PROJECT REPORT ON

DRUG REGULATORY AFFAIRS

Submitted in partial fulfilment of requirement

For the award of the degree of

BACHELOR OF PHARMACY

Submitted by:

ABHISHEK SAURABH

ROLL NO: - BPH/1044/2011

Under the guidance of

Dr. Kishanta Kumar Pradhan

Assistant Professor

Department of Pharmaceutical sciences and Technology

Birla institute of technology, Mesra, Ranchi-835215

2015
 DECLARATION

I hereby declare that the work embodied in this thesis entitled “DRUG
REGULATORY AFFAIRS” has been carried out by me in Department
of Pharmaceutical Sciences, Birla Institute of Technology, Mesra,
Ranchi, during the period 2014-2015 and has not been submitted earlier
for the award of any degree or diploma to this or any other university.

PLACE: BIT Mesra, Ranchi ABHISHEK SAURABH

DATE: BPH/1044/2011
 CERTIFICATE
This is to certify that Mr Abhishek Saurabh (Bph/1044/2011) has worked
under my guidance and supervision for the project entitled “DRUG
REGULATORY AFFAIRS”. The details of the work carried out by him
have been incorporated in this project report and is being submitted by him
in partial fulfilment for the award of degree of Bachelor of Pharmacy.

Date:

Dr. K. K. PRADHAN
Department of Pharmaceutical Sciences and technology
Birla Institute of Technology
Mesra, Ranchi-835215

Forwarded by EXTERNAL EXAMINER

Dr. B.N. SINHA

Professor and Head,
Department of Pharmaceutical Sciences,
Birla Institute of Technology,
Mesra, Ranchi-83521
 ACKNOWLEDGEMENT
This thesis is the result of one year work, during which several people have
played a crucial role in its completion. It is great pleasure that now I have
the opportunity to express my gratitude to all of them.

Above all I thank the almighty for having given me, courage to undertake it
as my project, the patience for completing it and for a guide, so supportive,
without whom this gigantic task could never have been fulfilled.

I take this opportunity to express my heartfelt gratitude and indebtedness

to my respected guide Dr. K. K. PRADHAN, Assistant Professor, Department
of Pharmaceutical Sciences, Birla Institute of Technology, Mesra, Ranchi
who constantly motivated, supported, encouraged and guided me. His
invaluable guidance and continuous help in every aspect enabled me to
complete my thesis and without his cooperation I would not have presented
this dissertation successfully.

I am highly thankful, Dr. M. K. Mishra, Vice-chancellor, Birla Institute of

Technology, Mesra, Ranchi for providing all facility and infrastructure
during B.Pharm academic programme.

I take my deep sense of gratitude and reverence to Dr. B.N. Sinha, Head,
Department of Pharmaceutical Sciences, Birla Institute of Technology,
Mesra, Ranchi, for providing me the requisite opportunities and facilities.

I further avail this opportunity and profound privilege to optimize my

deepest sense of gratitude to all faculty members of Department of
Pharmaceutical Sciences, Birla Institute of Technology, Mesra, for their
immense guidance and help during my B.Pharm course.
Lastly I would like to thank my parents, my elder brother and all my
friends for their unconditional love, support and care.

ABHISHEK SAURABH
(BPH/1044/2011)
 CONTENTS

CHAPTERS PAGE
NO.

1. Introduction 1

2. Literature Survey 2-4

3. Objective and Plan of Work 5-6

3.1. Rationale 5

3.2. Study Objective 5

3.3. Plan of Work 6

4. Pharmaceutical regulatory Affairs 7-15

4.1. Historical Overview 7

-U.S.A 7- 9

-Europe 10-11

-India 12-15

4.2. Drug Regulatory Affairs 16-17

4.3. Importance of Regulatory Affairs 18

5. Regulatory department and professionals 19-21

5.1. Roles of Regulatory Affairs Professionals 20-21

5.2. Qualities of Good RA Professional 22

6. Different Important Regulatory acts 23-25

7. Regulatory Authorities of different countries 26-33

8. A Comparative study on Drug Regulatory bodies 34-42

In India, US, European Union (EU) and Japan

9. Explanation of some important terms in regulatory affairs 43-46

10. Conclusion and scope of work 47-48

10.1 Conclusion 47

10.2 Scope of work 47-48

References 49-52
INTRODUCTION
 INTRODUCTION:-

The Indian pharmaceutical industry is one of the fastest growing industries in

India, with a compounded annual growth rate (CAGR) of over 13 % in last 5 years
and it is expected to grow at a higher rate in coming 10 years.1 As the
pharmaceutical industries throughout the world are moving ahead towards becoming
more and more competitive, these are realizing that the real battle of survival lies in
executing the work by understanding the guidelines related to various activities carried
out to give an assurance that the process is under regulation . Pharmaceutical Industry,
being one of the highly regulated industries, is in immense need of people than ever
before who are capable of handling issues related to regulatory affairs in a
comprehensive manner.2 Regulatory Affairs (RA), also called as Government Affairs, is
a profession within regulated industries, such as pharmaceuticals, medical devices,
energy, and banking. A regulatory affair (RA) also has a very specific meaning within
the healthcare industries (pharmaceuticals, medical devices, Biologics and functional
foods).Most companies, whether they are major multinational pharmaceutical
corporations or small, innovative biotechnology companies, have specialist departments
of regulatory affairs (RA) professionals. The success of regulatory strategy is less
dependent on the regulations than on how they are interpreted, applied, and
communicated within companies and to outside constituents.3 Pharma regulatory affairs
professionals play an essential role in ensuring all pharmaceutical products comply with
regulations governing the industry.4 Those working in pharma regulatory affairs jobs
not only work in the initial application phase for a new or generic drug, but also in the
licensing and marketing stages – making sure all operations and products meet required
safety and efficacy standards.5 Organisations such as the FDA also provide roles for
those interested in working in the field. As biotechnology plays an increasing role
within drug development and the pharmaceutical industry, growing numbers of biotech
regulatory affairs positions are opening up.
LITERATURE SURVEY
In 2008, FDA blocked the import of generic drugs from India's Ranbaxy Laboratories,
based on regulatory compliance issues involving two of its plants--one in Dewas and
another in Paonta Sahib. Specifically, FDA inspections earlier in 2008 revealed
violations that could result in formulation problems and therefore instructed the
company to take steps toward resolving the issues, which Ranbaxy failed to do. The
company makes generic versions of much used drugs like Zocor, which physicians
prescribe to treat high cholesterol, and Cipro, an antibiotic. The FDA first noted quality
problems with Ranbaxy in 2006. The agency has now decided to take "proactive
measures" by blocking at least 30 drugs, including the antiviral drug, acyclovir, the
antibiotics, ciprofloxacin and clarithromycin, the diabetic med, metformin, and
cholesterol drugs, pravastatin and simvastatin. The FDA did not block sales of the drugs
in the U.S. and even told consumers they could keep using the drugs they had at home.
Although the agency said the quality problems could lead to contamination, adverse
reactions and additional troubles with the medications and pharmaceutical ingredients
manufactured at the plants, repeated testing has not revealed any such problems yet. As
far as whether Americans will be able to get the medications they need, the FDA
seemed to feel confident that other manufacturers will step up to the plate.6

In 2009, Another FDA import ban came. Apotex, Canada's biggest drug maker, saw its
products stopped at the U.S. border after a plant inspection identified deviations from
manufacturing rules. Problems at Apotex's Etobicoke facility were detailed in a
warning letter, which contended that Apotex did not thoroughly investigate its own
manufacturing failures and that an unusual number of batches ended up rejected. The
import ban affected a number of drugs made at two plants, mostly older products with
lots of competitors, Reuters reports, so shortages shouldn't be a problem. Among the
drugs cited are generic versions of diltiazem, a blood pressure and angina remedy. In a
statement, Apotex said it is "actively working with the FDA to resolve" the problems.
In this it's not alone; the FDA has been on something of a manufacturing crackdown of
late, stopping more than one company's products from entering the U.S.7
In 2013, Wockhardt Ltd faced a sharp drop in market share and delays in new launch
approvals after a second plant operated by the generic drug maker was hit by the US
Food and Drug Administration's "import alert", effectively a ban. An "import alert"
results in the detention without physical examination of drugs from firms that have not
met so-called good manufacturing practices, according to the FDA website. The latest
FDA action against Wockhardt's Chikalthana plant in western India, one of its key
export facilities, comes amid a slew of regulatory rebukes in recent months, which has
wiped off nearly three-quarters of the company's share value this year.8

