Regulatory Affairs

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M Pharmacy Notes
Pharmaceutics
Regulatory Affairs
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Syllabus:-
1. a. Documentation in Pharmaceutical industry: Master formula
record, DMF (Drug Master File), distribution records.
Generic drugs product development Introduction , Hatch- Waxman
act and amendments, CFR (CODE OF FEDERAL REGULATION) ,drug
product performance, in-vitro, ANDA regulatory approval process,
NDA approval process, BE and drug product assessment, in –vivo,
scale up process approval changes, post marketing surveillance,
outsourcing BA and BE to CRO.
b. Regulatory requirement for product approval: API, biologics,
novel, therapies obtaining NDA, ANDA for generic drugs ways and
means of US registration for foreign drugs.
2. CMC, post approval regulatory affairs. Regulation for combination

products and medical devices.CTD and ECTD format, industry and
FDA liaison. ICH - Guidelines of ICH-Q, S E, M. Regulatory
requirements of EU, MHRA, TGA and ROW countries.
3. Non clinical drug development: Global submission of IND, NDA,

ANDA. Investigation of medicinal products dossier, dossier (IMPD)
and investigator brochure (IB).
4. Clinical trials: Developing clinical trial protocols. Institutional

review board/ independent ethics committee Formulation and
working procedures informed Consent process and procedures.
HIPAA- new, requirement to clinical study process,
pharmacovigilance safety monitoring in clinical trials.

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5. General principle of IPR: IP protection, economic importance,

mechanism of protection. Patent, criteria, types of patent application-
steps, trademark and copyright

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UNIT 1.a. Documentation in Pharmaceutical

Industry
What are Regulatory A
Affairs?
A regulatory affair is a profession which acts as interface between

pharmaceutical industry and drug regulatory authority around the
world.
Goals of RA
 Protection of Human health

 Ensuring safety, efficacy and quality of drugs
 Ensuring accuracy of product information
MAJOR REGULATORY AUTH

AUTHORITY

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Role of Regulatory Affairs
 To give strategic & technical advice to R&D,QC, PRODUCTION

 To keep Track in every change in legislation
 Registration document to regulatory Agency
Master Formula Record

 Master Formula Record (MFR) is a master document for any
pharmaceutical product.
 MFR contains all information about the manufacturing process for
the product.
 MFR is prepared by the research and development team of the
company.
 MFR is used as reference standard for preparing batch
manufacturing record (BMR) by manufacturing units.
 MFR is also called Master Manufacturing Record, Master Production
Record.
Master Formula Record Contains: - Product Details
 Name, logo and address of the manufacturing company

 Dosage form name
 Brand name
 Product code
 Product description
 Batch size
 Pack size and packing style
 Shelf life
 Storage conditions
 MFR number and date
 Authorization by the production and quality assurance head

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Drug Master File

It is a submission to USFDA or too concerned regulatory authority,
that may be used to provide confidential and detailed information
about manufacturing, processing, packaging or storing of one or more
human drugs.
 DMF is not mandatory by law or FDA regulation.

 DMF is submitted by API manufacturers.
 The information in DMF is used to support NDA, ANDA, IND.
 It is a submission that indicates that product of one company is a
quality product and meets the required standards.
Types of Drug Master Files
1. TYPE 1 - Manufacturing Site, Facilities, Operating Procedures, and

Personnel
2. TYPE 2 - Drug Substance, Drug Substance Intermediate, and
Material Used in Their Preparation, or Drug Product
3. TYPE 3 - Packaging Material
4. TYPE 4 - Excipients, Colorant, Flavor, Essence, or Material Used in
Their Preparation
5. TYPE 5 - FDA-Accepted Reference Information

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Distribution Records
Distribution: The division and the movement of pharmaceuticals
products from the premises of the manufacturer to the end user or to
an intermediate point by means of various transport methods.
Distribution records: Are written data related to distribution of drug

products from manufacturer to the distributor.
Distribution Procedure
1. A procedure whereby the oldest approved stock of a drug product is

distributed first.
2. It must be constructed and procedures established to facilitate
recall of defective product.
3. The manufacturer must maintain records of all distribution
transactions involving in process or finished goods.
4. Computerized tracking systems are most common.
Distribution Records Should Contain
 Nam
 Strength of the product
 Name and address of consignee

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 Date and quantity shipped

 Control number of drug product.
GENERIC DRUG PRODUCT DEVELOPMENT

Generic Drug - A generic drug is a drug product that is comparable to/
bioequivalent to brand/innovator drug in dosage form, strength, route
of administration, quality & performance characteristics".
After the expiry of the patent or marketing rights of the patent drug,
generic drugs are marketed.
Product Development
Product: A product is something sold by an enterprise to its customers.
Product Development: Product development is the set of activities

beginning with the perception of a market opportunity and ending in
the production, sale and delivery of a product.
Generic Product Development Process
The input of the process is a mission statement and the output of the
process is the product launch.
Mission Statement: Identifies the target market for the product,

provides a basic functional description of the product, and specifies

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the business goals of the effort; results from well executed product
planning phase.
Product Launch: Occurs when the product becomes available for

purchase in the market place.
HATCH WAXMAN ACT

It is otherwise called as "Drug Price competition & Patent term
Restoration Act".
 Established in 1984.
The main objective is
 to reduce the cost

 to make available more low cost generic drugs
 Motivating the generic drug Manufacturer
Generic drug manufacturers files ANDA that incorporates safety and

effectiveness data submitted by original pioneer drug manufacturer
and adds only bioequivalence study.

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Provisions of the Act
1. Paragraph I: that such patent information has not been filed

2. Paragraph II: that such patent has expired
3. Paragraph III: of the date on which such patent will expire
4. Paragraph IV: that such patent is invalid or will not be infringed by
the manufacture, use, or sale of the new drug for which the
application is submitted
ORANGE BOOK
 Contains the list of all FDA approved Drug products

 It is updated monthly.


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Code of Federal Regulations (CFR)

 CFR is the codification of the general & permanent rules and
regulations (also called as Administrative law) published in the
federal register by the executive departments & agencies of the
federal government of the United States.
 It is divided into 50 tit
titles that represent broad areas.
 Each title is further divided into chapters, subchapters, parts, and
sections.
 A regulation is cited by title, part, and section, e.g. 14 CFR 121.313
(Title 14, Part 121, Section 313).
 Title 21 of the CFR is reserved for rul
rules
es of the Food and Drug
Administration.

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 In all, 21 CFR consists of 1499 parts.

 There are a number of electronic sources for accessing CFR.
Notable Sections
 11 Electronic records and electronic signature related.

 50 Protection of human subjects in clinical trials.
 54 Financial Disclosure by Clinical Investigators.
 56 Institutional Review Boards that oversee clinical trials.
 58 Good Laboratory Practices (GLP) for nonclinical studies.
DRUG PRODUCT PERFORMANCE (DPP)

 DPP is defined as the release of the drug substance leading to
bioavailability of the Drug substance.
 Assessment of DPP is important since bioavailability is related both
to the pharmacodynamic response and to adverse effects.
 DPP - determined by In-vivo Bioequivalence studies or in-vitro by
comparative drug dissolution studies.

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NDA Regulatory Approval Process

NDA (New
New Drug Application
Application) - The vehicle through which drug
sponsors formally propose that the regulatory body approve a new
pharmaceutical for sale and marketing.
The data gathered during the animal studies and human clinical trials
of an Investigational new product become part of the NDA.

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Fundamentals of NDA Submission
 Index
 Summary
 Microbiology (for anti-microbial drugs only)
 Chemistry, Manufacturing, and Control
 Samples, Method Validation Package, and Labeling
 Nonclinical Pharmacology and Toxicology

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 Human Pharmacokinetics and Bioavailability

 Clinical Data
 Safety Update Report (typically submitted 120 days after the
NDA's submission)
 Statistical
 Case Report Tabulations
 Case Report Forms
 Patent Information
ANDA Regulatory Approval Process

Abbreviated new drug application (ANDA) is an application for a U.S.
generic drug approval for an existing licensed medication or approved
drugs.
A generic drug product is one that is comparable to an innovator drug

product in its dosage form, strength, quality etc.0

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CONTENT AND FORMAT OF AN ABBREVIATED APPLICATION
1. Application form
2. Table of contents
3. Basis for abbreviated new drug application submission
4. Conditions of use
5. Active ingredients
6. Route of administration, dosage form and strength

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7. Bioequivalence
8. Labeling
9. Chemistry, manufacturing and controls.
10. Samples
11. Patent certification.
BE AND DRUG PRODUCT ASSESSMENT

Two pharmaceutical products are bioequivalent if they are
pharmaceutically equivalent, and their bioavailability, in terms of rate
(Cmax and tmax) and extent of absorption (area under the curve),
after administration of the same molar dose under the same

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conditions, are similar to such a degree that their effects can be

expected to be essentially the same.
NEED OF BIOEQUIVALENCE
The need of bioequivalence studies is increasing due to the large

growth of the production and consumption of generic product
Bioequivalence studies are conducted if there is:
 A risk of bio in equivalence or

 A risk of pharmacotherapeutic failure
 No clinical studies have been performed in patient with the generic
product to support its efficacy and safety
Types of Equivalence
1. Chemical equivalence - Two or more drug product contain same

labelled chemical in a same amount.
2. Pharmaceutical equivalence - Two or more drug are identical in

strength, quality, purity, content uniformity, disintegration and
dissolution.
3. Therapeutic equivalence - Indicate that two or more drug product

that contain the same therapeutically active ingredient elicit identical
pharmacological effect and control the disease to the same extent.
4. Bioequivalence - It is a relative term which denotes that the drug

substance in two or more identical dosage form, reaches the systemic
circulation at the same relative rate and relative extent.
DESIGN AND EVALUATION OF BIOEQUIVALENCE STUDIES
1. Fasting study
 Use for immediate release and modified release oral dosage form

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 Overnight fast and 4 hour after dosing
2. Food intervention study
 Co-administration of food with an oral drug product may affect

the bioavailability of drug
3. Multiple dose study
 Multiple dose, randomized, crossover study

 Three consecutive Trough concentration on three consecutive
days
Type of Design
1. Complete randomized design - All treatment are randomly

allocated among all experimental subject.
Example: if there is 20 subjects, number them from 1 to 20. Random

select non repeating number.
2. Randomized block designs - Subjects are sorted into homogenous

group called blocks.
Method - Subjects having similar background characteristics are

formed as blocks
Scale-Up Process Approval Changes

The scale-up process approval changes made after approval in the
composition, Manufacturing process, mfg. equipment & change of site
have become known as Scale-up and Post Approval Changes.

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Abbreviated as SUPAC
 NDA → Larger Batch Size

 ANDA -> Larger Batch Size
The FDA has issued various guidance for SUPAC.
They are
 SUPAC - IR (For Immediate-release solid oral dosage form)

 SUPAC - MR (For Modified-release Solid oral dosage form)
 SUPAC - SS (For Non-sterile semisolid dosage form such as
creams, ointments, gels & lotions)
POST MARKETING SURVEILLANCE (PMS)

PMS is the practice of monitoring the safety of a pharmaceutical drug
or medical device after it has been released on the market.
It is an important part of the science of Pharmacovigilance.
Objective:

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 To develop information about drug effects under customary

condition of drug use.
 To assess a known serious risk related to the use of drug
Advantages
 Helps to detect rare ADR's

 Drug interaction
Methods of Surveillance:
Four types of studies are generally are used to identify drug effects
1. Controlled clinical trials.

2. Spontaneous & Voluntary recording
3. Cohort studies
4. Case Control studies.
Sources of PMS
1. Customer surveys
2. Literature reviews
3. Expert user groups
4. Customer complaints
5. The media
Outsourcing BA and BE To CRO

Definition - Contract research organisation (CRO) is an entity that
extends support to pharmaceutical, biotechnology and medical devices
industry in the form of research services outsourced on a contract
basis.

