REGULATORY AFFAIRS

Regulatory Affairs:-
• Regulatory Affairs is profession which has developed from the desire of
government to protect public health, by controlling the safety and efficacy of
the products in areas including pharmaceuticals, veterinary medicines, medical
devices, pesticides, agrochemicals, cosmetics and complementary medicines.
• As medicines play a vital role in human’s life there must be regulations for
medicines ensuring product compliance, Quality, Safety and Efficacy of drugs.
• It is actively involved in every stage of drug development in the case of a new
drug, and in post-approval surveillance in the case of an existing drug.
• Even a small mistake in any regulatory activity can lead to the product being
recalled and cause a loss of millions of dollars.
• Drug development to commercialization is highly regulated.

• These standards are set by regulatory

authorities of their respective
countries etc.
• Extensive evaluation of a drug
product to ensure protection of
public health, promotion of the
products, drug registration,
marketing authorization, import and
distribution.
Historical overview of Regulatory affairs:-
• Some notable cases in the history responsible for requirement strict
regulation for medicine were required.
1. Diphtheria disaster (1901)
2. Elixir- Sulfanilamide (1937)
3. Cutter incident (1955)
4. Thalidomide tragedy (1960)
 Diphtheria disaster:-

• In 1901, 13 children died from diphtheria antitoxin that had been

contaminated with tetanus spores.
• This tragedy led Congress in 1902 to pass a Biologics Control Act that
required commercial manufacturers to demonstrate the purity ( and later
potency) of their products.
• The serum, which was derived from animal blood (usually horses), was not
properly purified or sterilized. As a result, spores of Clostridium tetani (the
bacteria responsible for tetanus) could survive in the serum and infect the
patients, especially children.
• It caused tetanus infections, leading to paralysis and deaths.
 Elixir- Sulfanilamide Tragedy:-

• In 1937. S.E. Massengill Company. A pharmaceutical

manufacturer, created a preparation of sulfanilamide
using diethylene glycol (DEG) as a solvent, and
called the preparation “Elixir Sulfanilamide”.
• Watkins was unaware that DEG was toxic to humans,
even though there were extant known cases of
toxicity and that studies were published several years
which concluded that DEG was a highly
nephrotoxic agent and should be avoided in humans.
• Also known as the ‘Taste of Raspberries’ and the
‘Taste of Death
 Cutter incident:-
• In 1955, some batches of polio vaccine given to the public contained live
polio virus, even though they had passed required safety testing.
• Over 250 cases of polio were attributed to vaccines produced by one
company: Cutter Laboratories. This case, which came to be known as the
Cutter incident, resulted in many cases of paralysis and killing.
 Thalidomide tragedy:-
• Thalidomide was first marketed to health professionals as a sedative.
However, its use rapidly increased amongst pregnant women due to the drug’s
ability to alleviate morning sickness.