In 2014, The US Food and Drug Administration (FDA) warned privately owned drug
maker Cadila Pharmaceuticals Ltd that it was not following quality and manufacturing
standards at one of its plants, which caused impurities in drug ingredients made there.
In a warning letter posted on its website, the FDA said inspectors had found "significant
deviations" from standard manufacturing practices at Cadila Pharmaceuticals'
Ankleshwar plant in Gujarat state. The FDA issued the letter, and gave the company 15
days to respond. If Cadila Pharmaceuticals fails to take measures to correct the
violations, the agency can ban exports to the United States from the plant.9
In 2014, in a setback to the country’s largest drug maker Sun Pharmaceuticals, the US
FDA issued an “import alert” for all products manufactured at its cephalosporin
facility located at Karkhadi, Gujarat. The company manufactures active pharmaceutical
ingredients (API) and formulations in this unit. An “import alert” results in detention
without physical examination of drugs from firms that have not met “good
manufacturing practices”. According to the company, this alert was issued by the US
FDA as a follow-up to the last inspection of the facility, during which some non-
compliance of current good manufacturing practice (cGMP) regulations was
identified.10

In 2015, U.S. regulator the Food and Drug Administration banned imports from a
Madhya Pradesh manufacturing plant of generic drug maker Ipca Laboratories Ltd,
citing violations of standard production practices. Ipca suspended shipments to the
United States from the plant at Ratlam in Madhya Pradesh that makes drug ingredients,
after the FDA outlined half a dozen violations, including data integrity issues.11
OBJECTIVES AND PLAN OF WORK
RATIONALE:-
In the first place, 'regulation' is the jurisdiction of human and communal conduct by dint
of rules and precincts. The expression 'regulation' has not been quite novel to industries
like pharmaceuticals and biotechnology. The code of practice and laws that preside over
the pharma business were taken on board in interest of shielding the consuming
populace by struggling to supply drugs of uniform or reliable quality, efficacy and
safety. Interestingly, the prominence of the regulation and regulatory affairs
professional are the intention of this article.

Industries like pharma, biologics, food and medical equipment can be uncertain if the
new products and methods are not tested and checked for functionality with great
vigilance before being publicised. The first and foremost factor for the pharma sector
has been always in the time and occupied by the drug candidate to see the light of the
day which is very in-dispensable for the product's success and for the pharma
companies. Therefore, effective administration and superintendence of regulatory
affairs actions plays a crucial job towards economy of the corporation

STUDY OBJECTIVES:-

 To determine whether a regulatory function exists, how it is carried out and What
financial and human resources are available for its implementation
 To identify the strengths and weaknesses of drug regulation
 To propose strategies that can help policy-makers and implementers to improve
drug regulation.
 To map the legal and organizational structures of drug regulation in selected
countries
PLAN OF WORK:-
 Pharmaceutical regulatory affairs and its importance

 Regulatory department and professionals

 Different important regulatory acts

 Regulatory authorities of different countries

 A Comparative study on Drug Regulatory bodies In India, US,

European Union (EU) and Japan

 Explanation of some important terms in regulatory affairs

Pharmaceutical Regulatory Affairs

Historical overview

During 1950s, multiple tragedies i.e. sulfanilamide elixir, vaccine tragedy and
thalidomide tragedy have resulted in substantial increase of legislations for drug
products quality, safety and efficacy. This has also resulted into stricter norms for
Marketing Authorization (MA) and Good Manufacturing Practices (GMPs).

 AN OUTLOOK OF HISTORICAL DEVELOPMENT OF

PHARMACEUTICAL INDUSTRIES AND DRUG
REGULATORY AFFAIRS IN USA, EUROPE AND INDIA:-

UNITED STATE OF AMERICA

During the early Eighteenth century, chemical manufacturing factories had started
establishing and the first large scale manufacturing of glycerine started during 1818-
1840. However, with regard to medicines, it was being compounded by Pharmacists
and Doctors at Pharmacy laboratories. Crude drugs i.e. opium were extracted from
natural plants by compounding pharmacists and progressed further for identifying and
isolating active ingredients from the crude drug. In the USA, the root of modern
pharmaceutical industry was borne during Mexican- American war 1846-1848. The
American troops had suffered due to import of spurious medication for Malaria,
Cholera, Dysentery, Yellow Fever and that had brought federal government into action
for creation of Custom Laboratories. The first law which controlled import of medicines
was Import Drugs Act of 1848. As per this law, it was mandatory to inspect imported
drugs for quality and purity at the entry of port. To define the quality and purity of drug,
federal government recognized United States Pharmacopoeia (USP) as an official
compendium. Note that though United States Pharmacopoeia Committee (USPC) was
established in 1820, it was non- government body till Import Drugs Act of 1848. It was
formed with the objective of creating system for standards, quality control and national
formulary. At the start of the nineteenth century, new legislations for medicines control
started coming into effect
due to multiple tragedies worldwide. This was the era when ancient traditions of
manufacturing and distribution of drugs evolved into the modern highly organized
pharmaceutical industry and controlled system of Drug Regulatory Affairs (DRA).
Almost five decades after issuance of Import Drugs Act of 1848, vaccines tragedy
happened in 1901. During this era, City and State Health Departments use to maintain
stables and vaccine preparation facilities unlike the private industry today. Legislations
mandating exclusive manufacturing facility for vaccines enacted post two events of
death due to immunization failure. The diphtheria antitoxin developed by City Health
Department of St. Louis was contaminated by tetanus causing bacteria. This was ended
up with the death of 14 children in November 1901. Simultaneously, smallpox vaccine
administered was found contaminated and resulted into nine more death in Camden,
New Jersey.

The Biologics Control Act of 1902 was the result of the vaccine tragedy. This
legislation mandated manufacturing and distribution licensing of biological products i.e.
serum, vaccine, toxin, viruses as well as defined labelling in terms of manufacturer’s
name, address, license number, identification of product and expiry date. Proceeding
further from Import Drugs Act of 1848 to The Biologics Control Act of 1902, federal
government took steps for controlling adulteration or misbranding of foods, drugs,
medicines, liquors. This law prohibited interstate transportation of adulterated food and
drugs. With this law toxic colours and preservatives like borax, sulphuric acid,
formaldehyde, copper and sulphate were banned for usage in food and drugs. The Food
and Drugs Act of 1906 is best known as Wiley Act, named by Dr. Harvey W. Wiley.
This law made mandatory labelling of ingredients and its content for drugs i.e. alcohol,
cocaine, heroin, morphine, opium. This was the first wide ranging, national legislation
on food and medicines safety.

The Federal Food and Drugs Act 1906 was starting point for eventual creation of Food
and Drug Administration (FDA). Originally The Bureau of Chemistry was used to
regulate food safety, however in 1927, it was reorganized into the Bureau of Chemistry
and Soils and Food, Drug and Insecticide Administration. In 1930, the current Food and
Drug Administration (FDA) came into effect after shortening of earlier organization.
Since the root of FDA was born in 1906, FDA still celebrates 1906 as its establishment
year.
From the above act, regulatory control on food and drug has increased drastically.
However Sulfanilamide Elixir tragedy raised concern about the safety of drug products.
In 1938, more than 100 people were died due to diethylene glycol (highly toxic solvent)
utilised for mixing Sulfanilamide drug. Consequently, the law was enacted as Food,
Drug and Cosmetic Act of 1938 to oversee safety of medicine. With this law, pre-
marketing approval of all new drugs was made mandatory and proof for scientific
safety study was asked by FDA. This law also mandated the directions for safe use.
Raising the bar of regulation, federal government issued a law for categorising
medicines as Over-The-Counter (OTC) drugs and Prescription drugs which was not in
place earlier. As per this law, medicines for minor ailments i.e. indigestion, headache
can be fall under OTC drugs and freely sold at pharmacy store without prescription.
Major ailments drugs are “Prescription Only (RX)” and unsafe for self -medication. It
was mandated to put statement a labelling as “Caution- Federal Law prohibits
dispensing without a prescription”. This law was known as Durham-Humphrey
Amendment of 1951, best known as Prescription Amendment Act of 1951.

