organization, structure, function of FDA, FR, CFR, FFDCA, Approval process of IND, NDA, ANDA, orphan drug, combination product, changes to approved NDA, ANDA, packaging labelling of pharmaceutical.

1. REGULATORY ASPECTS
OF DRUGS AND
COSMETICS
MRA 201T
Unit 1
Ms. Dimple Marathe
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2. Organization, Structure and Function of
FDA
The Food and Drug Administration (FDA) is a regulatory, scientific, public health, and
consumer protection agency. The FDA is responsible for protecting public health by:
• Regulating and supervising food safety
• Ensuring the safety, efficacy, and security of human and veterinary drugs, biological
products, medical devices, cosmetics, and products that emit radiation
• Helping to speed innovations that make medical products more effective, safer, and
more affordable
• Helping the public get the accurate, science-based information they need to use medical
products and foods to maintain and improve their health
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3.  The FDA's approval process for new drugs and biological products includes:
• Demonstrating that the drug or biological product is safe and effective for the intended
use
• Demonstrating that the product can be manufactured to federal quality standards
• A five-step process that includes discovery/concept, preclinical research, clinical
research, FDA review, and FDA post-market safety monitoring
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4. The FDA's drug approval process includes:
• Pre-clinical, INDA
• Clinical
• New Drug Application (NDA) Review
• Post-marketing risk assessments
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5. 5

6. FR and CFR
 The Federal Register is the chronological publication of proposed
regulations, final regulations, and related materials. The Code of Federal
Regulations (CFR) is a subject arrangement of regulations. A regulation
will be published first in the Federal Register and will later be included in
the appropriate volume of the CFR.
Federal Register
• Notices of proposed rulemaking
• Proposed new rules and regulations
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7. • Rationale, statutory basis, and goals of proposed rules and regulations
• Final Rules
• Changes to existing rules
• Notices of meetings and adjudicatory proceedings
• Presidential documents (Executive orders, proclamations, administrative orders,
etc.)
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8. Publication Schedule and Contents
Published every weekday, except on federal holidays.
Each daily issue of the printed Federal Register is organized into four categories:
•Presidential Documents (executive orders and proclamations)
•Rules and Regulations (including policy statements and interpretations of rules by
federal agencies)
•Proposed Rules (including petitions to agencies from the public)
•Notices (such as scheduled hearings and meetings open to the public and grant
applications)
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9. CFR
Code of Federal Regulations
Final Rules
Publication Schedule and Contents
The Code of Federal Regulations is the annual codification of all
the general and permanent rules published in the Federal
Register, arranged by subject
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10. The CFR is divided into 50 titles, and those 50 titles are split
into four sections. Each of those sections is updated once a
year according to the following schedule:
•Titles 1–16 are updated as of January 1
•Titles 17–27 are updated as of April 1
•Titles 28–41 are updated as of July 1
•Titles 42–50 are updated as of October 1
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11. Federal Food, Drug, and Cosmetic Act
 he Federal Food, Drug, and Cosmetic Act (FFDCA) is a set of laws that the US
Congress passed in 1938 to oversee the safety of food, drugs, medical devices,
and cosmetics. The FFDCA also prohibits the distribution or importation of
adulterated or misbranded products.
Functions:
 Issue and enforce quality standards for food, drugs, medical devices, and
cosmetics. Inspect facilities where food, drugs, medical devices, cosmetics, and
tobacco products are manufactured, processed, packaged, and stored. Recall
and/or seize products it deems unsafe or not FDCA-compliant.