• Soon after its rise in popularity, medical

professionals began to note a series of
congenital mutations in children born from
mothers who used the drug during
pregnancy, resulting in the thalidomide
tragedy known today.
Regulatory Authorities:-
Regulatory authorities are government bodies or agencies responsible for
creating, enforcing, and monitoring rules and regulations to ensure the safety,
quality, and efficacy of products or services.
• Which regulates the following:-
1. Import or export of the drug
2. Manufacturing of drugs in the country
3. Approval of new drug
4. Approval for clinical trials
5. Issuing various types of license related to drug
6. The compliance with international guidelines
7. Regular inspection
Country Name of Regulatory Authority
USA Food and drug Administration (FDA)
UK Medicines and Healthcare Products Regulatory Agency
(MHRA)
Australia Therapeutic Goods Administration (TGA)
India Central Drug Standard Control Organization (CDSCO)
Canada Health Canada
Europe European Medicines Agency (EMEA)
Denmark Danish Medicines Agency
Costa Rica Ministry of Health
New Zealand Medsafe - Medicines and Medical Devices Safety Authority
Sweden Medical Product Agency (MPA)
Netherlands Medicines Evaluation Board
Role of Regulatory Affairs Department:-
Regulatory affairs department is a bridge between government regulatory authority and
pharmaceutical company. It also has a connection with all the departments of the
company internally.
Plays many important roles:-
1. Role in drug development and approval
2. Acts as an Adviser
3. Maintenance of licences
4. Preparation of documents
5. Execution of Clinical plan
6. Keep other departments updated
7. Data collection and storing
Responsibilities of RA Professional:-
• Keep up to date about international legislation, guidelines and customer practices.
• Update with company’s product.
• Compliance of company’s product with current regulation
• Import training to R &D, Pilot plant, ADL on current regulatory requirement.
• Formulate regulatory submission strategies.
• Prepare IMPD, DMF, ANDA, MAA, Dossiers amendments & supplements etc. As per regional
guidelines, submit them to regulatory authorities in a specific time frame.
• Monitor progress of all registration submissions.
• Respond to queries as they arise and ensure that registration/approvals are granted without delay.
• Handle regulatory and customers inspections, review audit report and compliance.
• Arranges consultations and meetings between the firm and government regulatory agencies.
Drug Development Team:-
• Drug development is the process of bringing a new pharmaceutical drug to the
market once a lead compound has been identified through the process of drug
discovery. It includes pre-clinical research on microorganisms and animal, filling
for regulatory status, for an investigational new drug (IND) to initiate clinical
trials on humans, and may include the steps of obtaining regulatory approval with
a new drug application to market the drug.
• The process of drug discovery and development is very long which includes the
close interactions of large number of scientific disciplines, most biotechnology
and pharmaceutical companies employ teams to mentor the process of various
stages of drug development and making the drug development and making the
drug candidate into therapeutic products.
• The DDT is comprised of different sub-teams namely drug discovery team,
preclinical drug development team and clinical drug development team.
1. Drug discovery team:
Drug discovery team is a small group of researchers and is the first team in DDT.
The primary responsibility of this team is the first team in DDT. The primary
responsibility of this team is to identify lead compounds or classes of compounds.
They screen existing compounds in the company’s archives or in the libraries of
compounds that company’s archives or in the libraries of compounds that are
optimized for activity using combinatorial chemistry.
Drug discovery team then includes other experts from various scientific disciplines,
such as pharmacology, chemistry, toxicology, drug metabolism and
pharmacokinetics and biopharmaceutics.
2. Preclinical drug development team: Once the managements accepts a lead
compound candidate as a drug candidate, its further establishment is carried out by
preclinical drug development team (PDDT). This new team also involves
researchers from the various scientific disciplines. Some companies have separate
groups to support discovery research and for conducting non-clinical and clinical.
• Its further establishment is carried out by preclinical drug development team (PDDT). The new
team also involves researchers from the various scientific disciplines. Some companies have
separate groups to support discovery research and for conducting non-clinical and clinical
developmental studies. In addition to the drug discovery team members, the PDDT has a number
of new players that include:
a) A management: They assign team leader and co-ordinator to the team who responsible for the
development of the new drug candidate.
b) RA and QA personal: These members are to ensure that the developmental studies meet with the
regulatory requirements and to see that the studies are conducted according to regulatory
guidelines.
c) Clinical researchers: They provide input study designs so that the generated results support the
proposed clinical program. They initiate development of protocols for clinical safety, tolerance
and efficacy as well as the investigators brochure.
d) Analytical chemist: They are responsible for development of assay method and for characterize
the new drug substance and new drug product.
e) Manufacturing chemist: They scale up the synthesis of drug candidate and provide GLP/GMP
quality material for research studies.
f) Marketing exports: They help to determine drug candidate’s potential market through survey for
other companies drugs under development or drugs that are already on the market for the disease
indication.
3. Clinical Drug Development team (CDDT):
Once the IND is submitted, the non-clinical project team is further expanded to include new
members and renamed as clinical drug development team (CDDT) where in team roles substantially
expand. Some of the old members, such as from chemistry and pharmacology disciplines, have
decreased roles but may continue to serve on the team to provide scientific expertise if new problems
arise. The new players and their expanded roles includes:
a) Physicians: They are involved in conducting Phase I, II and III clinical studies or serve as
medical mentors if these studies are conducted by a Clinical Research Organization (CRO).
b) Clinical research associates: They coordinate and monitor the Phase I, II and III studies and