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A CRO may offer such services like:
 Biopharmaceutical development
 Pharmacovigilance
 Clinical & preclinical research
 Clinical trial
 Biological assay development
Outsourcing is the business practice & hiring a party outside a company

to perform services & create goods that traditionally were performed
in-house by the company's own employee & staff.
It is generally done to
1. To reduce the costs and

2. Improving the efficient resources within a company
Eg: Outsourcing is Bioavailability, Bioequivalence, Research &

Development Department etc.
UNIT 1.b. Regulatory Requirement for Product

Approval
Active Pharmaceutical Ingredient (API or drug substances)

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Any substance or mixture of substances intended to be used in the

manufacture of a pharmaceutical dosage form and that, when used so,
becomes an active ingredient of that pharmaceutical dosage form. Such
substances are intended to furnish pharmacological activity or other
direct effect in the diagnosis, cure, mitigation, treatment or
prevention of disease or to affect the structure and function of the
body.
General work profile of a Regulatory Affairs professional in an API

manufacturing company
 Filing a DMF/ASMF with regulatory agencies in support of the

NDA/ANDA/ INDA /MAA filed by a Formulator (Drug Product
manufacturer who uses API of that particular API manufacturing
company).
 Filing dossier of API with EDQM for obtaining CEP.
 Assessing and filing amendments/variations to the information
(which may be related to manufacturing, control, stability studies,
etc) in DMF/ASMF/Dossier of particular API with the Regulatory
agencies. Major amendments are to be reported prior to their
implementation while minor amendments may be reported annually.
 Taking approval of customers of API before implementing any major
changes regarding the information mentioned in
DMF/ASMF/Dossier. The updated DMF/ASMF may be submitted to
the customer simultaneously along with amendments/variations filed
with the agency.
Regulatory Guidelines for APIs
In order to obtain marketing authorization for a drug product the

applicant has to show evidence of efficacy, safety, and quality of the
drug product

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Different countries have different procedures for regulatory filing for

API; in U.S. it has done as per the DMF procedure of the FDA while in
Europe it is done by ASMF procedure.
The older and off-patent APIs have an alternative assessment system

called the "Certification of Suitability" (CEP). It is used in the
countries that have signed the European Pharmacopoeia Convention.
Requirements for Registration of API
In the US active pharmaceutical ingredient is referred to as a drug

substance. Registration of active substances takes place along with
pre-marketing approvals like NDA & ANDA. That means there is no
separate registration process for API. The manufacturer of API need
to submit the information in the form of DMF. The FDA reviews the
information and gives the DMF number. When the drug product
manufacturer wants to get approval for the product, they mention the
DMF of the drug substance as a supporting document for the
applications like NDA & ANDA.
Regulatory Requirements for BIOLOGICS

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Biologics are the products manufactured, extracted from, or semi-

synthesized from a biological source that is regulated by FDA and are
used to prevent cure and treat diseases and medical conditions.
These are generally large, complex molecules produced through

biotechnology in a living system such as a microorganism, plant cell, or
animal cell.
These could be made of sugars, proteins, nucleic acids, or complex

combinations of these substances or may be living entities.
These are complex mixtures that are not easily identifiable and
characterized these tend to be heat sensitive and susceptible to
microbial contamination hence, it is necessary to use aseptic principles
from the initial manufacturing process.
Examples: Botox, Herceptin, Vaccines, Enbrel
Sources
 Mammalian cell culture

 Bacteria
 Insect cell culture
 Plant cell culture
 Yeast
 Transgenic
 Avian cell culture
 Humans
Types

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 Blood derivatives
 Vaccines
 Allergenic extracts
 Whole blood
 Blood components
 Proteins
 Human tissues
 Cellular and gene therapies
 Xeno-transplantation products
Biologics and its regulatory guidelines
Biological Product is a virus, therapeutic serum, toxin, antitoxin,

vaccine, blood, blood component or derivative, allergenic product, or
analogous product, applicable to the prevention, treatment, or cure of a
disease or condition of human beings.
Law or Act
 Drug Products fall under the Food, Drug, and Cosmetic Act
While,
 Biological products fall under the Food, Drug, and Cosmetic Act &
Public Health Service Act
USFDA Biologics Team
The FDA biologics team was established in 1997 to assure the quality
and safety of Biological products. It consists of a core team of,
1. Certified ORA investigator,

2. CBER-certified inspectors, and
3. Specially trained compliance officers representing both ORA
AND CBER
Regulatory authority for biologics

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 Centre for biologics evaluation and research (CBER) is the center

within FDA that regulates biological products for human use under
applicable Federal laws including the Public Health Services Act
(PHS) and the Federal, Food, Drug, and Cosmetics Act
 CBER protects and advances public health by ensuring that biological
products are safe and effective. > FDA's regulatory authority for
the approval of biologics resides in (PHS) Act.
 Biologics are subjected to regulation under the Federal, Food, Drug,
And Cosmetics act (FD&C) Act.
 Some medical devices which are used to produce biologics are
regulated by CBER under the FD&C Act's medical device
amendments of 1976.
FDA also reviews new biological products and new indications and
usage for already approved products on the market for the
treatment of known diseases.
It protects against threats of emerging infectious diseases.
It provides the public with information to promote the safe and
appropriate use of COPS DSU Department of Pharmaceutics
Development and approval process
 Advertising and Labeling

 Investigational New Drug Application (IND) or Device exemption
process (IDE)
 Expanded Access
 Premarket Approval (PMA)
 Biologics License Application (BLA) New Drug Application Process
(NDA).
 Biologics Approvals By Year.
Biologics license application (BLA)

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 The Biologics License Application (BLA) is a request for permission

to introduce or deliver for introduction a Biologic product into the
market.
 It is mainly regulated by 21 CFR 600-800. It is submitted by any
legal person or entity, who engaged in the manufacture or an
applicant for a license who takes responsibility for compliance with
the product and establishment of standards
 A Biologic License application generally applies to vaccines and other
Allergenic drug products and cellular and genetic therapies.
 A cover letter should always accompany any FDA submission.
Addressed below are Form FDA 356(h), the cover letter, and all 20
sections of the BLA application.
 Before each section is addressed individually, it is worth
emphasizing the importance of the application form [Form FDA
356(h)], the cover letter, and the first three sections.
 Under the Public Health Services Act, the Federal Food and Drug
Administration (FDA) has been given the authority, concurrent with
its authority under the Food Drug and Cosmetic Act, to regulate
biologics.
 The FDA regulates a wide range of biologics, including vaccines,
blood, and blood by-products, certain monoclonal antibodies, and
tissue and cellular products.
 within the FDA, the Center for Biologics as well as the Centre for
Drug Evaluation and Research, can be responsible for the regulation
of biologics.
 Biologics are evaluated for market by the FDA through the filing of
a Biologic License Application (BLA).
 A BLA, although similar to a New Drug Application (NDA), has its
own set of complex requirements.

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 Applicant has to provide the information in an acceptable format,

under the applicable regulations. However, applicants must be aware
that unique and specific information will be required depending on
the type of BLA (e.g. - blood, vaccines).

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Novel Drugs with its Regulatory Requirements

Novel drugs are often innovative products that serve previously unmate
medical needs and significantly help to advance patient treatments.
Novel drugs can represent important new therapies for advancing

patient care.
In 2017 CDER gave approval to many novel drugs includes as;
 Dupixent: to treat adult with moderate-to severe eczema (atopic

dermatitis).
Rules for approval of a novel drug
 FDA approval of a drug means that data on the drug's effects have
been reviewed by CDER.
 The drug is determined to provide benefits that outweigh its known
and potential risks for the intended population.
 These approaches can includes more interaction between CDER
staff and drug developers, and shortened timelines for review of
application.
 The drug approval process takes place within a structured
framework that includes:
Analysis of the target condition and available treatments
FDA reviewers analyse the condition or illness for which the drug is
intended and evaluate the current treatment landscape, which provide
the context for weighing the drug's risks and benefits.
Assessment of benefits and risks from clinical data
FDA reviewers evaluate clinical benefit and risk information submitted

by the drug maker,

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Strategies for managing risks-
All drugs have risks. Risk management strategies include on FDA-

approved drug label, which clearly describes the drug's benefits and
risks, and how the risks can be detected and managed.
Newer Approach- Faster Testing & Approval
The mechanisms speed up the approval process, and apply a degree of

flexibility with respect to the evidence requirements for the approval
of certain medicines.
In the U.S., accelerated pathways (APs) include Fast Track (FT),

Breakthrough Therapy Designation (BTD), Accelerated Approval (AA),
and Priority Review (PR).
Fast Track (FT)
 Fast track is a process designed to facilitate the development of

drugs to treat serious or prevent a condition.
 If there are available therapies, a fast track drug must show
some advantage over available therapy.
 Avoiding serious side effects of an available therapy
 Improving the diagnosis of a serious condition.
Breakthrough Therapy (BT)
 Breakthrough Therapy designation, clinically significant endpoint

generally refers to an endpoint that measures an effect on
irreversible morbidity or mortality (IMM) or on symptoms that
represent serious consequences of the disease.
 A clinically significant endpoint can also refer to findings that
suggest an effect on IMM or serious symptoms.
 An effect on an established surrogate endpoint.

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 A significantly improved safety profile compared to available

therapy (eg:- less dose-limiting toxicity for an oncology agent)
Priority Review (PR)
 Prior to approval, each drug marketed in the United States must

go through a detailed FDA review process.
 Under the Prescription Drug User Act (PDUFA), FDA agreed to
specific goals for improving the drug review time and created a
two-tiered system of review times - Standard Review and Priority
Review.
 A Priority Review designation means FDA's goal is to take action
on an application within 6 months (compared to 10 months under
standard review).
Accelerated Approval (AA)
 In 2012, Congress passed the Food and Drug Administration

Safety Innovations Act (FDASIA).
 These accelerated approval endpoints may includes ones that
shows benefits over a shorter duration of treatments.
 Accelerated approval brings drug that can provides important
advances to patients sooner than with traditional approvals.

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New Drug Approvals

It is a regulatory mechanism that is designed to give Food and Drug
Administration (FDA) sufficient information to make a meaningful
evaluation of a New Drug.
New Drug Application is the vehicle in the United States through which
the drug sponsors formally propose that the FDA approve a new
pharmaceutical for sale and marketing.
Objectives
Upon the completion of this presentation student gets to learn
 To know the approval process of NDA

 Drug development process
 Concepts of innovator and generic drugs
Clinical Trials:-
 10-15 years from lab to US patients.

 Only 1 in 5000 compounds makes it to the human testing.
 Only 1 in 5 tested in humans is approved.
 Testing phases in Humans
o Discovery
o Development
o Clinical Studies
o Medicine approved

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History
 When the federal food, drug and cosmetic act 1938 was passed, a
new era of drug product development began.
 The act required the assurance of safety and stated minimum
requirements for manufacturing and quality control.
 It provided only 60 days for review by FDA before the
distribution of any new drug product.
Goals:-
 Safety and effectiveness of a drug in its proposed use.

 Whether the drug proposed labelling (package insert) is
appropriate.
 Methods used in manufacturing the drug and the controls used to
maintain the drugs quality are adequate to preserve the drugs
identity, strength, quality and purity.
 The benefits of the drug outweigh the risks.

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UNIT 2 - CMC, Post Approval Regulatory Affairs

1. CMC (Chemistry, Manufacturing & control)
CMC means chemistry, manufacturing and control, CMC regulatory

affairs is a specific area with RA that has ultimate responsibility for
providing CMC regulatory leadership and strategy required to achieve
regulatory approvals, CMC RA provides knowledge, understanding,
interpretation and utilization of regulatory guidance and regulations, as
well as industry and government agency best practice and trends.
Example: including CMC regulatory submission may contain information

associated with API and the finished dosage form including:-
 Names and location of manufacturing and testing sites

 Characterization of the API and composition of the dosage form
 Raw materials used to manufacture the API and finished dosage
form
 Description of the product and process development
 Description of the manufacturing process
 Analytical methods and specifications used for testing and
release of raw materials, in-process controls and closure system,
API and dosage form
 Quality testing, bio equivalence testing
 Release and stability testing data for both API and the dosage
form.
It should be noted that CMC section is made up of three distinctly

different but overlapping disciplines/sciences which are:
1. Synthetic/ fermentation chemistry

2. Analytical chemistry
3. Formulation chemistry

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What is a CMC regulatory affair?
To conduct clinical investigations and market pharmaceutical products

pharmaceutical companies are legally required obtaining and maintaining
regulatory approvals.
The government regulatory agencies typically involved in the process

are:
1. the food and drug administration (FDA),

2. European medicines agency (EMA),
3. Japanese pharmaceuticals and medicinal devices agency (PMDA),
etc.
Regulation 21 CFR 312.23(a)(7)(i)
As appropriate for the particular investigations covered by the IND, a

section describing the composition, manufacture, and control of the
drug substance and the drug product sufficient CMC information to
assure the proper identification, quality, purity and strength of the
investigational drug.
CMC information
Same for all INDs or diseases, however, Regulations emphasize the

graded nature of CMC information needed in an IND. The amount of
CMC information needed varies according to type of trial-phase, size
and duration of clinical trial, dosage form, prior usage, history, etc.
FDA recognizes that CMC development parallels clinical investigations
CMC review at IND stages - Primary objective is to assure the safety

of patients, during all phases of the IND.
Phase 1 CMC evaluated mainly from the point of risk to patient, phase 2
and 3 CMC evaluates safety, and additionally the linkage of the clinical
test product to the to-be marketed product.