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12.  The 1938 Federal Food, Drug, and Cosmetic Act (FDCA) is a set of United States
(US) laws that authorize the Food and Drug Administration (FDA) to oversee and
regulate the production, sale, and distribution of food, drugs, medical devices, and
cosmetics. The FDCA intends to protect the general public from adulterated and
misbranded products manufactured and sold in the US. Its introduction was largely
influenced by a mass poisoning event in which elixir sulfanilamide, an untested
antibiotic containing the toxin diethylene glycol, led to over 100 deaths across 15
states
 Under the drug regulations at the time, drug manufacturers were not required to
submit evidence of the safety or efficacy of their drugs before marketing them to the
general public. On June 25th, 1938, President Franklin D. Roosevelt signed the
FDCA into law, marking a milestone for modern-day consumer protections. The
FDCA and its subsequent amendments paved the way for numerous public health
reforms from which we derive benefits today.
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13.  The FDCA is enforced by the FDA, a regulatory agency within the US
Department of Health and Human Services. The FDCA authorizes the FDA
with the following tasks, among many others:
• Mandate drug manufacturers to submit evidence of new drugs’ safety and
effectiveness before marketing and distribution to the general public.
• Issue and enforce quality standards for food, drugs, medical devices, and
cosmetics.
• Inspect facilities where food, drugs, medical devices, cosmetics, and tobacco
products are manufactured, processed, packaged, and stored.
• Recall and/or seize products it deems unsafe or not FDCA-compliant.
• Regulate advertising of prescription drugs and medical devices.
• Issue regulations for product labeling and claims, including nutrition
information found on food packaging and health claims for foods and dietary
supplements.
• Approve new drugs, medical devices, and food and color additives.
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14. DMF
 A Drug Master File (DMF) is a document that contains information about a
drug's active ingredient or dosage form. DMFs can be used to provide
confidential information about the manufacturing, processing, packaging, and
storing of drugs
 The submission of a DMF is not required by law or FDA regulation. A DMF is
submitted solely at the discretion of the holder. The information contained in
the DMF may be used to support an Investigational New Drug Application
(IND), a New Drug Application (NDA), an Abbreviated New Drug Application
(ANDA).
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15.  A DMF is NOT a substitute for an IND, NDA, ANDA, or Export Application. It
is not approved or disapproved. Technical contents of a DMF are reviewed only
in connection with the review of an IND, NDA, ANDA, or an Export
Application.
 Drug Master Files are provided for in 21 CFR 314.420. This guideline is
intended to provide DMF holders with procedures acceptable to the agency for
preparing and submitting a DMF.
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16. There are five types of DMF's:
 Type I Manufacturing Site, Facilities, Operating Procedures, and Personnel
 Type II Drug Substance, Drug Substance Intermediate, and Material Used in Their
Preparation, or Drug Product
 Type III Packaging Material
 Type IV Excipient, Colorant, Flavor, Essence, or Material Used in Their Preparation
 Type V FDA Accepted Reference Information
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17. IND- INVESTIGATIONAL NEW DRUG
APPLICATION
 It is an application filed to FDA prior to human testing. It gives a full description of
chemistry, manufacturing and controls, pharmacology and toxicology information, any
previous human experience.
Types of IND
 An Investigator IND: It is submitted by a physician who both initiates and conducts an
investigation and under whose immediate direction the investigational drug is
administered or dispensed. A physician might submit a research IND to propose
studying an unapproved drug, or an approved product for a new indication or in a new
patient population.
 Emergency Use IND: This allows the FDA to authorize use of an experimental drug in
an emergency situation that does not allow time for submission of an IND.
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18.  Treatment IND: It is submitted for experimental drugs showing promise in clinical
testing for serious or immediately life threatening conditions while the final clinical
work is conducted and the FDA review takes place.
Once the IND is submitted, the sponsor must wait 30 calendar days before initiating any
clinical trials. During this time, FDA has an opportunity to review the IND for safety to
assure that research subjects will not be subjected to unreasonable risk.
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19. IND Content and Format
 The requirements for the content and format of IND application are given in the 21
Code of Federal Regulations (CFR), Section 312. A sponsor (commercial organization)
or an investigator who intends to conduct a clinical investigation should submit an
“Investigational New Drug Application”
 1. Form FDA 1571
 2. Table of contents
 3. Introductory statement and investigational plan
 4. Investigator’s brochure
 5. Protocols
 6. Chemistry, manufacturing and control (CMC) information
 7. Pharmacology and toxicology information
 8. Previous human experience
 9. Additional information.
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20. New Drug Application (NDA)
 A New Drug Application is filed to get approval for marketing a new drug in the USA.
