Contents Outline

➢ What is FDA ?
➢ History of FDA / Website and contents of USFDA
➢ FDA Organization / Mission / Responsibilities
➢ What does FDA regulate and What FDA doesn’t regulate
➢ Code of Federal Regulations – CFR 21
➢ Drug Discov ery Process and Human drug approval steps within CDER
➢ IND - Forms and approval process flow
➢ NDA - Forms and approval process flow
➢ ANDA – Forms and approval process flow
➢ Guidance to Industry
➢ Overview of SUPAC
➢ Generic Drugs – Hatch Waxman Act / Orange Book Patent Listing and 180 days exclusiv ity
➢ Clinical trials regulations.
➢ Medical dev ices, cosmetics, biological products
➢ Dietary supplements, biosimilars
➢ FDA Inspections
➢ Recall / Field Alert / Warning Letters / product approv als
➢ QBD, PAT
➢ How to contact FDA ?
WHAT IS THE FOOD AND DRUG
ADMINISTRATION (FDA)?
The FDA is an agency within the U.S. Department of Health and Human
Services that is responsible for protecting the public health by:

1.Ensuring the safety and efficacy of human

and veterinary drugs, biological products,
medical devices

2.Ensuring the safety and security of our

nation’s food supply, products that emit
radiation

3.Regulating the manufacture, marketing,

and distribution of tobacco products

FDA also promotes the public health by

striving to foster innovative approaches and
solutions for some of nation’s most
compelling health and medical challenges.
website : www.fda.gov

Head Quarters

U.S. Food and Drug

Administration
10903 New Hampshire Avenue,
Silver Spring, MD 20993 ,
1-888-INFO-FDA (1-888-463-6332)
 HISTORY OF FDA

1800 – NO REGULATIONS

1862 – ABRAHAM LINCOLN – DEPARTMENT OF AGRICULTURE,

Dr. HARVEY W. WILEY – BUREAU OF CHEMISTRY

1906 – AFTER THE PUBLICATION OF THE JUNGLE , FOOD AND

DRUG ACT WAS PASSED.

DESPITE THIS LAW POISONOUS MEDICINES ANS UNSAFE FOOD
PRODUCTS CONTINUED TO BE SOLD.
107 PEOPLE WERE KILLED FROM AN ANTIBIOTIC
1938 – FOOD, DRUG, AND COSMETIC ACT WAS IMPLETED
Dr. Robert M. Califf, MD, is the
FDA's commissioner of food and
drugs. As the top official of the
Food and Drug Administration
(FDA), Dr. Califf is committed to
strengthening programs and
policies that enable the agency to
carry out its mission to protect and
promote the public health.
 Centre for
Devices
CDER –
Radiological
Centre for Centre for
Health
Food Safety Drug
and Evaluation
Applied and
Nutrition Research

FDA
ORGANIZATION CBER –
Centre for Centre for
Veterinary Biologics
Sciences Evaluation
and
Research

National
Centre for Centre for
Toxicological Tobacco
Research products
FDA is an agency within the Department of Health and Human Services.

The FDA's organization consists of the Office of the Commissioner and four
directorates overseeing the core functions of the agency:

➢ Medical Products and Tobacco,

➢ Foods,
➢ Global Regulatory Operations and Policy,
➢ Operations.
 WHAT DOES FDA REGULATE?

➢ FOOD AND ITS ADDITIVES

➢ INFANT FORMULAS
➢ DIETARY SUPPLEMENTS
➢ HUMAN DRUGS
➢ VACCINES, BLOOD PRODUCTS AND BIOLOGICALS
➢ MEDICAL DEVICES
➢ ELECTRONIC PRODUCTS
➢ COSMETICS
➢ ANIMAL PRODUCTS
➢ TOBACCO PRODUCTS
 WHAT DOESN’T FDA REGULATE?

➢ ADVERTISING (EXCEPT FOR PRESCRIPTION DRUGS, MEDICAL DEVICES AND

TOBACCO PRODUCTS)
➢ ALCOHOLIC BEVERAGES
➢ CONSUMER PRODUCTS
➢ ILLEGAL DRUGS FOR ABUSE
➢ HEALTH INSURANCE
➢ MEAT AND POULTRY
➢ RESTAURANTS AND GROCERY STORES
 CODE OF FEDERAL REGULATIONS - TITLE 21 - FOOD AND DRUGS

The Code of Federal Regulations (CFR) is a codification of the general and permanent rules
published in the Federal Register by the Executive departments and agencies of the Federal
Government.. Title 21 of the CFR is reserved for rules of the Food and Drug Administration.. The CFR is
divided into 50 titles that represent broad areas subject to federal regulation.