Milestone changes happened on the basis of Kefauver-Harris Drug Amendments 1962.

This was the after effect of Thalidomide tragedy in Western Europe. As per this law,
new drugs were required to be supported with efficacy as well as greater safety data,
Good Manufacturing Practices (GMPs) and prior Marketing Authorization Approval
was mandated by FDA in these amendments. Drug regulations evolved rampantly in
last five decades and many laws came into effect which resulted into organized
regulatory structure of FDA. The agency grew from single chemist from United Stated
Agriculture Department (USAD) to approximately 9100employees of varied category
i.e. physicians, pharmacologists, chemists, microbiologists, pharmacists, veterinarian
and lawyers. Currently, agency is responsible for protecting the public health by
assuring the safety, effectiveness and security of human and veterinary drugs. It
regulates over 1 trillion dollars worth of products in New Human Drug, Biologics,
Biologics, Complex Medical Devices, Food and Colour Additives, Infant formulas and
Animal Drugs.
EUROPEAN UNION

In European Countries, the healthcare regulations have developed with main objective
of keeping unsafe products out of marketplace. In addition to Quality, Safety and
Efficacy, few other factors were responsible for well defined legislation as well as
highly advanced pharmaceutical industry.

 Ethical considerations: To avoid unethical and unsafe clinical trials and have safe
and proper treatment of human subjects, the Helsinki Declaration has been set in
1964.
 Economic issues: First health insurance system was developed in later half of 20th
century. This has resulted in to pricing transparency due to the fact that cost of
medicines was transferred from customer to private and public health insurance
system.
 Unsafe products usage: In European Countries, major revolution of drug
regulations started post Thalidomide tragedy. In late 1950s, a German company was
marketing new sedative Pills throughout Europe, that supposedly helped reduced
nausea in pregnant women. While taking this drug during early pregnancy, it created
teratogenic effect which resulted into birth defects in almost 10000 children. The
babies born to women in Germany and England were without hands, feet, toes or
fingers like flippers growing out of their shoulders and trunk.

Until Thalidomide tragedy, the drugs were being sold by notification to health
authority and NO safety, efficacy or quality data were required to be submitted prior
marketing. However, this has changed with the formation of European Economic
Commission (EEC) in 1957 (Currently known as European Union-EU). The first
directive passed by European Economic Commission was 65/65/EEC mandating that
no medicines can be marketed in European Communities until and unless it is not
approved by at least one competent authority within Europe. The objective of this
legislation was to have standard common marketing approval for medicines process
within European Economic Commission. At the same time, few more directives
specific to the category of products i.e. radiopharmaceuticals, immunological and
homeopathic medicines as well as classification, labelling and promotion directives
were came into effect. Early 1990s in UK, Creuthfeldt-Jacob disease cases were
started increasing. This is a human equivalent Bovine Spongiform Encephalopathy
 (BSE), commonly known as “mad cow disease”. It was suspected that this disease
was due to consumption of Bovine Spongiform Encephalopathy (BSE) infected beef.
Based on this incidence, the legislation pertaining to Bovine Spongiform
Encephalopathy (BSE) and Transmissible Spongiform Encephalopathy(TSE) free
use of materials have come in to place. It is applicable to ingredients derived from
bovine materials i.e. lactose, magnesium stearate, gelatin.

 Free availability of information: Positive and negative news/information about

medicine is available almost to everyone due to wide spread use of media and World
Wide Web (internet) network. To ensure public’s confidence in healthcare system,
regulations pertaining to quality, safety, efficacy and clear instructions for use came
into effect.
 Products and technology innovation: Development of new products such as
biologics, blood and blood related products, and in-vitro diagnostics needed new
legislations. It has led to the development of “concertation procedure” in 1987,
where member states agreed to assess common Marketing Authorization Application
(MAA).
 Demands for products safety: Regulatory authority demands safety data to support
Marketing Authorization (MA) as well as monitoring of safety data throughout the
products post authorization cycle. New legislations have started coming in place due
to public demand of improved quality of life as well as improved survival rate and
longevity.
 Changes in market structure: Healthcare regulations were required due to creation
of single EU market by removing trade barrier. In this scenario, regulatory
framework was varied from one country to another. Hence common regulatory
framework was required. Since the market was open, the quality concern for
imported products was arise and led to the development of new regulations.
INDIA

The drug industry in India was at very primitive stage till 20th Century. Most of the
drugs were imported from foreign countries. Post First World War, the demand for
drugs had increased tremendously and that led to the cheap & substandard drugs into
the market, as like in USA post Mexican American war.12

a) 1900-1960:- To control cheap drugs in market, Government passed the Poisons Act
1919. This Act regulates possession of substance or sale of substances as specified as
poison. It also specifies the safe custody of the poisons, labelling and packaging of
poisons, maximum quantity to be sold and inspection as well as examination of the
poison sold by vendor during the year. The Poisons Act was followed by The
Dangerous Drugs Act 1930. This act regulates the opium plant cultivation, manufacture
and possession of opium, its import, export, tranship and sell of opium. The Narcotics
and Psychotropic Substances Act was passed in 1985 which revoked the Dangerous
Drugs Act 1930 and Opium Act, 1878.

 Following acts & rules were passed during this era:

• Drugs and Cosmetics Act, 1940: Regulate the import, manufacture, distribute and
sale of drugs. This act covers allopathic, homeopathic, Unani and Sidha drugs.

• Drugs and Cosmetics Rules, 1945: The rules under the Drugs and Cosmetics Act
regulate only manufacture of Ayurvedic drugs for sale, and not for consumption, use
or possession.

• Pharmacy Act, 1948: This law was amended lastly in 1986 and it regulates the
pharmacy profession of India.

• Drugs and Magic Remedies (Objectionable Advertisements) Rules, 1955: This

rules control the drug advertisement in India.

• Drugs Prices Control Order, 1955 (DPCO) (under the essential commodities
Act): DPCO was further amended in 1995. Under this rule, government may review
and fix maximum sale price for bulk drugs as well as formulation.

b) 1960-1970:- The market share was dominated by multinational companies and

very few Indian manufacturers were present. The Indian Pharmaceutical industry
was in an early stage of growth. Focus for pure research and development was very
little due to lack of patent protection. Due to very high import dependency on drugs,
the cost of drugs was very high as well as market availability was comparatively
low.

c) 1970-1980:- Government took control for the medicines regulation and issued
few acts and rules.

• Indian Patent Act 1970: It serves as the basis for patent protection in India. Based
on this, only process and method of manufacture of Drug substance was allowed to
get the patent. Product patent was not allowed under this act. Indian Patent Act of
1970 came into force from April 20, 1972. This new act replaced the Indian Patents
and Designs Act of 1911.

• Drug prices capped: Drug Prices Control Order (DPCO) was introduced to
control the high price against consumers.

• Local companies begin to make an impact: Since the product patent was allowed
by Indian Patent Act 1970; local companies began manufacturing products/ drugs
using different manufacturing process by reverse engineering. Due to this new drugs
were available cheaply as well as many more substitute drugs were available in the
market against costly imported new drugs. This has resulted in 1) increase the
exports to countries like Russia, Africa, China, and South America. 2) Export of
Bulk drug post patent expiry.

d) 1980-1990:- The industry has started investing in API process development and
created production infrastructure. Government has also issued export incentives. The
Narcotic Drugs and Psychotropic Substances Act, 1985 was issued which regulates
the operation of narcotic drugs and substances.

d) 1980-1990: - The industry has started investing in API process development and
created production infrastructure. Government has also issued export incentives. The
Narcotic Drugs and Psychotropic Substances Act, 1985 was issued which regulates
the operation of narcotic drugs and substances.

e) 1990-2000:- The pharmaceutical industry has observed a rapid expansion of

domestic market and during same era globalisation happened. The companies have
entered into research activity. India joined Paris Cooperation Treaty (PCT) in 1999
and implemented product patent effective from Jan 1, 2005.
f) 2000-2010:- This period is considered to be the Innovation and Research era.
During these years, innovative research activity, patenting of the drugs formula,
process, indication as well as merger of companies was started.