An NDA contains information included in the IND, as well as the results of clinical
studies proving safety and efficacy. The FDA shall start the review process within 60
days from the submission of an NDA. Contents and Format of NDA Two copies of the
application are: (a) Archival copy and (b) Review copy.
 Archival Copy: It serves as a reference source for FDA reviewers to locate information
not contained in the review copy; and it contains copies of tabulations and clinical study
case report forms. It contains the following elements:
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21.  Application form FDA 356
 Index
 Summary
 Technical sections: further typed to
 Chemistry, manufacturing and controls section
 Non-clinical pharmacology and toxicology section
 Human pharmacokinetics and bioavailability section
 Microbiology section
 Clinical data section
 Statistical section
 Pediatric use section
 Samples and Labeling
 Case report forms
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22.  Review Copy: Each technical section is separately bound in each folder. Each technical
section should contain:
 1. Index
 2. Copy of FDA Form 356 h
 3. Copy of cover letter
 4. Letters of authorization
 5. Copy of application summary.
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23. Abbreviated New Drug Application (ANDA)
 ANDA is applied for products with same or closely related active ingredients, dosage
form, and strength, route of administration, use and labeling as product already shown
to be safe and effective. It is used when the patent has expired for a product, and a
company wants to market its copy. Such drugs are called generic drugs, which should
meet bio and pharmaceutical equivalent standards . An ANDA is submitted to Center
for Drug Evaluation and Research, Office of Generic Drugs, where it is reviewed and
approved.
Content and Format of ANDA
 1. Application form
 2. Table of contents
 3. Basis for ANDA submission
 4. Conditions of use
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24.  5. Active ingredients
 6. Route of administration, dosage from, strength Bioequivalence
 7. Labeling
 8. Chemistry, manufacturing and control
 9. Human pharmacokinetics and bioavailability
 10. Samples
 11. Analytical methods
 12. Case report forms and tabulations.
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25. Regulatory Requirement for Orphan drugs
 The Food and Drug Administration (FDA) requires sponsors to submit an application to
receive an orphan designation for a drug from the FDA's Office of Orphan Products
Development (OOPD).
 The FDA considers a rare disease to be one that affects fewer than 200,000 people in
the United States or a condition that affects more than 200,000 people but for which
there is no reasonable expectation that pharmaceutical companies will recover the costs
incurred during drug.
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26. The Orphan Drug Act’s incentives and the Office of Orphan
Products Development’s clinical superiority criteria motivate
companies to develop orphan products
 According to FDA, the Orphan Drug Act has unquestionably stimulated the
development of drugs for rare diseases. A handful of such drugs were available before
1983, but since enactment of the law the Office of Orphan Products Development has
designated approximately 1,000 orphan products; over 200 of these subsequently
received marketing approval.
 Many orphan drugs, including those approved for multiple sclerosis, cystic fibrosis, and
hemophilia, are considered breakthroughs.
 “Orphan designations” are for products that FDA has determined could be used to treat
a rare disease (i.e., a condition affecting fewer than 200,000 individuals in the United
States). “Orphan approvals” are for products that FDA has determined are ready for
marketing in the United States.
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27.  How FDA Defines an Orphan Drug?
In USA, the term “Orphan drug” has two definitions. The first describes drugs or biologics
that are used for the prevention, diagnosis, or treatment of diseases or conditions affecting
fewer than 200,000 persons in the US. The second definition describes a drug or biologic
that is intended for diseases or conditions affecting 200,000 or more people, or for a
vaccine, diagnostic drug, or preventive drug to be administered to 200,000 or more persons
per year, where the drug will not be profitable within 7 years following FDA approval.