Title 21 is the portion of the Code of Federal Regulations that governs food and drugs within
the United States for the Food and Drug Administration (FDA), the Drug Enforcement
Administration (DEA), and the Office of National Drug Control Policy (ONDCP)

It is divided into three chapters:

•Chapter I — Food and Drug Administration
•Chapter II — Drug Enforcement Administration
•Chapter III — Office of National Drug Control Policy
 Code of Federal Regulations - Title 21 - Food and Drugs ….. contd
Chapter I

Most of the Chapter I regulations are based on the Federal Food, Drug, and Cosmetic Act -
Notable sections
50 Protection of human subjects in clinical trials
The 100 series are regulations pertaining to food
The 200 and 300 series are regulations pertaining to pharmaceuticals
210 - cGMPs for pharmaceuticals / 310 - Requirements for new drugs
The 600 series covers biological products (e.g. vaccines, blood)
The 700 series includes the limited regulations on cosmetics:

Chapter II - Notable sections

1308 — Schedules of controlled substances

1308.03(a) — Administrative Controlled Substances Code Number
1308.11 — List of Schedule I drugs
1308.12 — List of Schedule II drugs
1308.13 — List of Schedule III drugs
1308.14 — List of Schedule IV drugs
1308.15 — List of Schedule V drugs

Chapter III- Notable sections

1405 Government wide requirements for drug-free workplaces`

DRUG DISCOVERY PROCESS
 HUMAN DRUG APPROVAL PROCESS WITHIN CENTER
FOR DRUG EVALUATION AND RESEARCH (CDER) HAS
FOUR BASIC STEPS
Application filed FDA Review
• The FDA reviews the
• A drug company (also application and considers
called a "sponsor") benefits and risks
submits an application • May hold an Advisory
to the FDA Committee meeting to gain
• FDA decides if expert advice
application is complete • FDA may require sponsor to
create a risk evaluation and
mitigation strategy (REMS) to
ensure benefits outweigh risks
• FDA inspects the facilities the
drug will be made
• FDA reviews information that
will be on the drug's labeling
FDA monitors safety
FDA takes action
post-approval
• FDA decides whether • After a drug is approved,
the drug's benefits FDA monitors the safety of
outweigh the risks and that drug
can be approved, • Based on new safety data,
which would allow the FDA can decide to take
drug to be sold in the appropriate action, including
US adding new warnings or
requiring new studies,
contraindications,
withdrawal, REMS etc.
 FORM NO:
1571 AND 1572
 FORM NO:
365h, 3397 AND
3331
FORM NO:
356h
 GENERIC DRUG USER FEE AMENDMENTS OF 2012

GDUFA, an historic first: Providing user fees for FDA to ensure timely review of applications
for generic drugs

The Generic Drug User Fee Amendments of 2012 (GDUFA) is designed to speed access to
safe and effective generic drugs to the public and reduce costs to industry. The law requires
industry to pay user fees to supplement the costs of reviewing generic drug applications
and inspecting facilities. Additional resources will enable the Agency to reduce a current
backlog of pending applications, cut the average time required to review generic drug
applications for safety, and increase risk-based inspections.

FY17 GDUFA Fees Table

ANDA $70,480
PAS $35,240
DMF $51,140
Facility Domestic API $44,234
Foreign API $59,234
Domestic FDF $258,646
Foreign FDF $273,646
 Guidance (Drugs)

Guidance documents represent the Agency's current thinking on a particular subject. They do not
create or confer any rights for or on any person and do not operate to bind FDA or the public

The public can comment on FDA guidance documents at any time. Typically, for draft guidance
documents, the agency designates a comment period so that these comments on the document can
be considered as the draft is finalized.