• Patent Amendment Act 2005: With this act, provision for Black Box Application
made, as per that if patent application is filed before Jan 1, 2005, then under the
transit provision of Trade Related aspects of Intellectual Property Rights (TRIPS),
manufacturer can market this product post 2005 without infringing product patent, if
manufacturer has made significant investment in manufacturing of the product,
produced and marketed on or before Jan 1, 2005.

• Compulsory Licenses: Such licenses can be granted for manufacture and export of
the drug products “to any country having insufficient or no manufacturing capacity,
for the said product, to address public health problems”. Herbal preparations having
medicinal values can be patented under new amended law. Major regulatory changes
in terms of marketing authorization process as well guidelines have come into effect.
Few to name are as below:

•Drugs and Cosmetics (First Amendment) Rules, 2011: it mandates registration

of Clinical Research Organization (CRO) for conducting Clinical Trials (CT).
Schedule Y1 suggests requirements and guidelines for registration of Clinical
Research Organizations.

•Clinical Trial Registry: India (CTRI): It has been set up by the ICMR’s (Indian
Council of Medical Research) National Institute of Medical Statistics (NIMS). India
has developed on-line registry system and mandated registration of CRO before the
enrolment of first patient for clinical trials. CRO needs to disclose mandatory items
as mentioned under WHO International Clinical Trials Registry Platform (ICTRP)
dataset.

• Pharmacovigilance Programme of India (PvPI): The Central Drugs Standard

Control Organization (CDSCO) has launched Pharmacovigilance programme to
assure drugs safety to Indian patients. This will help monitoring adverse drug
reactions to Indian patients, as well as monitoring of benefit-risk ratio.

•Guidance documents: CDSCO has issued guidance for Industry for Fixed Dose
Combinations (FDCs) registration as well as Guidance for preparation of Common
Technical Document for Import/manufacture and Marketing Approval of New drugs
for Human Use (New Drug Application-NDA).

With this CDSCO has implemented system for preliminary scrutiny at the time of
application receipt for marketing approval of Fixed Dose Combinations (FDCs).
DRUG REGULATORY AFFAIRS

Drugs play an important role in the health of both people and the economy of a country.
People and Governments willing to spend money on drugs for many reasons so, it must
be safe, effective and good quality and used appropriately. This means, in turn, that
development, production, importation, exportation and subsequent distribution of drugs
must be regulated to ensure that they meet prescribed standards. Therefore, effective
drug regulation is required to ensure the safety, efficacy and quality of drugs as well as
accuracy and appropriateness of the drug information available to the public.

Drug Regulatory Affairs is a function which regulates the pharmaceutical science in

order to facilitate trade / business in and outside the country of origin for public interest
. Legislations for marketing authorization as well as standards and quality of drugs are
becoming more and more demanding and complex. Unlike earlier days, drugs are being
developed for specific market keeping regulations of that country or region in mind.
Without fulfilling requirements of law of land, it is practically impossible to have drug
products in market. It is not stopping till initial marketing approval of the product but it
goes beyond that and demands management of approval by submitting post marketing
surveillance data, variation application and renewal during the approval life cycle of
product.

Due to rapid increase in laws, regulations and guidelines for reporting safety, efficacy
and quality of new medicinal products, necessity for expert regulatory professional
arises tremendously. None of the drug manufacturing / marketing units are able to
launch drug in market until and unless respective health authority
(national/international) give green signal in writing.

Almost two decades before, drug regulatory affairs was least known/ needed by
pharmaceutical industry. It was in very nascent stage where registration executives were
working under export department12.

However, the situation has changed drastically where fully fledged Global Regulatory
Affairs department become mandatory to define drug development, approval and
marketing strategy. Hence, the scope of Drug regulatory affairs has become vast and
experts are needed in health authorities and pharmaceutical industry at various levels
and departments.
Different regions have come together to form the Union so as to have harmonized
regulatory requirements for particular regions and have same quality drugs available for
all patients. i.e European Union, Gulf Co-Operative Countries (GCC), Association of
South East Asian Nations (ASEAN). It is very difficult to segregate the markets like
regulated, semi regulated or less regulated since the technical requirements for all
markets are more or less same as well as the drug approval period is 18-24 months for
majority of the markets. At the same time, the regulation pertaining to
pharmcovigilance requirements mandates companies to monitor new drugs safety
aspects throughout the life cycle of product. In this scenario, the role of regulatory
expert is very critical and important for deciding the entry strategy into various national
and international markets.

Regulatory Affairs is a unique mix-up of science and management to achieve a

commercially important goal within a drug-Development organization. It touches
everything relating to drugs from the earliest non-clinical studies, through development,
into routine manufacture and marketing. It can add significant impact for patients and
drug companies. It is one of the dynamic and challenging Profession which helps to
protect public health by constant monitoring and controlling the safety and efficacy of
Pharamaceuticals. Regulatory Affairs in the Pharma industry may be defined as "The
interface between the pharmaceutical company and the regulatory agencies across the
world.”1
 Importance of regulatory affairs :-

In today’s competitive environment the reduction of the time taken to reach the market
is critical to a product’s and hence the company’s success. The proper conduct of its
Regulatory Affairs activities is therefore of considerable economic importance for the
company. Inadequate reporting of data may prevent a timely positive evaluation of a
marketing application. A new drug may have cost many millions of Euros or dollars,
pounds, to develop and even a three- month delay in bringing it to the market has
considerable financial considerations. Even worse, failures to fully report all the
available data or the release of product bearing incorrect labelling, may easily result in
the need for a product re-call . Either occurrence may lead to the loss of several millions
of units of sales, not to mention the resulting reduction in confidence of the investors,
health professionals and patients. The Regulatory Affairs department is very often the
first point of contact between the government authorities and the company. The
attitudes and actions of the Regulatory Affairs professionals will condition the
perceptions of the government officials to the company –for better, or for worse!
Officials respond much better to a company whose representatives are scientifically
accurate and knowledgeable than to one in which these qualities are absent.4 The
importance of the Regulatory Affairs function is such that senior Regulatory Affairs
professionals are increasingly being appointed to boardroom positions, where they can
advise upon and further influence the strategic decisions of their companies.13
REGULATORY DEPARTMENT AND PROFESSIONALS

Today most companies, whether they are major multinational pharmaceutical

corporations or small medium enterprises, innovate biotechnology companies, they all
have specialist department of Regulatory affairs. Almost every company has this
regulatory department to keep track on the legislations of countries where companies
wish to market their product. This track includes collection and analysis of legal As
well as scientific requirement for particular country to obtain and maintain marketing
authorizations of health care products. Regulatory Affairs bring about a variety of
disciplines and job responsibilities, which starts during the product development, its
manufacture and continue till the product is widely available for use.

This department is responsible for knowing the regulatory requirements for getting new
products approved. They know what commitments the company has made to the
regulatory agencies where the product has been approved. They also submit annual
reports and supplements to the agencies. Regulatory Affairs typically communicates
with one of the Centers (e.g., Center for Drug Evaluation and Research) at the FDA
headquarters, rather than the FDA local district offices. Gimps do not directly apply to
Regulatory Affairs; however, they must understand and evaluate changes to drug
manufacturing and testing activities to determine if and when the FDA must be notified.
The Regulatory Affairs department will take part in the development of the product
marketing concepts and is usually required to approve packaging and advertising before
it is used commercially. Many companies operating in the high-technology health-care
and related industries operate on a multinational basis and are very significant
exporters. Their Regulatory Affairs departments must be aware of the regulatory
requirements in all the company’s export markets.