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Post phase 1 submissions
Continue to provide CMC data to support clinical studies, develop data

for future NDA submission. Demonstrate that to-be-marketed drug
has same/similar identity, quality, purity and strength as that of the
investigational drug proven to be effective and safe through clinical
studies. Demonstrate consistency and reliability of drug manufacturing
process over product life.
Development elements ICH Q8
1. Quality target product profile (QTPP)
 Intended use
 Route of administration
 Dosage form
 Delivery
 Bioavailability
 Strength
 Container closure
 Stability
 QTPP example: - pediatric suspension for oral administration
2. Identity critical quality attributes (CQA) of the drug product,

drug substance and excipients
 For manufacture - particle size, polymorphic form

 For performance - dissolution/disintegration
 For stability - water content, light protection, impurity control.
3. Control strategy
 Control of drug substance

 Control of excipients and intermediates
 Process control

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 In-process testing
 Container closure system
 Drug product specification
4. Manufacturing process
 Systematic and thoughtful design incorporating QTPP, CQA,etc

elements
 Process improvement and control
 Process robustness
CMC regulatory submission contains
 CMC regulatory submissions are not limited information

associated with API and the finished dosage form, it contains
 Names and location of manufacturing and testing sites
 Characterization of the API and composition of the dosage form
 Description of the product and process development
 Description of the manufacturing process
 Analytical methods and specifications used for testing and
release of raw material, in-process controls, container and closure
systems, API and the dosage form
 Release and stability testing data for both the API and the
dosage form.

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2. Post Approval Regulatory Affairs

The FDA may require a post-approval study at the time of approval of a
premarket approval (PMA), humanitarian device exemption (HDE) or
product development protocol (PDP) application to help assure
continued safety and effectiveness (or continued probable benefit, in
the case of an HDE) of the approved drug product of medical device. A
sponsor's failure to comply with any post-approval requirement may be
grounds for withdrawing approval i.e. whether the post approval study
will be terminated or revised/replaced. The safety surveillance is
designed to detect any rare or long-term adverse effects over the
much larger population and longer time period. Harmful effects shown
in this trial may result in drug ban or restricted in certain usages.
Post approval studies.
 Drug-drug interaction
 Drug-food interaction
 Drug-herbal interaction
 Pharmacoeconomics
 Expanded efficiency/safety
 Additional indication
 Strategies for minimization of adverse effect
 Strategies for dose individualization
 Optimization of surrogate lab test
 Special populations
 New formulation
When to submit post approval study protocol
Ideally, the final protocol for a post-approval study and the schedule
for study completion are based on agreements reached between FDA
and the sponsor during the PMA review process prior to approval of the

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PMA, accordingly it is recommended you submit a proposed post-

approval study protocol or, at minimum, post-approval study plans, in
the original PMA submission
How to submit changes
If you wish to propose a change to an approved post-approval study

protocol, it is recommended you submit a PMA supplement clearly
labeled as a post-approval study protocol, for FDA review and approval.
If multiple protocols are to be revised, we recommended each be
submitted as a separate PMA supplement.

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3. Regulation for Combination Products and Medical

Devices
A combination product is a product composed of any combination of a
drug and a device, a biological product and a device, a drug and a
biological product, or a drug, device, and a biological product.
Under 21 CFR 3.2 (e). a combination product is defined to include.
1. A product comprised of two or more regulated components (i.e.,

drug/device, biologic/device, drug/biologic, or drug/device/biologic)
that are physically chemically or otherwise combined or mixed and
produced as a single entity (often referred to as a "single entity"
combination product)
2. Two or more separate products packaged together in a single
package or as a unit and comprised of drug and device products,
device and biological products, or biological and drug products (often
referred to as a "co- packaged" combination product).
3. A drug, device or biological product packaged separately that
according to its investigational plan or proposed labeling is intended
for use only with an approved individually specified drug, device or
biological product where both are required to achieve the intended
use, indication or effect and where, upon approval of the proposed
product, the labeling of the approved product would need to be
changed (e.g. To reflect a change in intended use, dosage form,
strength, route of administration, or significant change in dose)
(often referred to as a "cross labeled" combination product) or
4. Any investigational drug, device, or biological product packaged
separately that according to its proposed labeling is for use only
with another individually specified investigational drug, device, or
biological product where both are required to achieve the intended

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use, indication, or effect (another type of "cross-labelled"

combination product).
Examples of combination products: -
Examples of single-entity combination products (where the

components are physically, chemically or otherwise combined) (21
CFR 3.2 (e)(1),
 Monoclonal antibody combined with a therapeutic drug

 Device coated or impregnated with a drug or biologic. Drug-
eluting stent, pacing lead with steroid-coated tip, catheter with
antimicrobial coating, condom with spermicide, Transdermal patch
 Prefilled drug delivery systems (syringes, insulin injector pen,
metered dose inhaler)
Examples of co-packaged combination products (the components are

packaged together) (21 CFR 3.2 (e)(2).
 Drug or vaccine vial packaged with a delivery device

 Surgical tray with surgical instruments, drapes, and anesthetic or
antimicrobial swabs
 First-aid kits containing devices (bandages, gauze), and drugs
(antibiotic ointments, pain relievers)
 Example of a product that may be cross-labeled combination
products (components are separately provided but specifically
labeled for use together) (21 CFR 3.2 (e) or (e)(4)
 Photosensitizing drug and activating laser/light source

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Who regulate?
In US the lead center is defined by the primary mode of action

(PMOA)
The lead center assignment can be from one of the following
1. Center for drug evaluation and research (CDER)

2. Center for devices and radiological health (CDRH)
3. Center for biologics evaluation and research (CBER)
Example
 Drug eluting stent or wound dressing with antimicrobial-typically

a device (CDRH)
 Asthma inhaler or medicinal patch typical a drug (CDER)
Currently Marketed Product Consideration
For example, developer should consider:-
 Are the constituent parts already approved for an indication?

 Is the indication for a given constituent part similar to that
proposed for the combination product?
 Does the combination product broaden the indication or intended
target population beyond that of the approved constituent part?
 Does the combination product expose the patient to a new route
of administration or a new local or systemic exposure profile for
an existing indication?
 Is the drug formulation different than that used in the already
approved drug?
 Does the device design need to be modified for the new use?
 Is the device constituent used in an area of the body that is
different than its existing approval?

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 Are the device and drug constituents chemically, physically or

otherwise combined into a single entity?
 Does the device function as a delivery system, a method to
prepare a final dosage form and/or does it provide active
therapeutic benefit?
 Is there any other change in design or formulation that may
affect the safety/effectiveness of any existing constituent part
or the combination product as a whole?
 Is a marketed device being proposed for use with a drug
constituent that is a new molecular entity?
 Is a marketed drug being proposed for use with a complex new
device?
Device Constitute Consideration
For example it may be appropriate to conduct studies to evaluate the

potential for the following: -
 Leachable/extractable of the device material into the

drug/biologic substance or final combination product
 Changes in stability of the drug constituent when delivered by
the device or when used as a coating on the device
 Drug adhesion/absorption to the device materials that could
change the delivered dose
 Presence of inactive breakdown products or manufacturing
residues from device manufacture that may affect safety or
device actions that could change the drug performance
characteristics at the time of use, or
 Changes in stability or activity of a drug constitute when used
together with an energy emitting device

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Role of the Office of Combination Product
 To serve as a focal point for combination product issues and for

medical product classification and assignment issues for agency
staff and industry
 To develop guidance and regulations to clarify the regulation of
combination products
 To classify medical products as drugs, devices, biological products,
or combination products and assign them to an FDA center for
premarket review and regulation where their classification or
assignment is unclear or in dispute
 To ensure timely and effective premarket review of combination
products by overseeing the timeless, alignment of coordination of
reviewers involving more than one agency center, including through
monitoring and management of the intercenter consult process
 To ensure consistent and appropriate post market regulation of
 To resolve disputes regarding the timeliness of premarket review of
What type of marketing application required for combination

product?
Combination products are typically marketed under a marketing

authorization type associated with the constituent part that provides
the primary mode of action (PMOA) for the combination product (i.e., a
new drug application (NDA) or abbreviated new drug application
(ANDA) if it has a drug PMOA, a biologic license application (BLA) if it
has a biologic PMOA, or a premarket approval application (PMA) de novo
certification, or premarket notification (510 (K)) if it has a device

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PMOA. A single marketing application is generally sufficient for a

combination product. In some cases, however a sponsor may wish to
submit separate marketing applications for different constituent parts
of a combination product, and FDA may consider this permissible.
Example of combination products
1. Drug eluting stents

a. Peripheral vascular stents
b. Coronary stents
2. Infusion pumps
a. Implantable infusion pumps
b. Ambulatory infusion pumps
3. Orthopedic combination products
4. Wound care combination products
5. Inhalers and nebulizers
a. Dry powder inhalers
b. Metered dose inhalers
c. Nebulizers (ultrasonic nebulizers, compressor nebulizers, mesh
nebulizers)
6. Transdermal patches
7. Other products

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Inhaler (data required to be submitted)
 Physical characterization
 Minimum fill justification
 Extractable/leachable
 Delivery dose uniformity and fine particle mass through container
life
 Delivered dose uniformity and fine particle mass over patient flow
rate range
 Fine particle mass with spacer holding chamber use
 Single dose fine particle mass
 Particle/ droplet size distribution
 Actuator/ mouthpiece deposition
 Drug delivery rate and total drug delivered
 Shaking requirements
 Initial priming of the container
 Re-priming of the container
 Cleaning requirements
 Low temperature performance
 Performance after temperature cycling
 Effect of environmental moisture
 Robustness
 Delivery device development
 Preservative effectiveness/ efficacy
 Compatibility

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Drug product specification
 Assay
 Moisture content
 Mean delivered dose
 Delivered dose uniformity
 Content uniformity/ uniformity of dosage units
 Fine particle mass
 Leak rate
 Microbial/ microbial limits
 Sterility
 Leachable
 Preservative content
 Number of actuations per container

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4. CTD and ECTD Format

CTD: - common technical document. It is a format set by ICH which
was agreed by the regulatory agencies of Europe, Japan, and the U.S.
the FDA characterized the CTD as "an information package of clinical,
non-clinical, manufacturing, technical data in the same content that
would be submitted for registering new drugs in all 3 ICH regions i.e.,
“U.S, European union and Japan" the concept of CTD was introduced
by ICH in the year of 2000 for the public consultation. Before 2000
there was no uniformity to submit dossier in regulatory authority. This
creates many hassles for applicant as well as auditors to submit and
reviewing the dossier information in an organized manner. Hence
concept of CTD was come for harmonization in dossier submission. It is
important to note that on July 1, 2003 use of the CTD format will
become mandatory across all three regions like EU, FDA and Japan.
Impact of CTD
The ICH CTD represents one of the most ambitious and successful
international harmonization activities undertaken for medicine
products for human use. It will significantly reduce time and resources
needed by industry to compile applications for global registration.
Applies to all NDAs, ANDAS, BLAs and INDS applications.
Benefits of CTD
 Easy "reviewable" applications

 Complete, well-organized submission More predictable format
 More consistent reviews
 Easier analysis across application
 Easier exchange of information.
 Facilitates electronic submission

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CTD structure
Module 1 - Administrative information (region specific)
This module should contain documents specific to each region, the

content and format of this module can be specified by the relevant
regulatory authorities.
Module 2 - CTD summaries (QOS)
It should begin with a general introduction to the pharmaceutical,

including its pharmacological class, mode of action and proposed clinical
use, i.e., information should not exceed one page.
It contain 7 section in the following order
 CTD TOC (module 22-5) (table of content)

 CTD introduction
 quality overall summary
 nonclinical overview
ew
 clinical overview

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 non-clinical summary
 clinical summary
The organization of these summaries is described in 3 separate

documents: -
A. M4 Q-the CTD quality

B. M4 S- the CTD safety
C. M4 E-the CTD efficacy
Module 3 - Quality (CMC)
 TOC of module 3
 Body of data
 3.3 Drug substance
 General information
 Manufacture
 Characterization
 Control of drug substance
 Reference standards or materials
 Stability
 Drug product
 Description and composition of the drug product
 Pharmaceutical development
 Manufacture
 Control of excipients
 Control of drug product
 Reference standards or materials
 Stability
 Appendices (facilities and equipment, novel excipients)

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Module 4 - Non-clinical study reports
 TOC of module 4
 study reports
 Pharmacology
 Pharmacokinetics
 Toxicology
 literature references
Module 5 - Clinical study reports
 TOC of module 5
 Tabular listing of clinical studies
 Clinical study reports
 Reports of biopharmaceutical study (BA-BE)
 Reports of PK (biomaterial) study
 Reports of PK studies
 Reports of PD studies
 Reports of efficacy and safety studies
 Reports of post marketing experience
 Case report forms and individual patient listings
E-CTD: - it is electronic version of CTD, so called as electronic

common technical document.
E-CTD composed of 2 types of specifications
1. Content specification- as defined by ICH

2. Technical specification- electronic software
E-CTD is highly recommended by USFDA for NDAs, BLAs, DMFs and

INDs filing. From year 2010 European Union also make compulsory for
electronic CTD submission to all procedures.