Browse Guidance Documents By Topic

•Advisory Committees
•Animal and Veterinary
•Biologics
•Clinical Trials
•Color Additives
•Combination Products
•Cosmetics
•Drugs
•Food
•Import and Export
•International Conference on Harmonisation (ICH)
•Medical Dev ices
•Radiation-Emitting Products
•Tobacco Products
•Veterinary International Conference on Harmonization (VICH)
 TYPE OF CHANGES: SUPAC GUIDELINES DEFINE
➢Components and composition
➢ Lev els of change
S - SCALE
➢Manufacturing
➢Batch size ➢ Recommended chemistry,
➢Manufacturing site changes manufacturing and controls (CMC)
for each lev el of change
➢ In-vitro and/or in-v ivo requirements
for each lev el of change
U – UP ➢ Required documentation to
support the change
SUPAC DOCUMENTS:
➢Immediate release (IR)
➢Modified release (MR)

P – POST ➢IR/MR equipment addendum

➢Non sterile semi solids (SS)

A – APPROVAL LEVELS OF CHANGES:

➢Lev el 1
➢Lev el 2
➢Lev el 3
C - CHANGES
 FACTS ABOUT GENERIC DRUGS

Generic Drug – A drug product that is comparable to the brand / reference listed drug product in dosage
form, strength, route of administration, quality and performance characteristics and intended use.
Generic drug applications are termed "abbreviated ANDA – An abbreviated New Drug Application is
submitted to sell the Generic Drug in US market.

Today, nearly 8 in 10 prescriptions filled in the United States are for generic drugs.
On an average the cost of a generic drug is 80 to 85 percent lower than the brand name product

Cheaper does not mean lower quality - When a generic drug product is approved, it has met rigorous
standards established by the FDA with respect to identity, strength, quality, purity, and potency. The
generic drug manufacturer must prove its drug is the same as (bioequivalent) the brand name drug.
Drug Price Competition and Patent
Term Restoration Act of 1984," also
known as the WAXMAN-HATCH ACT
1994

All approved products, both innovator and

generic, are listed in FDA's Approved Drug
Products with Therapeutic Equivalence
Evaluations (Orange Book)
 18O DAYS GENERIC DRUGS EXCLUSIVITY

WAXMAN HATCH AMENMENTS BENIFITS CONCEPT OF PARAGRAPH I TO IV

For filing ANDA, generic company must include a

patent certification as per section 505(j) (2) (A) (vii)
of the Hatch Waxman Act. The certificate has to
make one of the following statements
TO INOVATOR’S COMPANIES TO GENERIC DRUG COMPANIES

180 DAY EXCLUSIVITY PERIOD I. No patent information on the drug product

45 DAY TO CLAIM that is the subject of the ANDA has been
submitted to FDA
TO CHALLEGE PATENT DRUG II. That such patent has expired
III. The date on which such patent expires and
IF SUIT NOT SUIT applicant wish to sell the product after the
patent expiry
IV. That such patent is inv alid or will not be
infringed by the manufacture, use, or sale of
the drug product which the ANDA is
DELAYED FOR 30 MONTHS
submitted
http://www.thehindubusinessline.com
News: Aurobindo Pharma gets USFDA nod for Generic, Scrip gains / July 30, 2016:

The stock of Aurobindo Pharma gained sharply last month, when the company
reported that it had received the final approval from the US-FDA to manufacture and
market Rosuvastatin tablets in the US. Rosuvastatin is used in treating high cholesterol
levels. The company is eligible for 180 days of generic drug shared exclusivity.

The approved ANDA is bioequivalent and therapeutically equivalent to the reference

listed drug product rosuvastatin tablets 5mg, 10mg, 20mg, 40mg of innovator IPR
pharmaceuticals lnc

http://www.livemint.com / Sat, Aug 13 2016

Sun Pharma profit triples to Rs2,034 crore in Q1 on higher sales of cancer drug
The firm benefited from the launch of Imatinib Mesylate tablets (therapeutic
equivalent to anti-cancer drug Gleevec of innovator NOVARTIS) in the US market in
February. Being a first-to-file product, it was granted 180 days of marketing
exclusivity by the Food and Drug Administration from the time of its launch
 CLINICAL TRIALS
In general, FDA recommends that a Form FDA 3674 accompany
the following applications and submissions to FDA:

➢ Investigational New Drug Application (IND)

➢ New Clinical Protocol Submitted to an IND
➢ New Drug Application (NDA)
➢ Efficacy Supplement to an Approved NDA
➢ Biologics License Application (BLA)
➢ Efficacy Supplement to an Approved BLA
➢ Abbreviated New Drug Application (ANDA)
➢ Premarket Approval Application (PMA)
➢ PMA Panel Track Supplement
➢ Humanitarian Device Exemption (HDE)
 Medical devices are classified into
MEDICAL DEVICES Class I, II, and III.