Regulatory professionals plays a very important role in coordinating scientific

endeavours with regulatory demands throughout the life of the product and helps the
companies meet all the regulations and guidelines and in turn maximize the profits.14
hence, a sound regulatory professionals with a right first time approach is necessity of
all pharmaceutical companies.

As RA Professionals, they are often responsible for tracking changes in regulatory

guidelines as they may occur.in order to do this, they must take the initiative to keep
current on all the changes in regulations. Changes must be interpreted and
communicated to appropriate people in the company, including management.
Management then determine what changes in company procedures and process may be
required by stay in compliance.1

 ROLES OF REGULATORY AFFAIRS PROFESSIONALS :-

a) Evaluation of MAA (Marketing Authorization Application)

1. Evaluation of Marketing Authorization Application i.e. New Drugs Application,

New Biologics Application, Medical Device and Cosmetics application, Generic
Application, Clinical Trial Application, Variation Application, Drug Master Files for
API, Excipients and Packaging Materials, Site Master File for GMP inspection

2. Issuance of Evaluation comments/ Exigencies to Manufacturers

3. Managing variation application, post approval changes and keeping record of annual
update

4. Post Marketing Approval Management

5. Issuance of Marketing Authorization Approval, GMP, and GCP approval certificate

6. Managing MAA On-line and up-gradation towards common technical document

format

b) Input for guidelines and guidance documents

1. Issuance of guidelines & guidance documents for Quality, Safety, Efficacy and
Pricing Control as well as CTD for implementation
2. Collaboration with Global and Regional Harmonization units for exchange of
technical knowledge, developing guidelines as well as allotting mutual recognition
status for technical documents, GMP status and product approval

3. Part of foreign trade delegation to facilitate smooth management of Pharmaceutical

business within countries and minimising barrier by reducing duplicate generation of
Technical data and timeline for evaluation and approval by respecting each other
regulatory framework

c) Inspection

1. Performing GMP Audit for Drug Manufacturing Site, GCP Audit for Clinical Study
Site and Bio-equivalence Centre, and issuing certification confirming approval status

d) Support to Pharmaceutical Manufacturers

1. Supporting Manufacturer in defining drug development pathway during Pre-NDA

meeting and providing comments / confirming development pathway

2. Time to time meeting with pharmaceutical manufacturers association to discuss

ongoing challenges, technical issues, guidelines/ guidance documents discussion and
future development

e) Monitoring of Drug Safety and Efficacy

1. Monitoring Drug Safety by collecting Pharmacovigilance data and reviewing drugs

in markets time to time by reviewing labels and taking appropriate action accordingly

2. Monitoring Clinical Trials as well as approving study results for next phase of study

3. Allowing speedy or fast track designation for essential drug to patient population.
 QUALITIES OF A GOOD RA PROFESSIONAL

 Team player
 Good communication skill
 Ability to work with and respect other disciplines (scientific and non-scientific
 Decisive and diligent
 Negotiating skill
 Good information technology skill
 Commercially aware
 Flexible-always willing to learn
 Analytical Skill- Ability to evaluate the strengths and weakness of the technical and
legal options open to a company
 Authoritative and Creative
 DIFFERENT IMPORTANT REGULATORY ACTS

Most of India's pharmaceutical product policy is governed by the Drugs and Cosmetics
Act (DCA). The DCA was first enacted in 1940 and has been amended many times
since then.

All regulatory aspects related to import, manufacture, sale and advertisements of drugs
in India are covered under three separate enactments, namely, Drugs & Cosmetics Act
1940 and the Drugs & Cosmetics Rules 1945, The Pharmacy Act 1948 and the Drugs
& Magic Remedies (Objectionable Advertisements) Act 1954.

Under the current Indian legal and regulatory regime, the manufacture, sale, import,
exports and clinical research of drugs and cosmetics is governed by the following laws:-

-The Drugs and Cosmetics Act, 1940

-The Pharmacy Act, 1948
-The Drugs and Magic Remedies (Objectionable Advertisement) Act, 1954
-The Narcotic Drugs and Psychotropic Substances Act, 1985
-The Medicinal and Toilet Preparations (Excise Duties) Act, 1956
-The Drugs (Prices Control) Order 1995 (under the Essential Commodities Act).

 Drug & Cosmetic Act

1940 to 1945: India's parliament, under British rule, passed the Drug & Cosmetic Act of
1940, which led to the Drugs & Cosmetics Rules of 1945, the central legislation that
regulates India’s drug and cosmetic import, manufacture, distribution and sale. This
established the Central Drugs Standard Control Organization (CDSCO), and the office
of its leader, the Drugs Controller General (India) (DCGI)15

It contains in detail the regulations divided in different schedules A to Y, Schedule I

and Schedule II. Some very important schedules are as follows:

Schedule M of the Drugs and Cosmetics Act specifies the general and specific
requirements for factory premises and materials, plant and equipment and minimum
recommended areas for basic installation for certain categories of drugs. Part I describes
good manufacturing practices for premises and materials. Part II deals with
requirements of equipments.

Schedule T of the Drugs and Cosmetics Act prescribes Good Manufacturing Practices
(GMP) specifications for manufacture of Ayurvedic, Siddha and Unani medicines. It is
divided in two parts. Part I deals with Good Manufacturing Practices, while Part II deals
with list of machinery, equipment and minimum manufacturing premises required for
their manufacture.

Schedule Y of the Drugs and Cosmetics Act specifies about the requirement and
guidelines on clinical trials for import and manufacture of new drug. Additionally this
act provides for construction and functioning of various regulatory bodies like Drug
Technical Advisory Board, Drug consultative Committee, Central Drugs Laboratory
etc.

 Pharmacy Act 1948

Pharmacy Act was enacted for the regulation of the profession and practice of
pharmacy in the country. The Act has led to the formation of the Pharmacy Council of
India (PCI) which regulates the functioning of pharmacy education institutions through
state pharmacy councils. PCI is also the statutory body to register pharmacy graduates,
thereby turning them eligible for practicing as community pharmacists.

 Drugs & Magic Remedies (Objectionable Advertisements) Act 1954

Drugs and Magic Remedies Act talks about controlling the advertisement of drugs in
certain cases, to prohibit the advertisement for certain purposes of remedies alleged to
possess magic qualities and to provide for matters connected therewith. State drug
regulators are the enforcement agencies of D &MR Act.

 The Narcotic Drugs and Psychotropic Substances Act, 1985:

This is an Act to consolidate and amend the law relating to Narcotic Drugs, to make
stringent provisions for the control and regulation of operations relating to Narcotic
Drugs and Psychotropic Substances and for matters connected therewith.
 The Medicinal and Toilet Preparations (Excise Duties) Act, 1956:

This act lay down the regulations for the levy and collection of duties of excise on
medicinal and toilet preparations containing alcohol. It also specifies the manufacturing
conditions to be maintained for such products.
 REGULATORY AUTHORITIES OF DIFFERENT COUNTRIES

 Regulatory Network:-

Drug Regulatory Affairs regulate pharmaceutical business through designing appropriate

laws (rules) and enforcing the same so that the drugs meeting the highest standards of
Quality are brought into the Global Trade. Rules and regulations are being prepared
considering Global, Regional and National pharmaceutical trade as well as necessity of
the drugs based on patient population.12

Most of the national guidelines for drug development and marketing authorization
application are defined based on Global and Regional Harmonized guidelines.

To understand it better, let’s see

 Global Regulatory Network

 Regional Regulatory Network
 National Regulatory Network

 Global Regulatory Network :-

Global regulatory network are defined by regulatory representative of each country in

the world.

ICH in collaboration with USA, EU and Japan issues Harmonized technical

requirements for manufacturers to follow for MAA in these three regions.

WHO is comprise of balance all countries of world (except USA, EU and Japan) and
prepares harmonized MAA guideline and technical data requirement for registration in
all countries.
 Regional Regulatory Network :-

To facilitate trade within specified regions, countries have come together and form a
common trade association. Regional trade associations define rules and regulations for
common marketing authorisation application as well as technical data requirement for
Pre-marketing authorization

 ASEAN- Association of South East Asian Nations SADC-South African

Development Community
 APEC- Asia Pacific Economic Cooperation
 GCC- Gulf Cooperative Countries
 PANDRH- Pan American Network on Drug Regulatory Harmonization
 EU- European Union

 National Regulatory Network :-

National Government issues mandatory laws based on healthcare status in respective

country and at par with global and regional legislation to regulate healthcare business.