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E-CTD characteristics
 All modules 1 to 5 have granularity options (level of detail a

document has)
 PDF documents linked via xml backbone
 Increased document granularity
 Transparency of entire submission
 Ease of navigation and review
Benefit of E-CTD
 Improve the submission and review process

 Increase accuracy of the submission
 Decrease total costs
 Immediate access to complete and up to date information
 Reduced workload
 Better communication with industry
Example of E-CTD software
1. ROSETTA regulatory software

2. PHARMAREADY e-CTD product which is fully validated,
international regulatory complaint software

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COMPARING PAPER CTD AND e

e-CTD

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5. Industry and FDA liaison

Experienced drug regulatory affairs (DRA) personnel are essential in
the process of new product development. They are largely responsible
for establishing a liaison with their counterparts at the US food and
drug administration (FDA) and other regulatory agencies globally. FDA
is one of our nation's oldest consumer protection agencies dating back
to 1862.
U.S. FDA: - the U.S FDA (food and drug administration) is an agency
of the U.S department of health and human services (DHHS) that is
responsible for the safety regulation of: - most type of foods, dietary
supplements, vaccines, biological medical products, drugs, blood
products, cosmetics.
The FDA also enforces other laws, notably section 361 of the public
health service act and associated regulations, many of which are not
directly related to food and drugs. They include sanitation
requirements on interstate travel and control of disease on products
ranging from certain household pets to sperm donation for assisted
reproduction. The FDA has its headquarters at white oak, Maryland.
The agency also has 223 field offices and 13 laboratories located
throughout 50 states.

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Who makes up the FDA?
The FDA consists of employees drawn from a wealth of science and

public health professions. Biologists, physicians, chemists, biomedical
engineers, toxicologists, pharmacologists, veterinarians and specialists
in the public health education and communication. FDA employs
approximately 11,516 people who work in locations around the united
states.
FDA advisory committee
They provide FDA with independent advice from outside experts on

issues related to human and veterinary drugs, vaccines and other
biological products, medical devices and food. In general, advisory
committee includes a chair, several members, plus a consumer,
industry, and sometimes a patient representative. Additional experts
with special knowledge may be added for individual committee meetings
as needed. Although the committees provide advice to the agency, FDA
makes the final decisions.
FDA initiatives to speed drug approval
The FDA has instituted several programs designed to hasten a drug

approval process for effective drugs. FDA alternative to expendite
new drug approval are described below: - subpart E section 312 of the
code of federal regulations establishes procedures to expendite the
development, evaluation, and marketing of new therapies intended to
treat people with life threatening and severely debilitating illness
(debilitating comes from the Latin word debilis, means weak) especially
where no satisfactory alternative exist.

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FDA guidance documents/guidelines
 A regulatory professional must be aware of the guidance documents

that FDA has made available to assist industry to understand
expectations regarding drug development and the approval process
 The website providing the complete list of FDA guidance is updated
almost daily
 It may be accessed at http:/www.fda.gov/cder/guidance/index.htm.

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6. ICH guidelines of ICH- QSEM

The international conference on harmonization of technical
requirements for registration of pharmaceuticals for human use (ICH)
is a unique project that brings together the regulatory authorities of
Europe, Japan and the United States and experts from the
pharmaceutical industry in three regions to discuss scientific and
technical aspects of product registration. The international conference
on harmonization of technical requirements for the registration of
pharmaceuticals for human use (ICH) was established in 1990 as a joint
regulatory/industry project to improve. Through harmonization the
efficiency of the process for developing and registering new medicinal
products in Europe, Japan, and the United States. In order to make
these products available to patients with a minimum of delay the six
parties of ICH represent the regulatory bodies and research based
industry in the three regions. Europe, Japan and the USA where the
vast majority of new medicines are currently developed.
ICH PARTIES
 European commission- European union (EU)

 European federation of pharmaceutical industries and associations
(EFPIA)
 Ministry of health, labor and welfare, Japan (MHLW)
 Japan pharmaceutical manufacturers association (JPMA)
 US food and drug administration (FDA)
 Pharmaceutical research and manufacturers of America (PHRMA)
Objectives
 More economical use of human, animal and material resource

 Elimination of unnecessary delay in the global development and
availability of new medicines

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 Maintaining safeguards on quality, safety, efficacy and regulatory

obligations to protect public health.
Topic of ICH
Four broad categories- QSEM
 Quality (Q)- those relating to chemical and pharmaceutical

quality assurance (stability testing, impurity testing, etc)
 Safety (S)- those relating to in vitro and in vivo pre-clinical
studies (carcinogenicity testing, genotoxicity testing, etc)
 Efficacy (E)- those relating to clinical studies in human subject
(dose response studies, good clinical practices, etc)
 Multidisciplinary (M)- cross- cutting topics which do not fit
uniquely into one of the above categories (MedDRA, ESTRI, M3,
CTD, M5)
Overview of ICH
1. Quality (Q)
 Q1 A (R2)- stability testing of new drugs and products

 Q1 B- photo stability testing
 Q1 C-stability testing of new dosage forms
 Q1 D- bracketing and matrixing designs for stability testing of
drug substances and drug products Q1 E- evaluation of stability
data
 Q1 F- stability data package for registration in climatic zones 3
and 4
 Q2 A- definitions and terminology: analytical validation
 Q2 B- methodology
 Q3 A(R2)- impurities in new drug substances
 Q3 B(R2)- impurities in new drug product
 OQ3 C(R3)- impurities guidelines for residual solvents

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 Q4- pharmacopoeia
 Q4 A- pharmacopoeial harmonization
 Q5 A- viral safety evaluation
 Q5 B- genetic stability
 Q5 C- stability of biotechnology products
 E14- the clinical evaluation of QT/QTC interval prolongation and
proarrhthmic potential for non- antiarrhyhmic drugs
 E15- definitions for genomic biomarker, pharmacogenomics,
pharmacogenetics, genomic data and sample coding categories
 E16- genomic biomarkers related to drug response
 Q5 D-cell substrates
 Q6 A- specifications, test procedures and acceptance criteria
for new drug substances and products
 B- specification test procedure and acceptance criteria for
biotechnological/ biological products Q7 A- GMP for active
pharmaceutical ingredients
 Q8- pharmaceutical development
 Q9- quality risk management
 Q10- pharmaceutical quality system
2. Safety (S)
 S1 A- guideline on the need for carcinogenicity studies of

pharmaceuticals
 S1 B -testing for carcinogenicity of pharmaceuticals
 S1 C(R2)-dose selection for carcinogenicity studies of
pharmaceuticals
 S2 (R1)- guidance on genotoxicty testing and data interpretation
for pharmaceuticals intended for human use S3 A- note for

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guidance on toxicokinetics the assessment of systemic exposure

in toxicity studies
 S3 B- pharmacokinetics guidance for repeated dose tissue
distribution studies
 S4- duration of chronic toxicity testing in animals (rodent and
non-rodent toxicity testing)
 S5 (R2)- detection of toxicity to reproduction for medicinal
products and toxicity to male fertility
 S6 (R1)- addendum to ICH S6- preclinical safety evaluation of
biotechnology- derived pharmaceuticals
 S6- preclinical safety evaluation of biotechnology-derived
pharmaceuticals
 S7 A- safety pharmacology studies for human pharmaceuticals
 S7 B- the non-clinical evaluation of the potential for delayed
ventricular repolarization (QT interval prolongation) by human
pharmaceuticals
 S8- immunotoxicity studies for human pharmaceuticals
 S9- non-clinical evaluation for anticancer pharmaceuticals
3. Efficacy (E)
 E1- the extent of population exposure to assess clinical safety

 E2 A- clinical safety data management
 E2 B (R2)- maintanance of the ICH guideline on clinical safety
data management
 E2 B (R3)- revision of the ICH guideline on clinical safety data
management, data elements for transmission of individual case
safety reports
 E2 C (R1)- clinical safety data management periodic safety update
reports for marketed drugs

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 E2 D-post-approval safety data management definitions and

standards for expedited reporting
 E2 E- pharmacovigilance planning
 E2 F- development safety update report
 E3- structure and content of clinical study reports
 E4- dose-response information to support drug registration
 E5 (R1)- ethnic factors in the acceptability of foreign clinical
data
 E6 (R1)- guideline for good clinical practice
 E7- studies in support of special populations geriatrics
 E8- general considerations for clinical trials
 E9- statistical principles for clinical trials
 E10- choice of control group and related issues in clinical trials
 E11- clinical investigation of medicinal products in the pediatric
population
 E12- principles for clinical evaluation of new antihypertensive
drugs
4. Multidisciplinary (M)
 M1-MedDRA- medical terminology

 M2-ESTRI- electronic standards for the transfer of regulatory
information
 M3 (R2)- non-clinical safety studies for the conduct of human
clinical trials and marketing authorization for pharmaceutcals
 M4-CTD- the common technical document
 M5- data elements and standards for drug dictionaries

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7. Regulatory requirements of EU (European Union)

A political union also called as Europe union formed in 1993 for purpose
of achieving political and economic integration, the EU includes 28
member states located in Europe. the EU total population is about 500
million people. The EU operates through a system of 1) supranational
independent institution, 2) intergovernmental negotiated decisions by
its member of the states. It is legal entity and can negotiate
international agreement on behalf of its member states. In the EU
there are two regulatory steps by which a drug is approved in the
market 1) clinical trials application (approved at member state level), 2)
marketing authorization (approved by both member state and
centralized level)
Regulation in the industry
Pharmaceutical industry is most regulated of all the industries.

Regulations are put in order to develop the most efficient and safe
pharmaceutical products. It takes more than 8 to 15 years to develop
new drug products and costs more than $800 million
When did regulation came?
During the 20th century, there were no law's and regulation to product
public from the unfavorable effects of the drugs. Misfortune, disaster
and tragedy had triggered most of the advances in drug regulation.
There are some examples of disaster which leads to the formation of
regulation in the industry. Thalidomide tragedy (1962), Elixir
sulfanilamide (1937) (taste of death)
The EU regulatory system for medicine
The European medicines regulatory system is based on a network of

around 50 regulatory authorities from the 31 EEA countries, the

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European commission and EMA. This network is what makes the EU

regulatory system unique. The network is supported by a pool of
thousands of experts drawn from across Europe, allowing it to source
the best possible scientific expertise for the regulation of medicines
in the EU and to provide scientific advice of the highest quality.
28 European Union member countries
1. Austria
2. Belgium
3. Bulgaria
4. Croatia
5. Cyprus
6. Czech republic
7. Denmark
8. Estonia
9. Finland
10. France
11. Germany
12. Greece
13. Hungary
14. Ireland
15. Italy
16. Latvia
17. Lithuania
18. Luxembourg
19. Malta
20. Netherlands
21. Poland
22. Portugal
23. Romania

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24. Slovakia
25. Slovenia
26. Spain
27. ·Sweden
28. United Kingdom
Marketing authorization
To protect public health and ensure the availability of high quality,

safe and effective medicines for European citizens, all medicines must
be authorized before they can be placed on the market in the EU. The
European system offer different routes for such an authorization. The
centralized procedure allows the marketing of a medicine on the basis
of a single EU-wide assessment and marketing authorization which is
valid throughout the EU. Pharmaceutical companies submit a single
authorization application to EMA. The agency's committee for
medicinal products for human use (CHMP) or committee for medicinal
products for veterinary use (CVMP) then carries out a scientific
assessment of the application and gives a recommendation to the
European commission on whether or not to grant a marketing
authorization. Once granted by the European Commission, the
centralized marketing authorization is valid in all EU member states.
The use of the centrally authorized procedure is compulsory for most
innovative medicines, including medicines for rare diseases. Rules and
requirements applicable to pharmaceuticals in the EU are the same,
irrespective of the authorization route for a medicine. A European
public assessment report (EPAR), is published for every human or
veterinary medicine that has been granted or refused a marketing
authorization following an assessment by EMA.