 When to Request an Orphan Drug Designation (ODD)?
A sponsor may request for an orphan drug designation (ODD) at any time during the drug’s
development process and prior submitting a marketing application for the drug for the same
rare disease or condition. The sponsor can also request and ODD of an already approved
drug for an unapproved use without regard to whether the prior marketing approval was for
a rare disease or condition. More than one sponsor may receive (ODD) of the same drug for
the same rare disease or condition, but each sponsor seeking orphan-drug designation must
file a complete request for designation.
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28.  How to Submit an ODD Application to FDA?
The submission of ODD application to the FDA Office of Orphan Products Development
(OOPD) is performed online through FDA CDER NextGen Portal for Submission of
Orphan Drug Designation Requests: online Portal for submission of new orphan drug
designation requests. This submission process is easy and has many advantages. It provides
the applicant an automated confirmation just after submitting the ODD application. It
allows the applicant to see all historical records related to its application and check on the
status of any submission at any time.
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29. Regulatory Requirement for Combination Products
 A combination product is a product that is sold separately but labeled for use
together. The constituent parts of a combination product retain their regulatory status as
a drug or device after they are combined.
 Here are some regulatory requirements for combination products:
• Drug/device combination products with main effects as medical devices are regulated
as Class III medical devices.
• Drugs in combination products should have a drug registration certificate issued by the
National Medical Products Administration (NMPA).
• If a combination product or device constituent part received marketing authorization
under a device application, you must comply with the requirements for postmarketing
safety reporting.
• Article 117 of the MDR / Annex I Section 3.2 point 12 of Directive 2001/83/EC
requires manufacturers to obtain an opinion from a Notified Body.
• ISO 12417-1:2015 specifies requirements for vascular device-drug combination
products (VDDCPs)
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30. Changes to approved NDA , ANDA
 This guidance provides recommendations to holders of new drug applications (NDAs) and
abbreviated new drug applications (ANDAs) who intend to make postapproval changes in
accordance with section 506A of the Federal Food, Drug, and Cosmetic Act (the Act) and §
314.70 (21 CFR 314.70). The guidance covers recommended reporting categories for
postapproval changes for drugs other than specified biotechnology and specified synthetic
biological products. It supersedes the guidance of the same title published November 1999.
Recommendations are provided for postapproval changes in (1) components and
composition, (2) manufacturing sites, (3) manufacturing process, (4) specifications, (5)
container closure system, and (6) labeling, as well as (7) miscellaneous changes and (8)
multiple related changes.
 CDER has published guidances, including the SUPAC (scale-up and postapproval changes)
guidances, that provide recommendations on reporting categories. To the extent that the
recommendations on reporting categories in this guidance are found to be inconsistent with
guidances published before this guidance was finalized, the recommended reporting
categories in such previously published guidances are superseded by this guidance.
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31. REPORTING CATEGORIES
Section 506A of the Act and § 314.70 provide for four reporting categories that are
distinguished in the following paragraphs.
 major change
 moderate change
 Supplement - Changes Being Effected
 minor change
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32. GENERAL REQUIREMENTS
 Other than for editorial changes in previously submitted information (e.g., correction of
spelling or typographical errors, reformatting of batch records), an applicant must notify
FDA about each change in each condition established in an approved application
beyond the variations already provided for in the application
 An applicant making a change to an approved application under section 506A of the Act
must also conform to other applicable laws and regulations, including current good
manufacturing practice (CGMP) requirements of the Act (21 U.S.C. 351(a)(2)(B)) and
applicable regulations in Title 21 of the Code of Federal Regulations (e.g., 21 CFR
parts 210, 211, 314). For example, manufacturers must comply with relevant CGMP
validation and recordkeeping requirements and ensure that relevant records are readily
available for examination by authorized FDA personnel during an inspection.
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33. MANUFACTURING PROCESS
 General Considerations
The potential for adverse effects 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 depends on
the type of manufacturing process and the changes being instituted for the drug substance or drug
product. In some cases, there may be a substantial potential for adverse effect regardless of direct
testing of the drug substance or drug product for conformance with the approved specification.