Few examples are USFDA, CDSCO, MHRA, TGA etc.

GLOBAL REGINOL

ICH &WHO EU, APEC, ASEAN,

GCC, PANDRH, SADC

NATIONAL

USFDA, CDSCO, MHRA,

TGA

Worldwide Regulatory Network

 Drug Regulatory Bodies: -

The field of Drug regulatory science, both pharmaceutical and biopharmaceutical is

emerging rapidly. The drug regulatory authorities as well as evaluation agencies either
governmental or private are widening their vision emphasizing more and more on
delivering the public with drug products of high quality, efficacy and safety. A range of
regulatory agency and industry initiatives, including better quality dossiers, has
contributed to improving the licensing dossier review process both for
biopharmaceuticals and for pharmaceuticals.16

Regulations and derived procedures have increased globally and this can be partly
explained by the great progress of science in the last 10 years.17 The level of regulations
varies significantly in different countries. The developed countries have set up stringent
laws and regulations governing the flow of pharmaceuticals within their territories
while developing countries offer a level of relaxation to back their domestic market and
encourage pharmaceutical growth. In poorer countries regulatory capture is prevalent as
government has little capacity18. No doubt such countries also keep their vision open for
moving parallel to the way by updating their existing system of evaluation and
approvals.

The regulations to control the purchases by internet are also an area of consideration.
The harmonization of regulation is emerging area providing more encouragement for
industries. International harmonization such as ICH as well as regional harmonization
such as ASEAN regulations demonstrates the cooperation and willingness of new world
for providing the public best medical care. Many countries regulate the price that
consumers pay for pharmaceuticals. The regulated price is normally well below the
market price.19 Even it has been observed that countries with strict price regulation
(France, Italy, and Japan) have lower prices than the less regulated markets of the
United States and the United Kingdom.20

International Conference on Harmonization of Technical Requirements for the

Registration of Pharmaceuticals for Human Use (ICH) is a collaborative initiative
between the EU, Japan and the United States with observers from WHO, EFTA
(European free trade area) and Canada. ICH harmonization focuses primarily on
technical requirements for new, innovative medicines. However, countries with limited
resources are mostly generic markets and may have difficulties of implementing
numerous sophisticated ICH standards. Pharmaceutical regulatory harmonization
facilitates the availability of safe, effective and good quality pharmaceuticals. World
Health Organization (WHO) supports harmonization on national, regional, inter-
regional and international levels.21 WHO‘s role in drug regulation is fourfold. First,
issuing the necessary norms and standards through its Expert Committees. Second,
supporting regulatory capacity building leading to implementation of drug regulation on
national level and its harmonization on regional and Global level. Third, in selected
areas of essential products, ensuring the quality, safety and efficacy of limited high
public health value essential medicines and vaccines through ―prequalification.
Fourth, WHO plays a very important role in facilitating exchange of regulatory
information.22
 Every country has its own regulatory authority, which is responsible to enforce the
rules and regulations and issue guidelines for drug development, licensing,
registration, manufacturing, marketing and labelling of pharmaceutical products.

 COUNTRYNAME OF REGULATORY AUTHORITY

1. USA Food and Drug Administration (FDA)

2. UK Medicines and Healthcare Products

Regulatory Agency (MHRA)

3. Australia Therapeutic Goods Administration (TGA)

4. India Central Drug Standard Control Organization

(CDSCO)

5. Canada Health Canada

6. Europe European Medicines Agency (EMEA)

7. Denmark Danish Medicines Agency

8. Costa Rica Ministry of Health

9. New Zealand Medsafe - Medicines and Medical Devices

Safety Authority
 10. Sweden Medical Products Agency (MPA)

11. Netherlands Medicines Evaluation Board

12. Ireland Irish Medicines Board

13. Italy Italian Pharmaceutical Agency

14. Nigeria National Agency for Food and Drug

Administration and Control (NAFDAC)

15. Ukraine Ministry of Health

16. Singapore Centre for Pharmaceutical Administration

Health Sciences Authority

17. Hong Kong Department of Health: Pharmaceutical

Services

18. Paraguay Ministry of Health

19. Sweden Medical Products Agency (MPA)

20. Thailand Ministry of Public Health

21. China State Food and Drug Administration

22. Germany Federal Institute for Drugs and Medical

Devices

23. Malaysia National Pharmaceutical Control

Bureau, Ministry of Health

24. Pakistan Drugs Control Organization, Ministry of

Health

25. South Africa Medicines Control Council

26. Sri Lanka SPC, Ministry of Health

27. Switzerland Swissmedic , Swiss Agency for

Therapeutic Products

28. Uganda Uganda National Council for Science and

Technology (UNCST)
 29. Brazil Agencia Nacional de Vigiloncia Sanitaria

(ANVISA

30. Japan Ministry of Health, Labour &

Welfare (MHLW)

 INTERNATIONAL ORGANIZATIONS :-

 World Health Organization (WHO)

 Pan American Health Organization (PAHO)
 World Trade Organization (WTO)
 International Conference on Harmonization (ICH)
 World Intellectual Property Organization (WIPO)
 A COMPARATIVE STUDY ON DRUG REGULATORY BODIES IN
INDIA,US, EUROPEAN UNION (EU), AND JAPAN:-

 INDIA

India’s federal regulatory structure has been plagued by some of the classic problems of
developing countries, including red tape and corruption. India has a federal form of
government and the medical regulatory structure is divided between national and state
authorities.23 The principal national drug authority based in New Delhi is the Central
Drug Standards Control Organization (CDSCO). CDSCO is controlled by the Drug
Controller General India (DCGI). There are also 35 state-level Food and Drug
Administrations, one for each of India’s states and territories.24

The DCGI registers all imported drugs, new drugs, biological and drugs in selected
categories. It also has responsibility for medical devices, clinical trials and quality
standards.25 The state FDAs register all other products, accredit manufacturing plants,
and conduct the bulk of quality monitoring and inspections.

The Ministry of Health & Family Welfare and the Ministry of Chemicals and Fertilisers
of the Government of India play a major role in regulating the pharmaceutical sector in
the country. In India, state authorities are responsible for licensing a drug maker’s
research and manufacturing facilities. But the federal Central Drugs Standard Control
Organization (CDSCO) and the drugs controller general of India (DCGI) have been
responsible for approvals of preclinical and clinical trials, new drug applications, and
the importation of drugs from abroad. But, problem lies in state authorities. India’s state
drug regulatory authorities (DRAs) often lack the staff to monitor their work. This
staffing problem, combined with their relatively poor technical experience in such
issues worsens the problem. The DRAs have been susceptible to influence by local
political authorities, and thus unable to prevent illegal drug manufacturing and
marketing activities.26 Manufacturers that set up operation in states where regulatory
oversight and enforcement are weakest can then market their drugs in the rest of the
country.
 National government

Ministry of health and Ministry of chemical and

Family welfare fertiliser

Central drugs National

standard control pharmaceutical
organization pricing authority

Drugs controller Department of

general of India chemicals &
petrochemicals

Regulatory bodies in India

 Ministry of Health & Family Welfare (Department of

Health):

- Central Drugs Standard Control Organization (CDSCO)

As an agency of the Department of Health, the CDSCO works both at the Central and
the State level and is responsible for ensuring safety, efficacy and quality of drugs
supplied to the public. The agency performs the above mentioned functions with the
Drugs Controller General of India (DCGI) as the executive head.