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Pricing and reimbursement
Once a marketing authorization has been granted, decisions about price

and reimbursement take place at the level of each member state
considering the potential role and use of the medicine in the context of
the national health system of that country.
The role of the European Commission
The European commission pays an important role in the regulation of

medicines in the EU. On the basis of scientific assessments carried out
by EMA, it grants or refuses, changes or suspends marketing
authorizations for medicines that have been submitted via the
centralized procedure. The European commission can take action
concerning other aspects of medicine regulation: - right of initiative,
implementation, and global outreach.
The Role of EMA
EMA is responsible for the scientific evaluation, primarily of innovative

and high-technology medicines developed by pharmaceutical companies
for use in the EU. EMA was established in the year 1995 to ensure the
best use of scientific resources across Europe for the evaluation,
supervision and pharmacovigilance of medicines. Experts participate in
the work of EMA as members of its scientific committees, working
parties, scientific advisory groups or as members of the national
assessment teams that evaluate medicines. The experts are chosen on
the basis of their scientific expertise and many of them are made
available to EMA by the NCAS in member states. Increasingly, patients
and healthcare professionals are involved in the work of the agency
including in the evaluation of medicines.

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Natural Component Authorities (NCAS)
The national component authorities (NCAs) are responsible for the

regulation of human and veterinary medicines in the EU coordinate
their work in a forum called heads of medicines agencies (HMA). The
heads of the NCAS work closely with EMA and the European
commission to maximize cooperation and ensure the European
medicines regulatory network functions efficiently. The HMA meets
four times per year to address key strategies issues for the network,
such as the exchange of information, sharing of best practices, and to
streamline mutual recognition and decentralized procedures.
Guideline and scientific advice
EMA prepares scientific guidelines in the cooperation with experts

from its scientific committees and working groups. These guidelines
reflect the latest thinking on developments in biomedical science. This
is an important tool to help develop and make available high-quality,
effective and safe medicines, for the benefit of patients. Scientific
advice can also be given by NCAS.
Safety monitoring of medicines
The European regulatory system for medicines monitors the safety of

all medicines that are available on the European market throughout
their life span. EMA has a committee dedicated to the safety of
medicines for human use- the pharmacovigilance risk assessment, or
PRAC. If there is a safety issue with a medicine that is authorized in
more than one member state, the same regulatory action is taken
across the EU and patients and healthcare professionals in all member
states are provided with the same guidance.

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Clinical trials
The authorization and oversight of a clinical trial is the responsibility

of the member state in which the trial is taking place. The European
clinical trials database (Eudra CT) tracks which clinical trials have been
authorized in the EU. It is used by NCAs and clinical trial sponsors to
enter information protocols and results of clinical trials. A subset of
this information is made publicly available by EMA via the EU clinical
trials register.

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8. Regulatory requirements of medicines and

healthcare products regulatory agency (MHRA)
The medicines and healthcare products regulatory agency (MHRA) is an
executive agency of the department of health of United Kingdom. The
MHRA was set up in April 2003 to bring together the functions of the
medicines control agency (MCA) and the medical devices agency (MDA).
The MHRA is responsible for ensuring that medicines and medical
devices work, and are acceptably safe.
Functions of MHRA
 Regulation of clinical trials

 Safety and efficacy monitoring
 Licensing
 Providing information to pubic and health professionals
 Enforcement of law
 Manufacturer and dealer licenses
 Clinical trial licenses
 Parallel import licenses
 MHRA does not regulate dietary supplements, veterinary
products and cosmetics.
What is Marketing Authorization?
Before any medicine can be used to treat people in the UK, a marketing
authorization, from MHRA is required. The MHRA operates a system
of licensing before the marketing of medicines. Medicines which meet
the standards of safety, quality and efficacy are granted a marketing
authorization (previously a product license), which is normally
necessary before they can be prescribed or sold.

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Marketing authorization for what?
 New biological or chemical compounds

 Different brands of existing medicines
 Generics (identical but cheaper versions of existing branded
medicines)
 New forms of existing medicines, such as syrups, patches, or
injections
 New uses for existing medicines, such as different patient groups
or different conditions.
Process of licensing
Firstly the applicant must file an application for clinical trials then it is
evaluated by the MHRA in a specific time duration if they do not
satisfies with that they immediately rejects the application and if they
are satisfies with that then clinical trials are done then clinical trial
results are checked by assessment of data by experts in the particular
field if they do not satisfies then no license is given and if they
satisfies with the results they gives licensing for marketing
authorization.
Who can apply?
Applications are generally submitted by the pharmaceutical industry,

but anyone with the necessary supporting data may apply for a license.
Types of procedures
A. Centralized procedure: - in the European union (EU), a company

may submit a single application to the European medicines agency
(EMEA) for a marketing authorization (license) that is valid
simultaneously in all EU member states.

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B. National procedure: - each EU member state has its own

procedures for the authorization of medicines that fall outside the
scope of the centralized procedure. Applicants must submit an
application to the competent authority of the member state. For e.g.
In the UK, this is the MHRA.
C. Decentralized procedure: - using the decentralized procedure,
companies may apply for simultaneous authorization in more than one
EU country of products that have not yet been authorized in any EU
country and that do not fall within the mandatory scope of the
centralized procedure.
D. Mutual recognition procedure: - in the mutual recognition
procedure, a medicine is first authorized in one EU member state, in
accordance with the national procedures of that country. Following
this, further marketing authorizations can be sought from other EU
countries in a procedure whereby the countries concerned agree to
recognize the validity of the original, national marketing
authorization.
Types of applications
1. Full applications: - applications for new active substances

described as full applications
2. Abridged applications: - applications for medicines containing
existing active substances are described as abbreviated or abridged
applications. Existing drugs with new forms, routes and indications.
Sometimes, although the drug is the same, the new product has a
different strength or pharmaceutical form or is used by a different
route or for different clinical uses. Existing drugs in new
combinations, new combinations of existing drugs may also be
proposed though they may need a full data package to support them.
Well-established drugs and products the new product may include a

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drug substance which has such a well-established medicinal use and

an acceptable level of safety that the applicant company can submit
published data to support the safety and efficacy aspects of their
application. Examples here may include some over-the-counter (OTC)
remedies.
3. Informed consent and change of ownership applications: - for
commercial reasons companies may want to take over or duplicate a
product license held by another company. Where the first company
agrees to this informed consent approach the second company can
get an exact copy license commonly known as a piggy-back license.
Alternatively, where the ownership of the company changes hands and

the new owners need to take over the old product licenses. These
applications are called change of ownership applications.
Parallel importing authorization
The UK parallel import licensing scheme allows medicinal products

authorized in other EU member states to be marketed in the UK,
provided the imported products have no therapeutic difference from
the equivalence UK products.
Types of parallel import application
1. Simple application: - this category will apply when the UK product

and the product to be imported from a member state are made
under license from the same licensor. This is the traditional common
origin criterion.
2. Standard application: - this category will apply when the UK and
imported products do not share a common origin (as defined above)
and the application is not complex
3. Complex application: - this category will apply when the UK and
imported products do not share a common origin and the imported

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product contains a new excipients, the imported product contains an

active ingredient made by a different route from that used in the
UK product, the imported product is e.g., a controlled release
preparation, a metered dose inhaler, a powder for inhalation. The
import product is sterile product which is sterilized in a different
way from the UK product, the imported product is a sterile product
in which the container is made from a different material to the
container of the UK product, the manufacturer of the active
ingredient contained in the imported product is different from the
manufacturer of the active ingredient contained in the UK product.
How to submit application?
All applications must follow the common technical dossier (CTD) format
which has been a requirement since 2003. The preferred format for
new marketing authorization (MA) applications is the electronic
common technical dossier (ECTD). eCTD applications must be created
according to the current specifications. However, MHRA accept that
many companies are not yet ready to submit applications in eCTD
format. Therefore, it accepts applications in PDF format also.
Fast-tracking of application
Under certain circumstances MHRA facilitates fast tracking of MA

applications, these circumstances are mainly categorized in two
headings
1) For major therapeutic breakthrough: - disease categories for

which fast tracking of applications may be applicable
 Chronic, debilitating diseases for which available treatments are

ineffective or otherwise inadequate
 Severe or life-threatening diseases for which available
treatments are ineffective or otherwise inadequate

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 The emergence in a disease with wide-spread resistance to

treatment with currently available therapeutic agents
 The emergence of a new disease entity which has severe or life-
threatening effects and for which currently available treatments
are ineffective or otherwise.
2) For shortfall of medicines: - MHRA facilitates fast tracking when

there is shortage of the essential or life saving medicines to avoid
harm to public health. In this case of scarcity of medicines MHRA
communicates with department of health and verifies the shortage.
Note: - for both the above situations, a decision to fast track an

application would mean that the assessment of the application is
commenced out of turn, ahead of its order in the sequence of
submitted applications. The document for such application should be
consistent with legal requirements and guidelines relating to
applications for marketing authorizations.
Renewal of license
New marketing authorizations (MAs) are valid for five years and then
may be renewed on the basis of a re- evaluation of the risk- benefit
balance, once renewed, the marketing authorization will be valid for an
unlimited period. Applications for renewal should be submitted at least
six months before expiry.
Cancellation of license
If MAS holder does not file an application for renewal within specified
time, MAS expires automatically. If the MAS holder does not wish to
renew the license, a letter should be sent indicating the cancellation to
Administrative support team, Medicines and healthcare products
regulatory agency (MHRA). MHRA has authority to cancel license of
product if it affects public health.

