The FDA regulates food, drugs, medical devices and other products. It oversees the drug approval process which involves preclinical testing in animals, followed by Phase I-III clinical trials in humans to test safety, efficacy and side effects. If approved, the drug can be marketed and is monitored for side effects. The document outlines the drug approval process and regulations around generic drugs, biologics, manufacturing and product changes.

1. FDA
Dr.Gurumeet C Wadhawa ,Assistant
Professor, Department of Chemistry.
Rayat Shikshan sansthas Veer Wajekar ASC
College,Phunde,Uran

2. Food and Drug Administration (FDA), a
federal agency of United States Department
of Health and Human Services was formed in
June 1906.
FDA is responsible for protecting and
promoting public health through the
regulation and supervision of
◦ Food safety
◦ Dietary Supplements
◦ Prescription and OTC pharmaceutical drugs
◦ Biopharmaceuticals &
◦ Medical Devices

3. Active Pharmaceutical Ingredient (API)
◦ A drug substance is the API or component that
produces pharmacological activity.
◦ API may be produced by chemical synthesis,
recovery from a natural product, recombinant DNA
technology, fermentation or combination of these
processes
New Chemical Entity (NCE)
◦ A drug substance with unknown clinical,
toxicological, physical and chemical properties.

4. Drug Product
◦ A drug product is the finished dosage form (e.g.
capsule, tablet, injectable etc) that contains API,
general in association with other excepient, or inert
ingredients.

6. Preclinical
Testing
Phase I Phase II Phase III Phase IV Phase IV

7. Preclinical Testing
◦ Animal pharmacology & toxicology data are
obtained to determine the safety and efficacy of the
drug.
◦ No attempt is made to develop a final formulation
during this stage.

8. Phase I
◦ An Investigational New Drug (IND) application is
submitted to the FDA. Clinical testing takes place
once the IND application is submitted and
approved.
◦ Healthy volunteers in phase I clinical studies to
determine drug tolerance and toxicity.
◦ Dually signed consents from investigator and
volunteers are pre requisite at this phase.
◦ Toxicological studies- including acute, chronic in
various animal species are planned during this
phase

9. Phase II
◦ Limited number of diseased volunteers (patients)
are treated for the ailment or condition for which
drug was developed under closed supervision.
◦ Dose-response studies, bioavailability,
Pharmacokinetics are performed to determine the
optimum dosage regimen for treating the disease.
◦ Safety is measured to determine Therapeutic Index.
◦ A drug formulation having good physico-chemical
stability is developed.
◦ Chronic Toxicity studies are started in two species;
such studies normally last more than 2 years
duration.

10. Phase III
◦ A large scale, multicenter clinical studies are
performed with the final dosage form developed in
phase II.
◦ Objective of these studies are to determine safety
and efficacy of the drug product in large diseased
human sample.
◦ Side effects are monitored.

11. Submission of New Drug Application (NDA)
◦ An NDA is submitted to FDA for review and
approval after the completion of clinical trials that
show to the satisfaction of the medical community
that the drug is satisfactory by all parameters and is
safe as demonstrated by animal and human studies.

12. Phase IV
◦ After NDA submission and approval large scale
manufacturing of product starts and is marketed
◦ Improvement in product formulation in terms of
manufacturing, packing carries on
◦ Additional clinical studies in special population is
conducted such as in elderly, pediatric and renal
impaired patients etc.
◦ Additional clinical studies may be performed to
determine if the drug can be used for new or
additional labeled indications.

13. Labeled indication
◦ It is the disease area where drug has been tested in
Phase III trials and has exhibited profound clinical
outcome compared with pre marketed standard
drug and hence is approved by FDA in that
particular ailment.
Off labeled Indication
It is the area where drug has not been approved by
FDA may be due to limited amount of evidence, or lack
of effectiveness.
Promotion of drugs in off labeled indications in not
allowed in by FDA

14. Phase V
◦ Drug formulation may be modified slightly
◦ Changes in drug formulation always comply with
SUPAC guidelines.

15. ◦ Product Line Extension
Only physical form or strength is changed in the same
indication.
Developing transdermal patch when only tablets have
been available, for example:
Progesterone
Nicotine
Estradiol
Ibuprofen
Nitroglycerine
Additional Strength
Example is Ibuprofen 200mg, 400mg
As long as the new strength is in the range of total daily
dose.

16. Biological Products
◦ Biological product according to FDA is “any virus,
serum, toxin, antitoxin, vaccine, blood, blood
component or derivatives, allergenic product, or
analogous product applicable to the preventions,
treatment or cure of disease or injuries.
◦ Biologic License Application (BLA) is approved for
marketing under the provisions of the Public Health
Services (PHS) act.