- Drugs Controller General of India (DCGI):

The DCGI is an apex body in the pharmaceutical industry governing issues such as
Approval/NOC for Clinical trials, Bioequivalence studies and Marketing permission in
India. Along with it is also responsible for approval for Test License, Testing of Drugs,
Registration for Import and Licensing, Export NOCs- Biological samples, Drugs, etc.,
Licensing of Blood Banks, r-DNA products, Vaccines and Medical Device,
Amendment in Drugs And Cosmetics Acts and Rules from time to time

 Ministry of Chemicals and Fertilisers:

The Ministry of Chemicals & Fertilizers constitutes bodies such as the Department of
Chemicals & Petrochemicals (DCP) and the National Pharmaceutical Pricing Authority
(NPPA). These departments are entrusted with the responsibility of policy making,
planning, development and regulations relating to Chemicals, Petrochemicals and
Pharmaceuticals.

 UNITED STATES (US)

In the US, drugs are regulated by the Food and Drug Administration (FDA). Every
new drug must receive marketing approval from the FDA prior to commercialization.
The US drug approval process is considered to be one of the most stringent in the world.
From the perspective of all consumers, the U.S. constitutes about 40 percent of the world
pharmaceutical market. As a result, its pricing and regulatory policies materially
influence world demand and hence the incentives of pharmaceutical firms to innovate.27
The development and evolution of US-FDA was not smooth, rather various public health
crisis and tragedies which took place in past century forced the governments to built
strong laws and respective amendments in FDA regulations and setting stringent criteria
as well as requirements for moving products in market.

In 1862 Abraham Lincoln appointed a chemist Charles M. Wetherill to the Department

of Agriculture for detection of food adulterants. Other agricultural chemists also hired
to form division of chemistry. In 1901 the Division of Chemistry was renamed as
Bureau of Chemistry. The administration of Pure Food and Drug Act was charged to
Bureau of Chemistry which was reorganized in two entities in 1927 and the regulatory
function became the responsibility of Food, Drug and Insecticide Administration
(FDIA). In 1930 this name was shortened to Food and Drug administration (FDA).
Walter G. Campbell was the first commissioner of agency under the name FDIA and
FDA.28 Food Drug and Cosmetic Act was passed in 1938 after the occurrence of Elixir
sulphonamide crisis. Until this point FDA had been under Department of Agriculture. It
was in 1940 when the agency was moved to new federal security agency. In 1953 it was
transferred to Department of Health Education and Welfare (HEW). It became part of
Public Health Services within the HEW. In 1980 the education functions from HEW
and rename it as Department of Health and Human Resources. FDA was officially
established in 1988 as agency of US Department of Health and Human Services.29

FDA is organized into 8 centers each having assigned responsibilities and functions.29

1. CDER (Center for Drugs Evaluation and Research) is mainly concerned with safety
and effectiveness of prescription and OTC drugs.

2. CBER (Center for Biologics Evaluation and Research) evaluates the

biotechnological and biologics including Blood products, vaccines, Protein based
products, Xeno-transplantation, transgenic plants and animals, genomics, proteomics
and bioinformatics. 1986 Childhood Vaccine Act was result of CBER work.

3. Center for food safety and applied nutrition (CFSAN) have the responsibility to
evaluate safety of food consumed within US. It Enforces the 1994 Dietary and
Supplemental Health and Education Act. The Regulations are not as close as Food,
Drug, and Cosmetic Act.

4. Center for Devices and Radiological Health.

5. Center for veterinary medicines is engaged in evaluating the safety of food as well as
drugs used for animals.

6. National center for toxicological research keep check on toxicity and contamination
of drugs, pharmaceuticals and food. It also keeps an account on terrorism biomarkers.

7. Office of Commissioner.

8. Office of Regulatory Affair.

 EUROPEAN UNION (EU)

In the EU, due to the Single European Market legislation, the European Medicines
Evaluation Agency (EMEA) has the power to centrally approve medicines, with one
single license.30

The European medicines evaluation agency is purely concerned for scientific evaluation
of medicines intended to be used in EU.31 The Agency gives scientific advice and other
assistance to companies for the development of new medicines. It publishes guidelines
on quality-, safety- and efficacy-testing requirements. The medicines that fall within the
scope of the centralised procedure are evaluated by agency but in case of any kind of
disagreement between member states regarding authorization of medicine, they can
refer those medicines to EMEA for evaluation. Another fact is very much true that
agency is not involved in any kind of research, medicine development or in establishing
ethical codes.

The scientific committees are responsible for the scientific evaluation of marketing-
authorisation application dossiers submitted by pharmaceutical companies. There are 6
scientific committees the professionals of which are nominated from member states.32
The committees are as follow:

 Committee for Medicinal Products for Human Use (CHMP)

 Committee for Medicinal Products for Veterinary Use (CVMP)
 Committee for Orphan Medicinal Products (COMP)
 Committee on Herbal Medicinal Products (HMPC)
 Paediatric Committee (PDCO)
 Committee for Advanced Therapies (CAT)

CHMP was first known as CPMP (Committee for Proprietary Medicinal Products)
which after 2004 was given the present form. It deals in the marketing procedures for
medicines for human use in the European Union. Assessments conducted by the CHMP
are based on purely scientific criteria and determine whether or not the medicines
concerned meet the necessary quality, safety and efficacy requirements in accordance to
Directive 2001/83/EC. The CHMP can issue an ‘Urgent Safety Restriction’ (USR) to
inform healthcare professionals about changes as to how or in what circumstances the
medication may be used. The agency aids in the preparation of scientific and regulatory
guidelines for the pharmaceuticals industry. Another important task performed by
agency is close cooperation with international partners on the harmonisation of
regulatory requirements for medicines

CVMP (Committee for Medicinal Products for Veterinary Use) was established by
Regulation (EC) No 726/2004. The prime act of CVMP is in the marketing procedures
for veterinary medicines in the European Union. A core activity of the CVMP is the
establishment of MRLs: the 'Maximum Residue Limits' of veterinary medicines
permissible in food produced by or from animals for human consumption, including
dairy products, meat, honey etc. These limits must be established for all
pharmacologically active substances contained in a medicine before it can be granted a
marketing authorisation. CVMP also involves itself in the preparation of scientific and
regulatory guidelines for the veterinary pharmaceuticals industry.

COMP (The Committee for Orphan Medicinal Products) advises the European
Commission on the establishment and development of a policy on orphan medicinal
products in the EU, and assists the Commission in drawing up detailed guidelines on
matters relating to orphan medicinal products. The committee reviews the applications
for 'Orphan Medicinal Product Designation' for products. The Orphan drugs are those
which are used for the diagnosis, prevention or treatment of life-threatening or very
serious conditions that affect not more than 5 in 10,000 persons in the European Union.

HMPC (The Committee on Herbal Medicinal Products) is engaged in assisting the

harmonisation of procedures and provisions concerning herbal medicinal products laid
down in EU Member States. Another main task performed by HMPC is establishment
of Community herbal monographs. Prior to 2004 this task was responsibility of CPMP
Working Party on Herbal Medicinal Products. But in September 2004 HMPC was
established in accordance with Regulation (EC) No 726/2004 and Directive
2004/24/EC, which introduced a simplified registration procedure for traditional herbal
medicinal products in EU Member States

PDCO (Paediatric Committee) was established in accordance with the 'Paediatric

Regulation' (Regulation (EC) 1901/2006 as amended). The committee assesses the
content of paediatric investigation plans (PIPs) and adopts opinions on them that the
data have been generated in accordance with an agreed PIP or not.32 This includes
assessing applications for full or partial waivers and assessing applications for deferrals.
It is also notable that PDCO is not responsible for marketing-authorisation applications
for medicines for use in children.33 This remains within the remit of the CHMP.

CAT (Committee for Advanced Therapies) performs the task of preparing the draft
opinion on each ATMP (advanced-therapy medicinal products) application submitted to
the European Medicines Agency, before the Committee for Medicinal Products for
Human Use (CHMP) adopts a final opinion on the granting, variation, suspension or
revocation of a marketing authorisation for the medicine concerned. The committee also
advises the CHMP on any medicinal product which may require, for the evaluation of
its quality, safety or efficacy, expertise in ATMPs. CAT actively participates in Agency
procedures for the certification of quality and non-clinical data for small and medium-
sized enterprises developing advanced-therapy medicinal products.