Regulatory control increases from Class I to

A medical device is "an instrument, apparatus, implement, machine,
contrivance, implant, in vitro reagent, or other similar or related article,
including a component part, or accessory which is:
➢ recognized in the official National Formulary, or the United States
Pharmacopoeia, or any supplement to them,
➢ intended for use in the diagnosis of disease or other conditions, or in the
cure, mitigation, treatment, or prevention of disease, in man or other
animals, or
Class III.
The device classification regulation defines the
regulatory requirements for a general device
type.
Most Class I devices are exempt from Premarket
Notification 510(k); most Class II devices require
Premarket Notification 510(k); and most Class III
devices require Premarket Approval.

➢ intended to affect the structure or any function of the body of man or other
animals, and which does not achieve any of its primary intended purposes
through chemical action within or on the body of man or other animals and
which is not dependent upon being metabolized for the achievement of
any of its primary intended purposes."

Medical devices range from simple tongue depressors and

bedpans to complex programmable pacemakers with
micro-chip technology and laser surgical devices.
 CLASSIFICATION

Class I – These devices present minimal

potential for harm to the user and are often
simpler in design than Class II or Class III
devices. Examples include enema kits and
elastic bandages. 47% of medical devices fall
under this category and 95% of these are
exempt from the regulatory process.

Class II – Most medical devices are considered

Class II devices. Examples of Class II devices
include powered wheelchairs and some
pregnancy test kits. 43% of medical devices fall
under this category.

Class III – These devices usually sustain or

support life, are implanted, or present potential
unreasonable risk of illness or injury. Examples of
Class III devices include implantable
pacemakers and breast implants. 10% of
medical devices fall under this category.
 BASIC REGULATORY REQUIREMENT FOR MEDICAL DEVICES

FDA's Center for Devices and Radiological Health (CDRH) is responsible for regulating firms who
manufacture, repackage, relabel, and/or import medical devices sold in the United States.

In addition, CDRH regulates radiation-emitting electronic products (medical and non-medical) such as
lasers, x-ray systems, ultrasound equipment, microwave ovens and color televisions.

The basic regulatory requirements that manufacturers of

medical devices distributed in the U.S. must comply with
are:

➢ Establishment registration,
➢ Medical Device Listing,
➢ Premarket Notification 510(k), unless exempt,
or Premarket Approval (PMA),
➢ Investigational Device Exemption (IDE) for clinical
studies
➢ Quality System (QS) regulation,
➢ Labeling requirements,
➢ Medical Device Reporting (MDR)
 COSMETICS
Cosmetic products are regulated by
FDA's Center for Food Safety and Applied
Nutrition (CFSAN). CFSAN is responsible for
assuring that cosmetics are safe and
properly labeled

How does the law define a cosmetic?

The Federal Food, Drug, and Cosmetic Act (FD&C Act) defines cosmetics by their intended
use, as "articles intended to be rubbed, poured, sprinkled, or sprayed on, introduced into, or
otherwise applied to the human body...for cleansing, beautifying, promoting attractiveness, or
altering the appearance" [FD&C Act, sec. 201(i)].

Among the products included in this definition are skin moisturizers, perfumes, lipsticks,
fingernail polishes, eye and facial makeup preparations, cleansing shampoos, permanent
waves, hair colors, and deodorants, as well as any substance intended for use as a
component of a cosmetic product.
 Who is responsible for substantiating the safety of
cosmetics?

Companies and individuals who manufacture or market

cosmetics have a legal responsibility to ensure the safety
of their products. Neither the law nor FDA regulations
require specific tests to demonstrate the safety of
individual products or ingredients. The law also does not
require cosmetic companies to share their safety
information with FDA.

If cosmetics are not FDA-approved, how are they regulated?

FDA-regulated does not mean FDA-approved.
FDA does not have the legal authority to approve cosmetics before they go on the market,
although FDA do approve color additives used in them (except coal tar hair dyes).

FDA can take action against a cosmetic on the market if we have reliable information
showing that it is adulterated or misbranded. FDA takes action within our legal authority,
based on public health priorities and available resources.
 BIOLOGICAL PRODUCTS

Biological products, or biologics, are

medical products.

Many biologics are made from a

variety of natural sources (human,
animal or microorganism). Like drugs,
some biologics are intended to treat
diseases and medical conditions.
Other biologics are used to prevent or
diagnose diseases.
WHAT BIOLOGICAL PRODUCTS DOES FDA REGULATE ???