ensure that the case report form (CRF) are correctly prepared.
c) Manufacturing chemist: They coordinate development of new drug substance and drug product
production facilities and ensure that all the necessary processes are in place.
d) Quality control analyst: They ensure that the appropriate assays are developed validated, and are
in place to support the manufacturing schedule.
e) Statisticians: Their responsibility is to assist is designing clinical protocols and evaluate generated
results from non-clinical and clinical studies.
f) Clinical pharmacokinetics: They participate in Phase I trials to support design of studies and
conduct pharmacokinetic studies.
g) Marketing personal: They evaluate the status of competitors’s drug candidates and the potential of
the new drug candidate to fulfill a medical need and to prepare for product launch.
Non- Clinical Drug Development:-
Pre-Clinical Trial: A laboratory test for a novel drug or a new medical device is usually done on
animal subjects, to see if the hoped for treatment really works and if it is safe to test on humans.
The primary aims of the non-clinical (or preclinical ) development phase is to analyze and determine
which candidate has the greatest probability of success, assess its safety, and raise firm scientific
foundations before transition to the clinical development phase. This process of non clinical
development of medicines is very complex, time consuming and regulatory driven.
The main objective of non-clinical study is to confirm that either the target drug is safe for use in
human or not. This is done by studying animal pharmacology and toxicology testing. This studies are
necessary before filing Investigational New Drug (IND) application.
Investigational New Drug (IND):-
• Investigational New Drug (IND) is a program by which any pharmaceutical
company can approach to obtain permission for the initiation of human clinical
trials and to ship an experimental drug across state lines (usually to clinical
investigators) before a marketing application for the drug has been approved.
• An investigational new drug (IND) application is to provide the data showing that
it is reasonable to begin tests of a new drug on humans.
• IND application is also the vehicle through which a sponsor advances to the next
stage to the drug development known as clinical trials.
• During a new drug’s early preclinical development, the sponsor’s primary goal is
to determine if the product is reasonably safe initial use in human and if the
compound exhibits pharmacological activity that justifies commercial
development.
• When a product is identified as a viable candidate for further development, the
sponsor then focuses on collecting the data and information necessary to establish
that the product will not expose humans to unreasonable risk when used in
limited, early- stage clinical studies.
Type of IND Applications:-
• Investigator IND application
• Emergency use IND application
• Treatment IND application
• Screening IND application
1. Investigational IND Application:
In this an application is submitted by a physicians, who both initiates and conducts
an investigation and under whose immediate direction the investigational drug is
administered or dispensed. A physician might submit a research IND application to
propose studying of:
• An unapproved drug
• An approved product for a new indication or
• An approved product in a new patient population.
2. Emergency Use IND Application:
The application allows the FDA to authorize use of an experimental drug in an
emergency situation that does not allow time for submission of an IND application,
in accordance with 21CFR, Sec 312.23 or Sec 312.20. It is also used for patients
who do not meet the criteria of an existing study protocol, or if an approved study
protocol does not exist. In such a case, FDA may authorize shipment of the drug for
a specified use in advance of submission of an IND application.
3. Treatment IND Application:
• This application is submitted for experimental drugs showing promise in clinical testing for
serious or immediately life- threatening conditions while the final clinical work is conducted and
the FDA review takes place.
• A drug that is not approved for marketing may be under clinical investigation for a serious or
immediately life- threatening disease condition in patients for whom no comparable or satisfactory
alternative drug or other therapy is available.
• In the case of a serious disease, a drug ordinarily may be made be made available for treatment use
during phase III investigations or after all clinical trials have been completed.
• In the case of an immediately life threatening disease, a drug may be made available for treatment
use earlier than phase III, but ordinarily not earlier than Phase II.
4. Screening IND Application:
It is filed for multiple, closely related compounds in order to screen for the preferred compounds or
formulations. The preferred compound can be developed under a separate IND. It can also be used
for screening different salts, esters and other drug derivatives that are chemically different, but
pharmacodynamically similar.
Investigator’s Brochure (IB):-
• It is a compilation of the clinical and non-clinical data on the investigational product that are
relevant to the study of the product in human subject.
• Provide information to the investigators and others involved in the trial such as the dose, dose
frequency/interval, methods of administration and safety monitoring procedures.
• Provides insight to support the clinical management of the study subjects during the course of the
clinical trial. The information should be presented in a concise and simple manner.
• Contents of Investigator’s Brochure:
1. Table of contents.
2. Summary not exceeding 2 pages, highlighting
3. Introduction: Chemical name, API, pharmacological class, anticipated therapeutic/diagnostic
indication(s). General approach to be followed in evaluating the IP.
4. Description of I.P.: Physical, chemical and pharmaceutical properties of I.P. Storage and handling
of I.P. and clinical data of IP.
5. Non-clinical studies: The results of all relevant non-clinical pharmacology,
toxicology, pharmacokinetic, and investigational product metabolism studies should
be provided in summary form.
The information provided may include: Species tested, Number of sex in each
group, Unit dose, Dose interval, Route of administration and Duration of dosing.
6. Effect in Humans: A thorough discussion of known effects of the investigational
product(s) in humans should be provided, including information on
pharmacokinetics , metabolism, pharmacodynamics, dose response, safety, efficacy,
and other product metabolism in humans.
7. Summary of data and guidance for the investigator: This section should contain