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9. Regulatory requirements of Therapeutics Goods

Administration (TGA)
Therapeutics goods administration is the regulatory body for
therapeutic goods in Australia. TGA is responsible for conducting
assessment and monitoring activities. To ensure that therapeutic goods
available in Australia are of an acceptable standard. Therapeutic goods
act 1989, which came into effect on 15 Feb, 1991.
Objectives of TGA
 To provide a national framework for the regulation of therapeutic

goods in Australia
 To ensure quality, safety and efficacy of the medicines
 To ensure quality, safety and performance of medical devices
 Essentially therapeutic goods must be entered on the Australian
register of therapeutics goods (ARTG) before they can be
supplied in Australia
 ARTG is a computer database of information about therapeutic
goods for human use approved for supply in or export from
Australia
 Australian manufacturers of all medicines must be licensed under
part 4 of the Therapeutic goods act 1989
 Their manufacturing process must comply with the principles of
recommends GMP
 Once approved for marketing in Australia, medicines are included
in the ARTG
 It can be identified by the AUST R number (for registered
medicines) or an AUST L number (listed medicines) that appears
on the packaging of medicines

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Elements to regulate
1) Licensing and audit of manufacturers
Act requires each Australian manufacturer of medicinal products for

human use to hold a manufacturing license
License holders are required to comply with the manufacturing

principles of the act, including compliance with GMP
2) Pre-Market assessment
This includes study of toxicity and dosage form of medicines. The

product risk is determined by side effects, inappropriate self-
medication, and adverse effect for prolonged use.
3) Post-Market regulatory authority
The essential elements of this systematic risk-based approach include:
 Monitoring of adverse reactions to medicines

 Targeted and random surveillance in the market place
 An effective, responsive and timely recalls procedure
 Audit of GMP
 Effective controls for the advertising of therapeutic goods

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10. Regulatory requirements of Rest of the World

(ROW) countries
World regions excluding US, CA (Canada), EU (Europe), CH
(Confoederatio Helvetica), AU (Australia), and NZ (New-Zealand)
Regions and sub-regions of ROW countries
 AMEA- Asia, Middle East and English speaking Africa

 LATAM-Latin America
 RIC- Russia and former Soviet States, Greater china, Greater
India, Israel, French-speaking Africa, South- east Europe
Regulatory requirements in ROW countries
 Key function of RA (regulatory agency)

 Product registration
 Adverse drug reaction monitoring
 Licensing of premises, person and practices
 Main goal of the agency is to guarantee the safety, efficacy and
quality of the available drug product
Asia
 India
 Sri-Lanka
 Bangladesh
ASEAN: - (10 countries group)
 Philippine
 Vietnam
 Singapore
 Malaysia
 Thailand

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 Indonesia
 Laos
 Cambodia
 Brunei Darussalam
 Myanmar
Recent queries raised by various ROW markets
 Complete supporting data for process validation

 Cleaning validation report
 Preservative content and microbial limits
 Redispersibility and rheological properties
 Particle size distribution
Registration requirements for Rest of the world
Administrative documents: -
 Certificate of pharmaceutical product

 Product permission
 Manufacturing license
 WHO-GMP certificate
 Free sale certificate/ export certificate
 Artwork (carton, label and package leaflet)
API DMF open part
 Nomenclature
 General properties
 Name of the manufacturer and site of manufacture

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 Route of synthesis, flow diagram in brief Structural elucidation

impurities
 Container closure system
Manufacturing formula and process
 Manufacturing formula.
 Description of manufacturing/packaging
 Description of manufacturing/packaging
 Scale, equipment by type, capacity, process parameters for steps
 Description of in process controls/test

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UNIT 3 - Non Clinical Drug Development

The non-clinical (or pre-clinical) development phase primarily aims to
identify which candidate therapy has the greatest probability of
success, assess its safety, and build solid scientific foundations before
transition to the clinical development phase.
Also, during the non-clinical development phase, the candidate

compound should meet non-medical objectives, including defining the
intellectual property rights and making enough medicinal product
available for clinical trials. The non-clinical development of a medicine
is complex and regulatory-driven.
The studies in non-clinical development are performed:
 In silico: 'performed on computer or via computer simulation', e.g.

predicting the toxicology profile of a product using its chemical
structure from data-based approaches.
 In vitro (Latin for 'within the glass'): performing a procedure in a
controlled environment outside of a living organism, e.g. use of
Hepatocyte (cells from the liver) cultures for metabolism studies.
 In vivo (Latin for 'within the living'): experimentation using a
whole, living organism as opposed to tissues or cells, i.e. animals,
humans or plants.
Non-clinical regulatory guidelines;
There are many players involved in the development of medicines, and

each organisation or institution follows their own set of rules. For
instance, companies have their Standard Operating Procedures (SOP).
In addition to Good Clinical Practice provisions, guidelines can be

consulted at the European Medicines Agency (EMA) website.

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 They are either general or more specific addressing scientific

and technical aspects (e.g. specific to required toxicology
studies).
 They must be strictly followed for any new marketing
authorization application; any deviation must be justified.
Non-Clinical Development in CTD modules

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Investigational New Drug (IND)

Investigational New Drug is defined under 21 CFR 312.3(b) as “a new
drug or biological drug that is used in clinical investigation”.
The term also includes a biological product used in-vitro for diagnostic
purposes.
 After pre-clinical investigations when the new molecule has been

screened for pharmacological activity and acute toxicity potential in
animals the sponsor requires permission from FDA for its clinical
trials in humans.
 The sponsor submits the application for conduct of human clinical
trials called Investigational New Drug (IND) application to FDA or
DCGI.
 Once IND application is submitted, the sponsor must wait for 30
days before initiating any clinical trial.
 Clinical trials in humans can begin only after IND is reviewed by the
FDA and a local institutional review board (IRB).
 IRBs approve clinical trial protocol, informed consent of all
participants and appropriate steps to prevent subjects from harm.
Types of INDs
A. Commercial INDs - These are applications that are submitted

primarily by the companies to obtain marketing approval for a new
product.
B. Non-commercial (Research) INDs - These INDs are filed for

noncommercial research.

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These are:
1. Investigator's IND - It is submitted by a physician who both

initiates and conducts an investigation and who also administers and
dispenses the IP. A physician might submit a research IND to propose
studying an unapproved drug or an approved drug for new indications or
in new patient population.
2. Emergency Use IND This IND allows FDA to allow the use of an
experimental drug in an emergency situation that does not allow
submission of an IND in accordance with 21 CFR Sec312.23 or Sec
312.34.
It can also be used for patients who do not meet the criteria of an
existing study protocol or if an approved study protocol does not exist.
3. Treatment IND - Also called Expanded Access IND
This IND may be submitted for experimental drugs showing promise in

clinical testing of serious and immediately life threatening conditions
while the final clinical work is conducted and the FDA review takes
place (21 CFR 312.34).
Criteria for IND application
 A new indication
 Change in the approved route of administration or dosage level.
 Change in the approved patient population (vulnerable subjects e.g.
pediatrics, elderly, HIV +ve, immunocompromised)
 Significant change in the promotion of an approved Drug.

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New Drug Application (NDA)

The New Drug Application is the vehicle through which the drug
sponsors formally propose FDA or DCGI to approve a new
investigational drug for sale and marketing after Phase IIIA Pivot
trials.
The official definition of New Drug is in Sec 201(p) of Federal Drug,

Food and Cosmetics Act as;
Any new drug, the composition of which is such that it is not

recognized among experts qualified by scientific training as safe and
effective for use under prescribed, recommended or suggested
conditions.
Any drug the composition of which is such that it as a result of

investigations to determine safety and efficacy for use has become
recognized, but which has not, otherwise in such investigations been
used to a material extent.
The following letter codes describe the review priority of the drug;
 S-Standard review: For drugs similar to currently available

drugs
 P-Priority review: For drugs that represent significant advances
over existing treatments.
Classification of drugs in NDA
Center of drug evaluation and Research (CDER) classifies new drug

applications according to the type of drug being submitted and its
intended use:
a. New molecular entity

b. New salt of previously approved drug

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c. New formulation of previously approved drug

d. New combination of two or more drugs
e. Already marketed
ed drug product
product- Duplication (i.e., new
manufacturer)
f. New indication (claim) for already marketed drug (includes
switching marketing status from prescription to OTC)
g. Already marketed drug product ( no previous approved NDA) S
Process of NDA:-

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Abbreviated New Drug Application (ANDA)

Generic drug applications are referred to Abbreviated New Drug
Application.
Pharmaceutical companies must admit ANDAs and receive FDA's

approval before marketing new generic drugs according to 21 CFR
314.105(d).
Once ANDA is approved, an applicant can manufacture and market

generic drug to provide safe, effective and low cost alternative of
innovator drug product to the public.
Generic drugs are termed 'abbreviated' as they are not required to

include preclinical and clinical data to establish safety and efficacy.
They must scientifically demonstrate Bioequivalence to Innovator
(brand name) drug.
A generic drug is comparable to Innovator drug I dosage form,

strength, route of administration, quality, performance and intended
use.
One of the ways to demonstrate bioequivalence is to measure the time

taken by generic drug to reach bloodstream in 24-36 healthy
volunteers. The time and amount of active ingredients in the
bloodstream should be comparable to those of Innovator drug.
Use of bioequivalence as base for approving generic drug products was

established in 1984, also known as WAXMAN-HATCH ACT. It is
because of this act that generic drugs are cheaper without conducting
costly and duplicative clinical trials.

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Investigation of Medicinal Products Dossier (IMPD)

The IMPD is the basis for approval of clinical trials by the competent
in the EU.
The Clinical Trial Directive came in force harmonizing the laws,

regulations and administrative provisions of the Member states
relating to the implementation of GCP in the conduct of clinical trials
on medicinal products for human use.
The directive introduced a harmonized procedure for the authorization

to perform a clinical study in any one of the EU Member States.
In addition, it defines the documentation to the documentation to be

submitted to the Ethics Committee as well as the IMPD to be
submitted to the competent authority for approval.
Dossier - A collection of documents about a particular person, event

or subject. E.g. Patient's medical record
Medicinal product dossier - File containing detailed records about a

particular drug product.
Objectives:
Since clinical trials will often be designed as multicenter studies,

potentially involving different Member States, it is the aim of this
guideline to define harmonized requirements of the documentation to
be submitted throughout the European Country.

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Investigator's Brochure
The Investigator's Brochure (IB) is a compilation of the clinical and

nonclinical data on the investigational product(s) that are relevant to
the study of the product(s) in human subjects.
Purpose:
 Its purpose is to provide Information to the Investigators and

others involved in the trial such as the dose, dose
frequency/interval, methods of administration, and safety
monitoring procedure.
 The IB also provides insight to support the clinical management
of the study subject during the course of the clinical trial.
 The information should be presented in a concise and simple
manner.
 IB enables a clinician or potential investigator, to understand it
and make his/her own unbiased risk benefit assessment of the
appropriateness of the proposed trial. For this reason, a medically
qualified person should generally participate in the editing of an
IB.
General Considerations - Title Page
1. Sponsor name
2. The identity of each investigational product (i.e., research number,
chemical or approved generic name, and trade name where legally
permissible and desired by the sponsor).
3. The release date.
4. Confidential statement

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Confidentiality Statement
The sponsor may wish to include a statement instructing the

investigator/recipients to treat the IB as a confidential document for
the sole information and use of the investigator's team and the
IRB/IEC.
The investigator brochure should include:
1. Table of Contents
2. Summary
3. Introduction
4. Description of IB
5. Nonclinical Studies
6. Effects in Humans
7. Summary of Data and Guidance for the Investigator.

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UNIT 4 - Clinical Trials

What is a Clinical Trial?
 Prospective ethically designed investigation in It human subjects to

discover/verify/compare the results of two or more therapeutic
measures (drugs)
 A clinical trial is a planned experiment that involves
volunteers/patients
 Aim to compare the response to new treatment with that of an
existing one
 Clinical trial is just a part of New Drug Discovery Process.
Why are clinical trials important?
Clinical trials translate results of basic scientific research into better

ways to prevent, diagnose, or treat disease
The more people take part, the faster we can:
 Answer critical research questions

 Find better treatments and ways to prevent disease

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Trial Protocol
It is a complete written description and scientific rationale for a
research activity involving human subjects.
1. Title Page
2. Signature Page
3. Content Page
4. List Of Abbreviations
5. Introduction/Abstract
6. Objectives
7. Background/Rationale Eligibility Criteria
8. Study Design/Methods (Including Drug/Device Info)
9. Safety/Adverse Events
10. Regulatory Guidance
11. Statistical Section (Including Analysis And Monitoring)
1. Title Page
Title page introduces the document, its title, precise number, sponsor
and author to the reader.
Protocol identifying number and date.
The protocol number must clearly indicate the version number, whether
it is final or draft and date of this version.
Title page should include:
 Full title should include summary study design, medicinal products,

nature of treatment (eg: treatment and diagnosis) indication patient
population setting (eg: in-patient, outpatient) Randomised double
bind multiple studies.
 Name and address of sponsor and monitor. Sponsor names and list of
responsibilities with agreed allocations

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 Name and address of the authorized person to sign the protocol and
protocol amendment for the sponsor. Generally, chief investigator
for trial or principle investigator for single center trials.
 Name, title, address and telephone number of the sponsor medical
expert for the trial
 Name and title of the investigator who is responsible for conducting
the trial, and the address and telephone number of the trial site.
Name, title, address and telephone number of the qualified physician
who is responsible for all trial site related medical decisions.
 Name and address of the clinical laboratory and other medical or
technical or institutions involved in the trial.
2. Signature Page - Signature page of all healthcare professionals in

the trial including contact details of participating site, sponsor and
sponsor medical advisor if not already given above.
3. Content Page - This help navigation through the document by large

number of different people that will be needed throughout the trial.
4. List of Abbreviations: All abbreviations used should be listed and

defined. Accepted international medical abbreviations should be
standardized within each project.
5. Introduction / Abstract - This summary should be only one to two

pages long. It should give the reader sufficient information to
understand the rationale for the trial, its objective and the methods
that will be used to achieve these objective.
6. Objectives
 Objectives should be stated clearly as hypotheses to be tested.