The Center for Biologics Evaluation and Research (CBER)

within FDA regulates a wide range of biological products,

The Center for Drug Evaluation and Research (CDER)

within FDA regulates other categories of biological
products mostly produced by biotechnology methods,
including:

➢ monoclonal antibodies designed as targeted

therapies in cancer and other diseases
➢ cytokines (types of proteins involved in immune
response)
➢ growth factors (proteins that affect the growth of
a cell)
➢ enzymes (types of proteins that speed up
biochemical reactions), such as thrombolytics
(used to dissolve blood clots)
➢ immunomodulators (agents that affect immune
response)
 DIETARY SUPPLEMENTS

The law defines dietary supplements in part as products taken by mouth that contain a
"dietary ingredient." Dietary ingredients include vitamins, minerals, amino acids, and herbs or
botanicals, as well as other substances that can be used to supplement the diet.

Dietary supplements come in many forms, including tablets, capsules, powders, energy bars, and
liquids.

These products are available in stores throughout the United States, as well as on the Internet.

They are labeled as dietary supplements and include among others

➢ vitamin and mineral products

➢ "botanical" or herbal products—These come in many forms and may include plant
materials, algae, macroscopic fungi, or a combination of these materials.
➢ amino acid products—Amino acids are known as the building blocks of proteins and play a
role in metabolism.
➢ enzyme supplements—Enzymes are complex proteins that speed up biochemical
reactions.
 ARE DIETARY SUPPLEMENTS APPROVED BY FDA ???

FDA regulates both finished dietary supplement products and dietary ingredients.

FDA regulates dietary supplements under a different set of regulations than those covering
"conventional" foods and drug products. Under the Dietary Supplement Health and
Education Act of 1994 (DSHEA):

•FDA is responsible for taking action against any adulterated or misbranded dietary
supplement product after it reaches the market.

Dietary supplement manufacturers and distributors are not

required to obtain approval from FDA before marketing
dietary supplements. Before a firm markets a dietary
supplement, the firm is responsible for ensuring that
➢ the products it manufactures or distributes are safe
➢ any claims made about the products are not false or
misleading
➢ the products comply with the Federal Food, Drug, and
Cosmetic Act and FDA regulations in all other respects
 Biosimilars

➢ The Patient Protection and Affordable Care Act (Affordable Care Act), signed into law by
President Obama on March 23, 2010, amends the Public Health Service Act (PHS Act) to
create an abbreviated licensure pathway for biological products that are demonstrated
to be “biosimilar” to or “interchangeable” with an FDA-licensed biological product.
FDA’s Overview of the Regulatory Guidance for the Development and
Approval of Biosimilar Products in the US
 Information for Consumers (Biosimilars)
➢Biological Products
✓ Many of today’s important medications are biological products. Biological products are made
from living organisms.
✓ The material they are made from can come from many sources, including humans, animals
and microorganisms such as bacteria or yeast.
✓ Biological products are manufactured through biotechnology, derived from natural sources
or, in some cases, produced synthetically.
✓ Most biological products are more complex in structure and have larger molecules or mixtures
of molecules than conventional drugs (also called small molecule drugs) that are more difficult
to identify or characterize.

➢What are biosimilar and interchangeable biological products?

✓ There are two new types of biological products- biosimilar and interchangeable.
✓ Biosimilars are a type of biological product that are licensed (approved) by FDA because
they are highly similar to an already FDA-approved biological product, known as the biological
reference product (reference product), and have been shown to have no clinically meaningful
differences from the reference product.
✓ An interchangeable biological product, in addition to meeting the biosimilarity standard, is
expected to produce the same clinical result as the reference product in any given patient.
 Biosimilars
➢ The pathway is provided in the part of the law known as the Biologics Price Competition and
Innovation Act (BPCI Act). Under the BPCI Act, a biological product may be demonstrated to
be “biosimilar” if data show that, among other things, the product is “highly similar” to an
already-approved biological product.

➢ FDA requires licensed biosimilar and interchangeable biological products to meet the Agency’s
rigorous standards of safety and efficacy.

➢ To have a product reviewed as a biosimilar or interchangeable, manufacturers must submit a

351(k) biologics license application (BLA) that includes, among other things, information
demonstrating biosimilarity based upon:

o Analytical studies demonstrating that the biological product is “highly similar” to the
reference product notwithstanding minor differences in clinically inactive components;

o Animal studies (including the assessment of toxicity); and

o A clinical study or studies (including the assessment of immunogenicity and

pharmacokinetics (PK) or pharmacodynamics (PD)) sufficient to demonstrate safety, purity,
and potency in 1 or more appropriate conditions of use for which the reference product is
licensed and for which licensure is sought for the biosimilar product.
 HOW DOES FDA PREPARES FOR INSPECTION ?