non- clinical.
New Drug Application (NDA):-
• If clinical studies confirm that a new drug is relatively safe and effective and will not pose
unreasonable risk to patients, the manufacturer files a new drug application, the actual request to
manufacture and sell the drug in the united states.
Aim of NDA:
• Safety and effectiveness of drug,
• Benefits overweight risks,
• Is the drug’s proposed labeling appropriate, and what should it contain?
• Are the methods used in manufacturing (GMP) the drug and the control used to maintain the
drug’s quality adequate to preserve the drug’s identity, strength, quality and purity?
Once the application is submitted, the FDA has 60 days to conduct a preliminary review which will
assess whether the NDA is ‘sufficiently complete to permit a substantive review’.
If everything is found to be acceptable, the FDA will decide if the NDA will get a standard or
accelerated review and communicate the acceptance of the application and their review choice in
another communication known as the 74-day letter.
NDA
Contents
Clinical Research/ Bio Equivalence studies:-
Clinical research ensures safety, efficacy, and quality of pharmaceutical products. It includes studies
from drug discovery to post-marketing surveillance.
Key areas:
 Bioequivalence (BE) Studies
 Clinical Research Protocols
 Biostatistics
 Data Presentation for FDA
 Management of Clinical Studies
BE studies refers to the drug substance in two or more identical dosage forms, reaches systemic
circulation at the same rate and to the same relative extent.
i.e. their plasma concentration time profile will be identical without significant differences.
Both Bioavailability and Bioequivalence focus on release of drug substance from its dosage form and
subsequent absorption in circulation.
Bioavailability: Bioavailability means the rate and extent to which the active ingredient or active
moiety is absorbed from a drug product and becomes available at the site of action.
Equivalence: It is a relative term that compares drug products with respect to a specific characteristic
or function or to a defined set of standards.
Biowaiver allows for the waiver of bioequivalence studies for regulatory approval of certain drug
products with saving of time, and money. They are given when in vitro studies data provides
sufficient estimate of relative in vivo performance of two products. These are given when API meets
certain solubility and permeability criteria.
Biowavers are given in case if :
• Drug are highly soluble and highly permeable.
• Highest dose strength of the drug is soluble in 250ml aq solution over a PH 1-7.5 at 37 °C
• 90% of the drug is absorbed if administered orally.
• 80% of the drug is absorbed with in 15min of administration at 37 ° C.
• Clinical research protocols.
Bioequivalence studies are not required in case of:
• Drugs are parenterally administered.
• Drugs in solution form.
• Drugs in gaseous form.
• The new drug has a therapeutic window.
• Drugs with rapid and similar dissolution.
Clinical Research Protocols:-
It is a complete written description of and scientific rationale or a research activity involving human
subjects. Sufficient information is to be gathered on the quality of the non-clinical safety to conduct
the protocol and health authority/ ethics committee approval is granted in the country where
approval of the drug or device is sought.
It is a document that states the background, objectives, rationale, design, methodology ) including
the methods for dealing with AEs i.e Adverse drug events, withdrawals etc.) and statistical
considerations of the study and also states the conditions under which the study shell be performed
and managed.
The protocols means:
• To clarify the research question
• To compile existing knowledge
• To formulate a hypothesis and objective.
• To decide about a study design.
• To ethical considerations.
• To apply for funding and to have a guidelines and tool for the research team.
Parts of the Protocol:-
1. Title page
2. Signature page
3. Content page
4. List of abbreviation
5. Introduction/ Abstract
6. Objectives
7. Background/ Rationale
8. Eligibility criteria
9. Study design/ Methods
10. Safety/ Adverse Events
11. Regulatory guidance
12. Statistical section (Including analysis and monitoring)
13. Human subject protection/ Informed consent.
Biostatistics in Pharmaceutical Product Development:-
• Statistics is the science which deals with collection, tabulation and classification of numerical facts
as the basis for explanation, description and comparison of the phenomenon.
• Biostatistics is the branch of statistics concerned with mathematical facts and data related to
biological events. There are two type of Biostatistics- Descriptive statistics & Inferential statistics
Statistics is involved in all stages of drug development, i.e. from drug discovery to post marketing
processes.
Data Presentation for FDA submissions:-
• Study data standards describe a standard way to exchange clinical and non clinical study data.
• These standards provide a consistent general framework for organizing study data, including template's
for datasets, standard names for variables identify appropriate controlled terminology and standard ways
of doing calculations with common variables.
• Data standards also help FDA receive, process, review and archive submissions more efficiently and
effectively. The FDA accepts electronic submissions, the electronic submission’s regulatory process is
divided into four steps:
• Early planning and management of the project
• Document preparation
• Dossier publishing
• Dossier submission
• FDA has been working towards a standardized approach to capture, receive and analyze study data.
• Standardization of study data is vital to integrate pre-marketing study data and post- marketing safety data
to improve public health and patient safety.
Management of clinical studies:-
• It involves planning, monitoring, and controlling clinical trials to ensure quality and
compliance.
• The process that an organization follow to ensure that quality (defined as minimized risks and
clean data) is delivered efficiently an punctually.
• It refers to a standards-driven process that a project manager initiates and follows in orders to
successfully manage clinical trial sites, clinical research associates, and workflow by using clinical
trial management tools or software prolonged timelines and heavy costs related to large trials have
been prompted a new focus on more efficient clinical trial management.
• It is possible to dramatically reduce the total cost of a clinical trial by 60%- 90% without
compromising the scientific validity of the results.
• Life cycle of Clinical trial project are into 4 phases:
• Conceptual
• Planning
• Implementation
• Analysis