17. Generic Drug Products
◦ After patent expiry of API or Branded Drug product,
generic drug product can be marketed.
◦ But the generic drug product should be
bioequivalent (I.e. having the same rate and extent
of drug absorption) to the branded product.
◦ These bioequivalence studies are normally
conducted in healthy volunteers.

18. Meanwhile, generic product may differ
physical appearance e.g. in color, shape, size
or in the amount of excepient used.
Generic product may also differ in dosage
form as well until the adequate safety studies
have been established.

19. Before the generic product is marketed, the
manufacturer must submit an Abbreviated
New Drug Applications (ANDA) to the FDA for
approval.
Since as NDA clinical trials have already been
performed, only bioequivalence studies are
required for ANDA approval.

21. A New Chemical Entity (NCE)
◦ Preformulation
◦ It is the characterization of the physical and chemical
properties of NCE.
◦ These evaluations are started in preclinical stage and
may continue up to Phase I and Phase II.
◦ Following information is usually required.
Physical- Size, Shape, crystallinity, polymorphism, Flow
properties, hygroscopicity
Solubility- Dissolution, pH solubility profile.
Chemical - excepient interaction, pH stability, pKa,
temperature stability
Analytical- Method development for quantitative analysis

22. Formulation Development
◦ When the submission of an NDA is considered the
manufacturer attempts to develop the final dosage
form.
◦ Injectable
Final injectable drug product is usually developed in
the preclinical phase.
Major concerns include, stability of the drug in
solution for and its sterility.
Acute toxicity studies are necessary in order to change
the dosage form.

23. Formulation Development
◦ Topical
Includes antibacterial, antifungal, corticosteroids and
local anesthetics.
The final dosage form for a topical drug product is
usually developed in Phase I.
Release of the drug from the matrix is measured in-
vitro with various diffusion cell models.
Following problems may be encountered and should
be kept under checked for topical formulation
Local Irritation
Skin Sensitization
System Drug absorption

24. Formulation Development
◦ Oral
Prototype dosage forms are often developed during
the preclinical phase to ensure that drug is optimally
available and dissolves in GI well.
In early stage of product development, hard gelatin
capsule, are formulated for phase I clinical trials.
Final dosage form is decided to develop before the
start of Phase III.

25. Regulatory Approvals for Product Line
Extension
◦ Analytical and manufacturing controls
◦ Stability Information
◦ Bioavailability and Bioequivalence studies
◦ Safety Studies (e.g. skin irritation studies for
transdermal patches)

26. Preapproval Inspections (PAIs)
◦ The manufacturing facility is inspected by FDA after
an NDA, abbreviated antibiotic drug application
AADA or ANDA is submitted.
◦ Pre approval Inspection may also be initiated if a
major change is reported in a supplemental
application to an NDA, AADA or ADNA.

27. Preapproval Inspections (PAIs)
During PAI, the FDA investigator:
◦ Performs a GMP inspection.
◦ Reviews the development report about the validated
product and rationale manufacturing directions.
◦ Consults the chemistry, manufacturing and control
(CMC) section of the NDA, AADA or ANDA and
determines the capability of manufacture to
produce the drug product as prescribed.
◦ Recommends approval for the manufacturing of the
drug product based

28. Scale Up and Post Approval Changes (SUPAC)
◦ Purpose. These guidelines are intended to reduce
the manufacturing changes that require pre-
approval by FDA.
◦ Function. To review slight changes in the amount of
excepient to aid in the processing of the product
during scale-up.
◦ Changing the site of manufacture.
◦ Scale up or Scale down the batch size of
formulation
◦ Changing the manufacturing process or equipment.

29. Product With drawl from market
◦ Initiation of recall may be voluntarily initiated from
company or it can be initiated
Black box Warning for serious adverse event
reported. This box warning is even
mandatory to be mentioned in leaf insert of
the product pack.

30. Pre
Clinical
Testing
FILE
IND Phase I Phase II Phase III
FILE
NDA
FDA Approval
Years 3.5 1 - 2 2 - 4 4 - 6 1.5 Total = 12 - 17
Test
Population
Laborato
ry and
Animal
Studies
20 to 100
Healthy
Volunteers
100 – 300
Patient
Volunteers
1,000 to 3,000
Patient Volunteers
Revie
w
Proces
s
Post
Marketing
Safety
Monitoring
Purpose
Assess
Safety
and
Biologica
l Activity
Determine
Safety and
Dosage
Evaluate
Effectiveness.
Look for Side
Effects.
Verify
Effectiveness,
Monitor Adverse
Reactions from
Long- Term Use
Large
Scale
Manufacturi
ng
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Distribution
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Education
%
of
all
new
drugs
that
pass
70% of INDs 30% of INDs 27% of INDs 20% of INDs