When there is a substantial potential for adverse effects, a change must be submitted in a prior
approval supplement
 Major Changes (Prior Approval Supplement)
.Changes that may affect the controlled (or modified) release
.Changes that may affect drug product sterility
.The following changes for a natural product
.Any fundamental change in the manufacturing process or technology from that currently used
by the applicant
.Changes for drug substance
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34.  Moderate Changes (Supplement - Changes Being Effected)
 Minor Changes (Annual Report)
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35. CONTAINER CLOSURE SYSTEM
 General Considerations
 Major Changes (Prior Approval Supplement)
 Moderate Changes (Supplement - Changes Being Effected)
 Minor Changes (Annual Report)
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36. LABELING
 General Considerations
 Major Changes (Prior Approval Supplement)
 Moderate Changes (Supplement - Changes Being Effected)
 Minor Changes (Annual Report)
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37. Guidelines for Pharmaceutical Packaging and
Labeling
 As a business that sells pharmaceutical products, it’s absolutely critical to understand the
guidelines that govern the labeling and packaging of those products. The Food and Drug
Administration is the regulator of labeling standards, and you’ll learn about their
requirements for proper pharma packaging and labeling, as well as where to go for quality
labeling solutions
 Primary and Secondary Pharma Packaging Design Guidelines
1. Primary packaging is any that comes into direct contact with a pharmaceutical, such as a
blister pack or pre-filled syringe. Secondary packaging is that which doesn’t come into direct
contact with a product and would include a carton or an accessory like a syringe plunger rod.
2. The FDA requires that all primary and secondary packaging materials be suitable for their
intended use. “Suitable for intended use” means that the packaging should not only protect the
product’s form of dosage, but also be compatible with that dosage form. It’s also required that
primary and secondary packaging be made of a material that’s considered safe to use, both with
the product’s administration route and its form of dosage.
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38. 3. Primary packaging of pharmaceuticals should protect products from degradation and
subsequent loss of efficacy due to:
• Microbial contamination
• Exposure to light
• Oxidation
4. Primary packaging is also not permitted to interact with the product in any way that
would alter its or its packaging’s essential properties, or release carcinogenic or mutagenic
substances into the product.
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39.  The secondary packaging of any product should serve at least one of the following. It
should provide:
• Light protection for the system of packaging
• Protection for any excessive emission of reactive gas in or out of the packaging system
• Protect packaging systems needing additional handling protection or those which are
flexible
• Protection from microbial intrusion
• Protection from excessive moisture or solvent transmission in or out of the packaging
system
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40. Labelling Guidelines
 Any pharma label printing for pharmaceutical use is required by the FDA to be designed and
applied in such a way that it can remain in place, and be legible in a number of environments
like use and storage for the entire lifespan of the product.
 All pharmaceutical labels need to display certain information on their labels, although the
requirements for content varies from product to product. In general, a label must include:
• Directions for use
• Warnings
• Active and inactive ingredients
• Official product name
• Dosage
 The design of a label must be of a legible font type and size, be in appropriate language and
format, and be made of approved materials. All labels should be thoroughly inspected to
ensure accuracy and consistency of information.
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41. regulatory considerations for pharmaceutical
manufacturing in the US include:
• Registration
Pharmaceutical products must be registered with the FDA through New Drug Application (NDA)
for an Investigational New Drug (IND), Abbreviated New Drug Application (ANDA) for a
generic drug, and through Biologics License Application (BLA) for a new biologic product.
• Drug approval process
The drug approval process has four phases: preclinical investigation, clinical investigation,
review of the new drug application, and postmarketing surveillance. The entire process can take
many years and cost millions of dollars.
• Compliance issues
Failure to follow ethical guidelines, obtain proper participant consent, or accurately report
clinical trial results can result in compliance issues.
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42. THANK YOU
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