REVIEW OF FDA INSPECTIONAL GUIDES

➢ INVESTIGATIONAL OPERATIONS MANNUAL (IOM)

➢ COMPLIANCE PROGRAM GUIDANCE MANNUALS (CPGM)
➢ COMPLIANCE POLICY GUIDES (CPG)
FORMS COMMONLY USED DURING
➢ INSPECTION TECHNICAL GUIDES
INSPECTION
➢ FORM 482 – NOTICE OF INSPECTION
➢ FORM 483 – INSPECTIONAL
OBSERVATIONS
➢ FORM 484 – RECEIPT FOR PHYSICAL
EVIDENCE BUT NOT FOR DOCUMENTARY
EVIDENCEG
 WHAT IS A RECALL???
A recall is when a product is removed from the market or a correction is made to the
product because it is either defective or potentially harmful. Sometimes a company
discovers a problem and recalls a product on its own. Other times a company recalls a
product after FDA raises concerns.

PRODUCT RECALL - EXAMPLE

Brand Reason/
Date Name Product Description Problem Company

08/18/2016 Sagent Oxacillin for Injection, May contain Sagent

Pharmace USP, 10 g small, dark Pharmaceuti
uticals, particulate cals, Inc.
Inc. matter (iron
oxide)

Sagent has initiated this voluntary recall to the user level

due to the receipt of a product complaint for a single vial
containing small, dark particulate matter found within the
solution after reconstitution. The particulate matter has
been identified as iron oxide.
 DEATHS DUE TO CONTAMINATED HEPARIN 2007
and
2008
The raw materials were manufactured in china

50% OF
OVERSULFATED
CHONDROITIN OSCS mimics heparin so closely it cannot be
SULPHATE distinguished in basic tests. It provides no
anticoagulant activity.

The adverse effects are caused by severe allergic

reactions, including low blood pressure which can
occasionally lead to fatal stroke.
EARLY 2008 19 people dead and 785 experienced severe adverse events.

Voluntary recall of 9 lots of heparin by BAXTER (100units/ml, 10ml and

25 JAN 2008
30ml multidose vials)
FDA issued public health advisory to inform public about ADR by vials
11 FEB 2008
produced by BAXTER.

28 FEB 2008 Voluntary recall of rest of the lots of heparin by BAXTER.

10 MAR 2008 Import alert by FDA to heparin from china to US

FDA issued an assignment to the field staffs to examine all the

14 MAR 2008
samples of heparin sodium API coming from china.
EARLY APRL
103 people died who were using heparin since 2007
2008
FDA announced a link between the ADRs and the contaminant
21 APRL 2008
found in the drug.

23 APRL 2008 FDA shared the scientific information in two journals.

 WHY DID THIS HAPPEN???

➢ The testing of the raw material before approval was ineffective.

➢ No proper regulatory inspections
➢ FDA did not inspect the before approving the heparin for sale.
➢ Human error during inspection of the site.
➢ Shortage of funding.
➢ It was intentionally added to save money.

There is no justification for the theory that contamination of heparin

➢ Development of new test methods using NMR, capillary electrophoresis,

enzymatic kinetics and bioassays.
➢ FDA devotes considerable effort to reviewing and monitoring drug
manufacturing activities.
➢ Develop synthetic source for anticoagulant.
SOLUTION ➢Additional training for those who do the data entry on which inspection
assignments.
 FIELD ALERT

The purpose of the New Drug Application (NDA) / ANDA Field Alert Program is to quickly
identify drug products that pose potential safety threats.

All drug manufacturers with approved New Drug Applications (NDAs) and Abbreviated
New Drug Applications (ANDAs) are required to submit Field Alert Reports to the FDA if they
find any significant problems with an approved drug. Reports must be submitted to district
FDA offices within three days of a problem being identified.
Information that must be reported in a Field Alert Report includes:
➢ any incident that causes the drug product or its labeling to be mistaken for or applied
to another article,
➢ bacterial contamination,
➢ a significant chemical, physical, or other change,
➢ deterioration in the distributed drug product, and
➢ failure of one or more distributed batches of the drug product to meet the
specifications established in its application.
 PILOT- Form FDA 3331-
Automated Pilot Program

FDA is launching a pilot program enabling

manufacturers to electronically subm it Field
Alert Reports (FARs) to improve the speed and
efficiency of reporting quality issues relating to
the manufacture of FDA-approved drug
products. The objective of this pilot program is to
provide for simultaneous reporting to both FDA
district offices and CDER, while determining the
feasibility of transitioning from a PDF form to an
electronic form. Currently, all FARs are submitted

by firms to the Agency in PDF or hardcopy form .

