavailability: This include information concerning
a) The Design
b) The Dosing procedure
c) The number & frequency of blood & urine collection & Methodology for the assay.
10. Samples : The sample of the Drug substance and finished product should be provided four individuals units
with sufficients quantities in each unit to permit the FDA to perform all the tests included in the specifications
at least three times.
11. Analytical method for drug substance & drug product : This section should consist of the specifications,
analytical method, certificates of analysis , method of analysis , method validation & stability indicating data
as contained in the chemistry , manufacturing and control part of the application .
12. Labelling : 12 specimens of the final printed label & all labelling for the drug product are to be included.
13. Case report forms & tabulations : The need for these should be discussed with appropriate personnel of the
division of bioequivalence prior to submission of the ANDA.

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CHANGES TO AN APPROVED ANDA
Section 506 A of the Federal Food, Drugs and Cosmetics Act and 21 CFR 314,70 provide for a reporting
categories of the post approval changes which are listed below.
1. Major change
2. Moderate change
3. Minor change
MAJOR CHANGE
• Change that has a substantial potential to have an adverse effect on identity , strength ,quality, purity or potency
of a drug product as these factors may relate to the safety or effectiveness of the drug product.
• Requires the submission of a supplement and approval by FDA prior to distribution of the drug product made
using the change.
• This type of supplement is called and should be clearly labelled as Prior approval supplement.

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MODERATE CHANGE
Change that has a moderate potential to have an adverse effect on identity , strength ,quality, purity or potency of a
drug product as these factors may relate to the safety or effectiveness of the drug product.
Categorized into 2 types based on the type of supplement being filed:-
a. Supplement- Changes being effected in 30 days.
b. Supplement- Changes being effected.
Supplement- Changes being effected in 30 days.
• Requires submission of supplement to FDA at least 30 days before the distribution of the drug product made
using the change.
• This type of supplement is called , and should be clearly labelled, a Supplement – Changes being effected in 30
days.
• The drug product made using moderate changes cannot be distributed if the FDA informs the applicant to file a
prior approval supplement for the changes made or if FDA informs that the information is missing or if FDA
disapproves the changes being affected in 30 days.

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Supplement- Changes being effected.
• This type of supplement contains changes for which distribution can occur when FDA receives the supplement.
• FDA may order the manufacturer to cease distribution of the drug products made using the disapproved change.
If, after review, FDA disapproves a changes-being effected.
MINOR CHANGE
Changes that has minimal potential to have an adverse effect on identity , strength ,quality, purity or potency of a
drug product as these factors may relate to the safety or effectiveness of the drug product.

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ASSESING THE EFFECT OF MANUTACTURING CHANGES
Assessment of the effects of the change
Equivalence
Adverse effects
Assessment of the effects of the change
The applicant must assess the effects of the change before distributing a drug product made with a manufacturing
change. Assessment should be made on the following:-
• Conformance to specifications
• Additional testing
Equivalence
The test results from pre- and post- change material are comparing and determining if the test results are
equivalent.

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Adverse effects
The reporting categories for the post approval changes are provided with respect to the following.
1. Components and composition
2. Manufacturing sites
3. Manufacturing process
4. Specifications
5. Container closure system
6. Labelling
7. Miscellaneous changes
8. Multiple related changes

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IN-VITRO STUDIES
‘In-vitro’, is a Latin word that means ‘ within the glass’ . Therefore the studies which are done outside the living
organism, inside glass ( test tubes or petri dishes) are known as in-vitro studies.
It is the experiment or observations done on the tissue outside of the living organism in a controlled
environment, usually using petri dishes or test tubes.
Most experiments in cellular biology are done through in-vitro studies and are not conducted in the organism’s
natural environment or inside a living organism. This results in the limited success of the experiments in
simulating the actual conditions inside an organism and makes its outcome less precise.
Compared to in-vivo experiments, it is less expensive and provides quicker results.
In-vitro methods are widely used in pharmaceuticals using microorganisms due to its ease of production and
economic benefits.
Example : Viruses which only replicate in living cells, are studied in the laboratory in cell or tissue culture.

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ADVANTAGES
• In vitro studies permit a species-specific
• Simpler
• More convenient
• More detailed analysis than can be done with the whole organism.
• Just as studies in whole animals more and more replace human trials, so are in vitro studies replacing studies in
whole animals.

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DISADVANTAGES
• The primary disadvantage of in vitro experimental studies is that it may be challenging to extrapolate from the
results of in vitro work back to the biology of the intact organism.
• Most candidate drugs that are effective in vitro prove to be ineffective in vivo because of issues associated with
delivery of the drug to the affected tissues, toxicity towards essential parts of the organism that were not
represented in the initial in vitro studies, or other issues.

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REFERENCES
1. A Textbook of PHARMACEUTICAL REGULATORY SCIENCE : by Dr Jiwan Lavenda, Dr Md Rageeb Md
Usman, Dr Sameer S Sheekh.
2. A Textbook of Pharmaceutical Regulatory Science : By Umesh D Laddha, Umesh B Mahajan, Sachin D
Shinde , Archana V Narpagar.
3. https://en.wikipedia.org/wiki/In_vitro#Species_specificity
4. https://www.slideshare.net/avinashmore399/in-vivo-and-in-vitro-studies

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THANK YOU