 Each objective should have a corresponding discussion in the
statistical section.

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7. Background and Rationale
 All protocols require a section detailing the scientific rationale

for a protocol and the justification in medical and scientific
literature for the hypothesis being proposed.
 Introductory section should be organized in a logical, sequential
flow.
8. Eligibility Criteria - Inclusion and exclusion criteria are the

conditions that must be met in order to participate in a clinical trial. •
The most important criteria used to determine appropriateness for

clinical trial participation include age, sex, the type and stage of a
disease, treatment history, and other medical conditions.
9. Study Design
The design study section of the protocol should contain a stepwise

description of all procedures that required to by study.
A good study design section includes sufficient information for the

participating site.
Parts of the study design section may include:
 Initial evaluations
 Screening tests
 Required lab tests
 Details of treatment or procedures
 Device specifications
 Dose scheduling and modification
 Calendars
10. Safety - Adverse effect and side effect are terms commonly
associated with drugs. They are used by nurses and doctors, to refer
to undesirable effects of a medication on a patient.

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The Safety (or Adverse Events) section should include:
 Detailed information for reporting adverse events, including

reporting to the FDA and/or the sponsor
 Unbinding processes (if applicable)
 Lists of expected adverse events
11. The Statistical Section
 The study objectives and study design elements in the statistical

section should be described in the Objectives section
 The descriptions and definitions of toxicities in the statistical
section match those in the Safety/AE section.
12. Human Subjects Protection
This section includes discussion of:
 Subject selection and exclusion

 Proposed methods of patient recruitment
 Minority representation
 Recruitment (or exclusion) of special subjects, including
vulnerable subjects
 Lists of potential risks and benefits, including justification for
risks.

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Institutional Review Board / Independent Ethics

Committee (IRB/IEC)
IRB/IEG serves as an independent body that reviews, evaluates,
approves and decides on the scientific and ethical aspects of the
clinical trial protocol as well as the benefits and risks to the study
participants
Main purpose of IRB/IEG is to protect the rights, safety, and well-

being of the subjects who participate in a trial
Composition of IRB/IEC
Consists of members, who collectively have the qualifications and

experience to review and evaluate the science, medical aspects, and
ethics of the trials.
Includes at least five members, of which at least one member whose

primary area of interest is non- scientific, and at least one member
who is independent of the institution/trial site.
Responsibilities of IRB/IEC
 Safeguard the rights, safety, and well-being of all trial subjects.

 Reviews a proposed clinical trial within a reasonable time and
document its views in writing.
 Conducts continuing review of each ongoing trial at least once per
year.
 Ensures that information regarding payment to subjects
(including the methods, amounts, schedule of payment) is set
forth in the written informed consent form and any other written
information is provided to the subjects.

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Procedures of IRB/IEC
 Determines its composition and authority under which it is

established.
 Schedules, notifies its members of, and conducts its meetings.
 Conducts initial and continuing review of trials.
 Specifies that no subject should be admitted to a trial before
the IRB/IEC issues its written approval or favorable opinion of
the trial.
 Specifies the information that the investigator should report to
the IRB/IEC (like deviations from the protocol, adverse drug
reactions etc).
Maintenance of records of IRB/IEC
 IRB/IEG retains all relevant records (e.g., written procedures,

lists of occupations/affiliations of members, submitted
documents, minutes of meetings, etc.) for a period of at least 3
years after complet of the trial and makes them available upon
request from the regulatory authority
 IRB/IEG may be asked by investigators, sponsors, or regulatory
authorities to provide copies of its written procedures and
membership lists.

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HIPAA
HIPAA is defined as the Health Insurance Portability and
Accountability Act (HIPAA) is a federal law that provides baseline
privacy and security standards for medical information. The U.S.
Department of Health and Human Services (HHS) is the federal
agency in charge of creating rules that implement HIPAA and also
enforcing HIPAA.
HIPPA Compliance in Clinical Trails
 The federal Medical Privacy Rule, authorized by the Health

Insurance Portability and Accountability Act of 1996 (HIPAA),
limits how covered physicians may use and disclose protected health
information (PHI) for any purpose.
 Throughout the clinical study process, researchers may need to
create, edit, and view PHI. HIPAA stipulates that participant PHI
must be used in a "specific and meaningful manner."
 All study participants must submit authorizations in order for the
researchers to have access to their pertinent information. This
authorization only applies to the current study, and not to any
future studies.
1. Pre-Research Review of Medical Records
 A prospective sponsor might request summary information about a

physician's patients to establish whether the physician's practice is
a viable site for a clinical trial.
 The Privacy Rule permits the physician to review her medical
records for this "pre-research" purpose, provided that no PHI is
disclosed to the sponsor.

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 If a third party, such as a contract research organization (CRO) or

another researcher will review medical or billing records for this
purpose, the review must occur at the practice and the physician
must obtain the following representations: The use or disclosure is
sought solely to review PHI as necessary to prepare a research
protocol or for similar purposes preparatory to research:
 No PHI will be removed from the covered entity during the review;
and
 The PHI that the researcher [or CRO] seeks to review is necessary
for the purpose(s) of the review.
 To document HIPAA compliance, the physician should ask the third
party to provide these representations in writing.
 Alternatively, the Privacy Rule allows the physician to share "de-
identified" data without restriction. The Privacy Rule's standard for
de-identification is quite strict, typically requiring removal of
eighteen specific identifiers that range from names and social
security numbers to dates of treatment and full zip codes.
 The de-identification of protected health information enables
HIPAA covered entities to share health data for large-scale medical
research studies, policy assessments, comparative effectiveness
studies, and other studies and assessments without violating the
privacy of patients or requiring authorizations to be obtained from
each patient prior to data being disclosed.

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2. Recruitment
 The Privacy Rule permits a physician to recruit her own patients, by,
for example, sending a letter to patients potentially eligible to enroll
in a clinical trial, or by discussing enrollment during an office visit.
(The institutional review board overseeing the study must approve
the recruitment plan.)
 If a CRO wishes to use a physician's records to recruit patients, the
study's principal investigator should seek a partial waiver of HIPAA
authorization from the institutional review board.
Uses and disclosures for which an authorization or opportunity to

agree or object is not required;
a. Uses and Disclosures Required By Law.

b. Uses and Disclosures For Public Health Activities.
c. Disclosures About Victims Of Abuse, Neglect Or Domestic
Violence
d. Uses And Disclosures For Health Oversight Activities
e. Disclosures For Judicial And Administrative Proceeding
f. Disclosures For Law Enforcement Purposes.
g. Uses And Disclosures About Decedents
 Participants must first review certain documents to ensure a

comprehensive understanding of the study. If you decide to
participate in a clinical trial, you may be asked to sign two
documents: an authorization form, and an informed consent
document.
 The informed consent document will detail the study methodology,
any potential risks, timeline, participant confidentiality and
healthcare coverage during the course of the study. This document
may or may not be combined with an authorization form.

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A few elements that may be present in the authorization may

include:
 Your health information will be disclosed when it is required by law

 Your health information will be shared when required by law, to
prevent or control injury or the spread of disease
 No publication or public presentation about the study will reveal
your identity
 To maintain the integrity of the study, you may not have access to
your PHI until the study is complete.
You do not have to sign this authorization, but if you decline, you may
not be eligible for study participation. Revoking this permission means
you will no longer be eligible for participation within the clinical study.
3. Enrollment and Conduct of Study
 A physician generally must obtain written HIPAA research

authorization to enroll a patient in a clinical trial.
 Though a research sponsor may provide a template consent form,
typically the research site, which is the covered entity, must supply
the HIPAA authorization.
 The study's authorization and consent forms are usually combined,
which is permitted, provided that the combined form contains all of
the elements required by both the Privacy Rule and federal research
regulations.
 A HIPAA research authorization must contain all the elements of a
valid general HIPAA authorization.

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To be valid, a HIPAA authorization must satisfy the following:
1. No Compound Authorizations - The authorization may not be

combined with any other document such as consent for treatment. An
authorization to use or disclose psychotherapy notes may not be
combined with an authorization to disclose other forms of PHI.
2. Core Elements - These include a description of the PHI to be used

or disclosed that identifies the PHI in a specific and meaningful
fashion.
 The name or specific identification of the person(s) or class of

person(s) authorized to make the use or disclosure.
 The date and signature of the patient or the patient's personal
representative.
 A description of each purpose for the requested use or
disclosure.
3. Required Statements - The authorization must also contain certain

required statements regarding patient rights.
 The patient or personal representative has the right to revoke the

authorization at anytime by submitting a written revocation except
to the extent the provider has taken action in reliance on the
authorization.
The provider generally may not condition its healthcare on the

provision of the authorization except
i. For research-related treatment, or

ii. If the purpose of the healthcare is to create information for
disclosure (e.g., an employment physical or independent medical

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exam), in which case the provider may refuse to provide the

healthcare if the patient refuses to execute an authorization.
 The information disclosed per the authorization may be subject to
re-disclosure by the recipient and no longer protected by HIPAA.
4. Marketing or Sale of PHI - If the authorization is to permit the

use or disclosure of PHI for purposes of marketing (as defined by
HIPAA) or the sale of PHI, and the provider will receive remuneration
for the PHI, the authorization must notify the patient that the
provider will receive the remuneration.
5. Completed in Full - The authorization and its required elements

must be completely filled out, i.e., there should be no blanks concerning
the required terms.
6. Written in Plain Language - The authorization must be written in

plain language. For patients with limited English proficiency, the
provider may need to translate the authorization for the patient.
7. Give the Patient a Copy - If the provider is requesting the

authorization from the patient, the provider must give the patient or
personal representative a signed copy of theauthorization. The
provider is not required to give a copy if the patient initiated the
authorization.
8. Retain the Authorization - The provider must retain a copy of the

authorization for six years.
 If an authorization is required, HIPAA prevents providers and

business associates from using or disclosing more PHI than is
allowed or in a manner that is different than as stated in the
authorization, SO providers should ensure that the authorization is

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broad enough to cover the requested use or disclosure, including any

disclosure of oral information in addition to records.
 Every HIPAA authorization must also tell the patient how to revoke
authorization. If a patient does revoke authorization, the physician
conducting the trial may continue to use and disclose (eg, provide to
the research sponsor) PHI obtained before the revocation. After
revocation the physician may use and disclose the patient's new PHI
only as necessary to maintain the integrity of the research (eg, to
report an adverse event or the death of a study subject).
4. Publication or Presentation of Results
HIPAA continues to apply when the results of clinical trials (or case
studies) are published or presented to an audience. Except when
conducting internal medical education activities, physicians must obtain
written HIPAA authorization before publishing papers or making
presentations containing PHI. An institutional review board may not
waive authorization for the publication or presentation of research.
Physicians whose publications or presentations will contain patient-level

data should determine whether the eighteen HIPAA identifiers have
been removed, and also whether the remaining information could be
combined with other publicly-available information to reveal the
identity of a participant. Materials involving photographs, rare
diseases, or highly publicized cases should be reviewed with particular
care.

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What Happens If You Break H

HIPAA Rules?
If you break HIPAA Rules there are four potential outcomes:
 The violation could be dealt with internally by an employer. o You

could be terminated.
 You could face sanctions from professional boards.
 You could face criminal charges which include fines and
imprisonment.

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Pharmacovigilance Safety Monitoring in Clinical Trials

Pharmacovigilance
Pharmacovigilance concerned with the detection, assessment and

prevention of adverse reactions of drug.
The science and activities relating to the detection, assessment,

understanding and prevention of adverse effects or any drug related
problems.
Safety Monitoring In Clinical Trials
Monitoring patient’s safety during clinical trials is a critical component

throughout the drug development life cycle.
Pharmaceutical sponsors must work proactively and collaboratively with

all stakeholders to ensure a systematic approach to safety monitoring.
Since clinical trials are experiments in human, they must be conducted

following established standard in order to protect the rights, safety
and well-being of the participants.
These standards include:
 The International conference on Harmonization Good Clinical

Practice (ICH-GCP) Guidelines.
 International Ethical Guidelines for Biomedical Research
Involving Human Subject issued by the Council for International
Organization of Medical Science (CIOMS).