 WARNING LETTERS

A Warning Letter is the agency's principal means of achieving prompt voluntary

compliance with the Federal Food, Drug, and Cosmetic Act (the Act). The Warning
Letter was developed to correct violations of the statutes or regulations.

When FDA finds that a manufacturer has significantly violated FDA regulations, FDA
notifies the manufacturer. This notification is often in the form of a Warning Letter.

The Warning Letter identifies the violation, such as poor manufacturing practices,
problems with claims for what a product can do, or incorrect directions for use.

The letter also makes clear that the company must correct the problem and provides
directions and a timeframe for the company to inform FDA of its plans for correction. FDA
then checks to ensure that the company’s corrections are adequate.
 Public Health Service
Food and Drug Administ ration
Silver Spring, MD 20993
Warning Letter: 320-16-23
Via UPS
Ret urn Receipt Requested
Until you completely correct all v iolations and we
July 26, 2016 confirm your compliance with CGMP, FDA may
withhold approval of any new applications or
supplements listing your firm as a drug product
Mr. John Zhao manufacturer. Failure to correct these v iolations
General Manager may also result in FDA refusing admission of
Concept Products Limited articles manufactured at Concept Product
No. 33, The Third Branch Saida Road Limited No. 33, the Third Branch Saida Road,
Xiqing Economic Development Area Xiqing Economic Dev elopment Area, Tianjin, into
Tianjin, 300385
China the United States under section 801(a)(3) of the
FD&C Act, 21 U.S.C. 381(a)(3)
Dear Mr. Zhao:

The U.S. Food and Drug Administration (FDA) inspect ed your drug manufacturing facilit y, Concept Product s Limit ed, No. 33, TheThird Branch Saida Road,
Xiqing Economic Development Area, Tianjin, from August 3-5, 2015.

This warning letter reviews significant violations of current good manufacturing practice (CGMP) regulations for finished pharmaceuticals. See 21 CFR,
part s 210 and 211.

Because your methods, facilities, or controls for manufacturing, processing, packing, or holding do not conform to CGMP, your drug products are
adulterated within the meaning of section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act (FD&C Act), 21 U.S.C. 351(a)(2)(B).
 DRUGS APPROVED RECENTLY...

Drug name Active Company Approval Approval

and FDA ingredient type date
appl#

TROXYCA ER Oxycodone Pfizer lnc Approval 19.08.2016

(NDA #207621 ) Hydrochloride;
Naltrexone
Hydrochloride

ARISTADA Aripiprazole Alkermes Inc Labelling 18.08.2016

(NDA # 207971) Lauroxil Rev ision

GLUCOTROL Glipizide Pfizer Labelling 08.18.2016

(NDA # 017783) Rev ision

MORTIN IB Ibuprofen J And J Consumer Inc Labelling 08.18.2016

(NDA # 019012) Rev ision
 What is Quality by Design (QbD)?
58

 In a Quality by Design system

 The product is designed to meet patient needs and performance

requirements
 The process is designed to consistently meet product critical quality
attributes
 The impact of starting raw materials and process parameters on
product quality is understood
 The process is evaluated and updated to allow for consistent
quality over time
 Critical sources of process variability are identified and controlled
Appropriate control strategies are developed
 Pro
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duc t Specifica ct
Pro ti o n
s Kn
Desired Pro duc o
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wl
Performance

ed
ge
e

Pr pk, robustness, nc

Pro
c.

ess Performa

duc
ss Controls

et

Dosa Product Design

t Quality Attribute
Quality

formulation, etc ty,

ge form, s ta
by
Proce
Design

bili
.
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g

C
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s
t a

Pro
ers

c es s D es ign
nd

Uni
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t ope l
s rati ons, contro
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c
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Pro cess Parameters

Con e nt
tinuous Improvem
 Approaches to Pharmaceutical Development

Aspects Current QbD

Pharmaceutical Empirical, Random, Focus on Systematic, Multivariate experiments,

Development optimization Focus on control strategy and
robustness

Manufacturing Fixed Adjustable within design space,

Process managed by company’s quality systems

Process Control Some in-process testing PAT utilized, Process operations tracked
and trended

Product Primary means of quality control, Part of the overall quality control
Specification based on batch data strategy, based on desired product
performance

Control Strategy By testing and inspection Risk-based control strategy , real-time

release possible
61 Why QbD?