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Common Practice in Safety Monitoring
1. Stakeholders in Safety Monitoring
A) Sponsors:-
Protocol - Clinical trials sponsors, usually pharmaceutical companies,

are responsible for developing the clinical trials protocol. The protocol
describes every aspect of the research, including the rationale for the
experiment.
The protocol also details the safety reporting procedures, specifically

on the requirements for expedited reporting of serious adverse events.
ICF - The informed consent form is used to disclose current

information about the investigational drug and about the procedure,
risk and benefits for subject who participate in clinical trials.
CRF - Case report form are designed by the sponsor as data collection
tools. This tool is based on electronic data capture module via internet
rather than the traditional based route.
B) Subject - Subjects are Patients or healthy volunteers who agree to

participate in clinical trials and have signed ICF.
C) Investigator - Investigators are qualified individuals who are

trained and experience to provide medical care to the subject enrolled
in the trails.
D) Institutional Review Board / Ethics committee - The institutional

Review Board (IRB) also known as Ethics Committee, is charged with
protecting the rights and welfare of human subject recruited to
participate in research protocol.

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The IRB review all the Clinical trials protocol involving human subjects
that the particular institution is involved with has authority to approve,
disapprove or require modifications in the protocol.
E) Data and Safety Monitoring Board - The Data and Safety

Monitoring Board (DSMB), also called as Data Monitoring Committee
(DMC) is an expert committee, chartered for one or more clinical
trials.
The DSBM is to review on the regular basis the accumulating data of

the clinical trials to ensure the continuing safety of current
participants and those who have yet to be enrolled.
F) Regulatory Authority - Prior to the initiation of a first human in

clinical trials, pharmaceutics sponsors must submit as Investigational
New Drug (IND) application to the FDA has require by the law. The
FDA reviews the IND (within the 30 calendar day) for safety to ensure
that research subjects will not be subjected to unreasonable risk.
G) Medical Community and Patients - Clinical trials generate data

that contribute to the body of knowledge about the treatment and the
disease that benefit the broader medical community and, ultimately,
the patients. Safety information of one product may be informative to
other practitioners using similar class of agent.

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Unit 5 - General principle of IPR

Intellectual property broadly means the legal right which results from
intellectual activity in the industry, scientific literary and artistic
fields.
Countries have laws to protect intellectual property for two main

reasons, one to give statutory expansion to the moral and economic
right of creators in their creations and the right of the public in
access to those creations.
The second is to promote, as a deliberate act of government policy

creativity and the dissemination and application of its result's and to
encourage fair trading which would contribute to economic and social
development.
Intellectual property is traditionally divided into two branches,

'industrial property and copy right'.
The Convention establishing the World Intellectual Property

Organization (1967) gives the following list of the subject matter
protected by intellectual property rights:
 literary, artistic and scientific works,

 performances of performing artists, phonograms and broadcasts,
 inventions in all fields of human endeavour,
 scientific discoveries,
 industrial designs,
 trademarks, service marks and commercial names and
designations
 protection against unfair competition, and
 all other rights resulting from intellectual activity in the
industrial, scientific, literary or artistic fields.”

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Intellectual Property
Intellectual property re
refers
fers to the creation of human mind like
Inventions, literary and art
artistic
istic works and symbols, names, images,
designs used in commerce.
IP divided into two categories

categories:-
1. Copyright covers literary works (such as novels, poems and plays),

films, music, artistic works (e.g., drawings, paintings, photographs
and sculptures) and architectural design.
2. Industrial Property includes patents for inventions, trademarks,
industrial designs and geographical indication
indications.
Intellectual Property Protection

Since 1300 several understandings were made among countries to
encourage, safeguard intellectual property of nationals in foreign
countries. Such provisions were fruitful in harmonization of application
procedure, examination procedure among countries.
List
st of treaties/conventions /agreements

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Economic Importance
Economic development is the increase in the standard of living in a
nation's population with sustained growth from a simple, low-income
economy to a modern, high-income economy.
IPR could well increase economic growth and foster beneficial technical
change, thereby improving development prospects, if they are
structured in a manner that promotes effective and dynamic
competition.
How IPR helps in Economic Development

Intellectual property rights could play a significant role in encouraging
innovation, product development, and technical change to help in
development of the economy through low-cost imitation of foreign
products and technologies. However, inadequate IPR could stifle
technical change even at low levels of economic development because
much invention and product innovation are aimed at local markets and
could benefit from domestic protection of patents, utility models, and
trade secrets.

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Protection of Intellectual Property in India (Patents, Trade Marks

& Copyrights)

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Factor Affecting on Intellectual Property

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PATENTS
 The word patent was coined from Latin term 'patent- em' meaning
open. A patent is a document issued by government to the inventor
granting him exclusive rights to make, sell, use, or import upon
disclosure of the invention for a definite period of time
 An invention must, in general, fulfil the following conditions to be
protected by a patent.
 It must be: novel, non obvious, useful, and enable.
There are three types of patents:
1. Utility patents may be granted to anyone who invents or discovers

any new and useful process, machine, article of manufacture, or
composition of matter, or any new and useful improvement
thereof;
2. Design patents may be granted to anyone who invents a new,
original, and ornamental design for an article of manufacture;.
3. Plant patents may be granted to anyone who invents or discovers
and asexually reproduces any distinct and new variety of plant
 In India, the patent act, 1970 governs the protection of inventions
as intellectual property. India intellectual property office located at
Kolkata, Delhi, Mumbai and Chennai receives applications and grants
patents for invention.
 The term of patent is for 20 yrs. from the date of filling.
 After 20 years patent becomes off-patent.

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Types of Patent Application

1. Provisional application
2. Ordinary or Non-provisional application
3. Convention application
4. PCT international application
5. PCT national phase application
6. Patent of addition
7. Divisional application
1. Provisional Application
A provisional application, also known as a temporary application, is filed

when an invention is under experimentation and isn't finalized.
Moreover, it is a preliminary application which is filed before the

patent office for claiming priority, as the Indian Patent Office follows
the 'First to File' system.
2. Ordinary or Non-Provisional Application
This type of application is filed if the applicant doesn't have any

priority to claim or if the application is not filed in pursuance of any
preceding convention application.
A complete specification contains the following:
 Title
 The technical field of the invention
 Background of the invention
 Objects of the invention
 Statement of the invention
 A brief description of the drawings
 A detailed description of the invention

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 Claims
 Abstract
 A preamble to the invention
3. Convention Application
A convention application is filed for claiming a priority date based on

the same or substantially similar application filed in any of the
convention countries.
To avail a status of convention, an applicant is required to file an

application in the Indian Patent Office within a year from the date of
the initial filing of a similar application in the convention country. To
re-iterate in simpler terms, a convention application entitles the
applicant to claim priority in all the convention countries.
4. PCT International Application
As can be deciphered from its name, a PCT Application is an

international application. Though the application does not provide for
the grant of an international patent, it paves the way for a streamlined
patent application process in many countries at one go. It is governed
by the Patent Corporation Treaty and can be validated in up to 142
countries. Filing this application would protect an invention from being
replicated in these designated countries.
Apart from this, it renders the following other benefits:
 The application provides an International Search Report citing

prior art, which discloses whether or not the invention is novel.
 It provides an option for requesting an International Preliminary
Examination Report, which is a report that contains an option on
the patentability of the invention.

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 The aforementioned reports facilitate the applicant to make

more informed choices early in the patent process, as he/she can
amend the application to deal with any conflicting material.
An applicant from India can file this application at:
 The Indian Patent Office (IPO), which acts as the receiving office.
 The International Bureau of WIPO(World Intellectual Property
Organization) either after availing a foreign filing permit from IPO
or after six weeks and 12 months of filing an application in India.
5. PCT National Phase Application
It is considered essential for an applicant to file a national phase

application in each of the country wherein protection is sought for. The
time-frame for filing the same is scheduled within 31 months from the
priority date or the international filing date, whichever is earlier. The
time- limit could be enhanced through National Laws by each member
country.
6. Patent of Addition
 This application must be filed if the applicant discovers that he has

come across an invention which is a slight modification of the
invention which has already been applied for or patented by the
applicant.
 It can only be filed if the invention doesn't involve a substantial
inventive step.
 A patent of addition is only granted after the grant of the parent
patent, and hence no separate renewal fee should be remitted
during the term of the main patent.

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7. Divisional Application
An applicant may choose to divide an application and furnish two or

more applications if a particular application claims for more than one
invention. The priority date for these applications is similar to that of
the parent application.
Trademark
Trademark is an indication of a product oriented from an individual or a
company signifying the quality of the product and distinguishes from
its competitor. A trademark is an alphabet, numerical, alpha numerical,
device or a combination of these.
Service mark is the same as a trademark except that it identifies and

distinguishes the source of a service rather than a product.
Use of TM (trademark) or SM (service mark) designation with the

mark to alert the public to the claim.
Trademark registry located at Mumbai, Kolkata, Delhi, Chennai,

Ahmadabad receives applications and registers the mark.
The term of trademark is for 10years and renewed from time to time.
Collective marks as registered marks are issued to several companies

having same product with individual trademarks.
such collective marks indicate the product is fulfilling the quality

guidelines set by organization issuing the collective mark. The symbol ®
indicates registered Trademark.

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COPYRIGHT ©
Copyright is a right given by the law to creators of literary, dramatic,
musical and artistic works and producers of cinematograph films and
sound recordings.
Unlike the case with patents, copyright protects the expressions and
not the ideas. There is no copyright in an idea
In India, the law relating to copyright is governed by the Copyright

Act, 1957 which has been amended in 1983, 1984, 1985, 1991, 1992,
1994, 1999 and 2012 to meet with the national and international
requirements.
Literary, dramatic, musical or artistic works enjoy copyright protection

for the life time of the author plus 60 years beyond i.e. 60 years after
his death. In the case of copyright in posthumous, anonymous and
pseudonymous works, photographs, cinematograph films, sound
recordings, works of Government, public undertaking and international
organizations, the term of protection is 60 years from the beginning of
the calendar year next following the year in which the work has been
first published.
In India, the copyright Act, 1957 governs registration of a work as a

copyright. Department of Higher education, Ministry of Human
Resources Development, Government of India implements the
intellectual property of protection of literacy and artistic work as
copyrights. Applications are received at New Delhi office.
Several pharmaceutical text books, figures, questionnaires are

copyright protected either directly by the author or throught a
publisher.

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2. CMC, post approval regulatory affairs. Regulation for combination

3. Non clinical drug development: Global submission of IND, NDA,

4. Clinical trials: Developing clinical trial protocols. Institutional

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5. General principle of IPR: IP protection, economic importance,

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UNIT 1.a. Documentation in Pharmaceutical

A regulatory affair is a profession which acts as interface between

 Protection of Human health

MAJOR REGULATORY AUTH

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Role of Regulatory Affairs

 To give strategic & technical advice to R&D,QC, PRODUCTION

Master Formula Record

Master Formula Record Contains: - Product Details

 Name, logo and address of the manufacturing company

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Drug Master File

 DMF is not mandatory by law or FDA regulation.

Types of Drug Master Files

1. TYPE 1 - Manufacturing Site, Facilities, Operating Procedures, and

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Distribution records: Are written data related to distribution of drug

1. A procedure whereby the oldest approved stock of a drug product is

Distribution Records Should Contain

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 Date and quantity shipped

GENERIC DRUG PRODUCT DEVELOPMENT

Product: A product is something sold by an enterprise to its customers.

Product Development: Product development is the set of activities

Generic Product Development Process

Mission Statement: Identifies the target market for the product,

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Product Launch: Occurs when the product becomes available for

HATCH WAXMAN ACT

The main objective is

 to reduce the cost

Generic drug manufacturers files ANDA that incorporates safety and

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Provisions of the Act

1. Paragraph I: that such patent information has not been filed

 Contains the list of all FDA approved Drug products

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Code of Federal Regulations (CFR)

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 In all, 21 CFR consists of 1499 parts.

 11 Electronic records and electronic signature related.

DRUG PRODUCT PERFORMANCE (DPP)

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NDA Regulatory Approval Process

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Fundamentals of NDA Submission

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 Human Pharmacokinetics and Bioavailability

ANDA Regulatory Approval Process

A generic drug product is one that is comparable to an innovator drug

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CONTENT AND FORMAT OF AN ABBREVIATED APPLICATION

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BE AND DRUG PRODUCT ASSESSMENT

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conditions, are similar to such a degree that their effects can be