Current System

Submission
Development Traditional
(Lack of PD
(Empirical) CMC Review
& MS)

Desired State

Submission
Development (Knowledge PQAS
(QbD) Rich in PD
& MS)
 What is PAT ? ( Process Analytical Technology )

PAT Definition
“Systems for continuous analysis and control of manufacturing processes based on real-time
measurements, or rapid measurements during processing, of quality and performance attributes of raw
and in-process materials and processes to assure end product quality at the completion of the process.”

PAT provides an opportunity to move

from the current “testing to
document quality” paradigm to a
“Continuous Quality Assurance”
paradigm that can improve our
ability to ensure quality was “built-in”
or was “by design” - ultimate
realization of the true spirit of cGMP!
WHY PAT ? ( Process Analytical Technology )
 Write to:
How to Call: Food and Drug Administration Email: Contact FDA
1-888-INFO-FDA
Contact FDA (1-888-463-6332)
10903 New Hampshire Ave Centers and Offices
Silver Spring, MD 20993-0002

Report an emergency
•If you are experiencing a life-threatening medical emergency, call 9-1-1.
•To report an emergency involving food, drugs, medical devices, dietary supplements, or cosmetics,
call 1-866-300-4374 or 1-301-796-8240.

Contact FDA Centers and Offices

•Center for Food Safety and Applied Nutrition (CFSAN, includes Cosmetics)
1-888-SAFEFOOD (1-888-723-3366) or go to cfsan.force.com/Inquirypage
•Center for Drug Evaluation and Research (CDER)
1-855-543-3784 or 1-301-796-3400 or druginfo@fda.hhs.gov
•Center for Devices and Radiological Health (CDRH)
1-800-638-2041 or 1-301-796-7100 or DICE@fda.hhs.gov
•Center for Biologics Evaluation and Research (CBER)
1-800-835-4709 or 1-240-402-8010 or ocod@fda.hhs.gov
•Center for Veterinary Medicine (CVM)
240-276-9300 or 1-888-INFO-FDA (1-888-463-6332) or AskCVM@fda.hhs.gov
•Center for Tobacco Products (CTP)
1-877-CTP-1373 (1-877-287-1373) or AskCTP@fda.hhs.gov
•National Center for Toxicological Research (NCTR)
1-870-543-7000 or NCTRInformation@fda.hhs.gov
•Office of Regulatory Affairs (ORA)
1-301-827-3101
 THANKYOU

ANY QUESTIONS ???

BACK UP SLIDES
 LEVEL 1 LEVEL 2 LEVEL 3

Unlikely to have detectable Could hav e significant impact Likely to hav e significant impact on the
impact. quality of the product.
Eg: changes in the color, Eg: change in the technical Eg: addition/ deletion of any excipient.
flav or. grade of the excipients.

CHANGE LEVEL 1 LEVEL 2 LEVEL 3

COMPONENT Addition or deletion of color or flavor. Change in the technical Changes in addition or deletion of
& COMPOSITION Total additive effect should not exceed grade of an excipient.Total any excipient.(except color or
5% of FPP weight. additive effect should not flavor)
exceed 10% of FPP weight.

MANUFACTURING SITE Same facility, may be different room. Same campus, different Different campus.
building.

SCALE UP/DOWN Scale up to 10x batch size of pilot Scale up beyond 10x batch NA
batch. size of pilot batch.

MANUFACTURING Changes in process within validation Changes in process outside Complete change of process
PROCESS range validation ranges. Eg: wet granulation-direct
eg: mixing speeds compression
EQUIPMENT Change in equipment for same Change in equipment to
design, operating principle. different design, operating NA
principle.
SCHEDULE I DRUGS - prohibited drugs. Ex narcotics.

SCHEDULE II DRUGS – The drug or other substance that has a high

potential for abuse. But in US they are currently accepted for
medical use . Ex opioids.

SCHEDULE III DRUGS – drug or other substance that has potential for
abuse less than the drugs or other substances in schedule I and II.
They are accepted for medicinal use. Ex stimulants (benzphetamine)
and depressants (amobarbital)

SCHEDULE IV DRUGS – the drug or other substances that has low

potential for abuse as compared to schedule III.

SCHEDULE V DRUGS - the drug or other substances that has low

potential for abuse as compared to schedule IV.