 JAPAN

Japan is the world‘s second largest pharmaceutical market next to the US occupying
about 11% of global sales and generates 67% of Asia-Pacific market [39]. The
Ministry of Health, Labour, and Welfare (MHLW) is in charge of pharmaceutical
regulatory affairs in Japan. Pharmaceutical and Medical Devices Agency (PMDA)
undertakes main duties and functions of the Ministry and performs the task of approvals
and licensing. PMDA is Japanese counterpart to the FDA and is involved in operational
aspects of drug development. PMDA consists of 22 offices and 2 groups. It has primary
responsibility for administering the approval of new pharmaceutical products and
medical devices in Japan, although final authority to issue approvals still rests with the
Ministry of Health, Labour and Welfare (MHLW).34 The Pharmaceuticals and Medical
Devices Evaluation Center in the National Institute of Health Sciences was established
to strengthen approval reviews. The Pharmaceutical Affairs and Food Sanitation
Council (PAFSC) serves as an advisory body to the MHLW, and reviews and discusses
important pharmaceutical and food sanitation-related matters.

A company wishing to import a pharmaceutical product into Japan or manufacture and

sell a pharmaceutical in Japan must conduct clinical trials in Japan and apply for
approval from the PMDA. This applies even if the drug has already been authorized and
is being sold in one or more foreign countries. In some cases, the PMDA permits
applicants to submit clinical data from overseas, but this depends on the specific drug.
Due to the activity of the International Conference on Harmonization (ICH), data from
clinical trials conducted in foreign countries can be used as a part of clinical data
packages for new drug applications in Japan.35 Average duration of a clinical trial in
Japan is approximately four years, much longer than U.S, France and U.K. Application
forms from both Japanese New Drug Application (J-NDA) and Japanese Abbreviated
New Drug Application (J-ANDA) for approval to market drugs are usually submitted to
the PMDA. When application forms for new drugs are received by the PMDA, an
approval review of the application data is done in consultation with experts from the
PAFSC. PMDA also does the compliance review of GCP/GMP on-site inspection, and
the team prepares a review report. This report then refers to MHLW which evaluates
the application for medical needs, social issues in addition to scientific review and
issues the final decision for approval. In reviews of new drugs prepared from vaccine or
blood, the specifications and test methods are examined by the National Institute of
Health Sciences or by the Infectious Disease Surveillance Center (IDSC) prior to
approval. Applications using the ICH-CTD became obligatory for new products in
applications filed on or after July 1, 2003. In Japan, submission of eCTD is not
obligatory but it is recommended. If the data is being submitted in the form of eCTD as
original then it is no longer necessary to submit a copy of the paper data for approval
applications. For manufacturing facilities located in Japan, the manufacturing license is
generally issued by the governor of the prefecture in which the manufacturing facility is
located. For overseas manufacturing facilities, applications are made directly to the
MHLW. Licensed manufacturing facilities are required to satisfy criteria established by
the MHLW. Pharmaceutical Affairs Law (PAL) enacted in 1943 and has been revised
several times since then. Pharmaceutical Affairs Law (PAL) as revised in 2002 include
the revisions such as a new risk-based classification system for products, adoption of
internationally consistent pre-market submission documents, and a third-party
certification system for low-risk medical devices. The Pharmaceutical Affairs Law has
11 chapters and 91 articles. The Pharmaceutical

Affairs Law specifies that the data submitted to obtain approvals must be obtained and
compiled according to the standards specified in its Article 14, Paragraph 3.
Pharmaceutical Affairs Law (Article 77-(4)-2-1), requires the reporting of adverse drug
reactions and infections by pharmaceutical companies to the PMDA for information
processing. 36
Approval times differ among the US, the EU, and Japan, but the interpretations of such
comparison results always entail some difficulty because of the differences in the
review systems. According to the classification of therapeutic categories commonly
used in Japan, peripheral nervous system drugs (e.g., anesthetics), cardiovascular drugs,
gastric drugs except for peptic ulcer were associated with relatively shorter approval
times. Anti-HIV drugs were approved in exceptionally short periods, showing that the
Japanese government as well as the US FDA handled them differently from other
priority drugs.37 The Japanese Pharmacopoeia, Japanese Pharmaceutical Codex,
Japanese Pharmaceutical Excipients, and other similar standards have been specified as
quality standards. Laws and regulations related to pediatric field does not exist in Japan.
 EXPLANATION OF SOME IMPORTANT TERMS IN REGULATORY
AFFAIRS:
 Investigation new drug application (INDA)

It is an application which is filed with FDA to get approval for legally testing an
experimental drug on human subjects in the USA.38

There are three IND types:

- An Investigator INDA- is submitted by a physician who both initiates and

conducts an investigation, and under whose immediate direction the
investigational drug is administered or dispensed. A physician might submit
a research IND to propose studying an unapproved drug, or an approved
product for a new indication or in a new patient population.

- Emergency use INDA- Allows the FDA to authorize use of an experimental

drug in an emergency situation that does not allow time for submission of an
IND in accordance with 21 CFR, Sec. 312.23 or Sec. 312.34. 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.

- Treatment IND- 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.

There are two IND categories:

-Commercial
-Research (non-commercial)

The IND application must contain information in three broad areas:

-Animal Pharmacology and Toxicology Studies

-Manufacturing Info
-Clinical Protocols and Investigator Information

 New Drug Application (NDA) :

The FDA defines it as "The NDA application is the vehicle through which drug sponsors
formally propose that the FDA approve a new pharmaceutical for sale and marketing in
the U.S. The data gathered during the animal studies and human clinical trials of an
Investigational new drug become part of the NDA."39

The goals of the NDA are to provide enough information to permit FDA reviewer to
reach the following key decisions:

-Whether the drug is safe and effective in its proposed use(s), and whether the benefits
of the drug outweigh the risks.

-Whether the drug's proposed labelling (package insert) is appropriate, and what it
should contain.

-Whether the methods used in manufacturing the drug and the controls used to maintain
the drug's quality are adequate to preserve the drug's identity, strength, quality, and
purity.

In simple terms - "NDA is an application which is filed with the FDA by a pharma
company for getting approval for their newly discovered drug".

 Abbreviated New Drug Application (ANDA):

It is an application for a U.S. generic drug approval for an existing licensed medication
or approved drug.

A generic drug product is one that is comparable to an innovator drug product in dosage
form, strength, Route of administration, quality, performance characteristics and
intended use. All approved products, both innovator and generic, are listed in FDA's
Approved Drug Products with Therapeutic Equivalence Evaluations.

 Marketing authorisation application (MAA):

It is an application (to the relevant authority ) typically the UK's MHRA or the European
Commission's Committee for Medicinal Products for Human Use (CHMP) to market a
drug or medicine.

The U.S. Food and Drug Administration equivalent of marketing authorisation

application (MAA) is a New Drug Application (NDA).

 Active Pharmaceutical Ingredient (API) (or Drug Substance):

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

(medicinal) product and that, when used in the production of a drug, becomes an active
ingredient of the drug product. 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.

 Active Substance Master File (ASMF)/Drug Master File (DMF) :

It is a document containing complete information on an Active Pharmaceutical

Ingredient (API) or finished drug dosage form. It is known as European Drug Master
File (EDMF) or Active Substance Master File (ASMF) and US-Drug Master file (US-
DMF) in Europe and United States respectively.

The DMF contains factual and complete information on a drug product's chemistry,
manufacture, stability, purity, impurity profile, packaging, and the cGMP status of any
human drug product.

 Current good Manufacturing Practice (cGMP) :

These are practices and the systems required to be adapted in pharmaceutical

manufacturing, quality control, quality system covering the manufacture and testing of
pharmaceuticals or drugs including active pharmaceutical ingredients, diagnostics,
foods, pharmaceutical products, and medical devices.

 International Conference on Harmonisation of Technical Requirements for

Registration of Pharmaceuticals for Human Use (ICH):

It is a project that brings together the regulatory authorities of Europe, Japan and the
United States and experts from the pharmaceutical industry in the three regions to
discuss scientific and technical aspects of pharmaceutical product registration.
 Good Clinical Practice (GCP):

It is an international quality standard that is provided by International Conference on

Harmonisation (ICH), that defines standards, which governments can transpose into
regulations for clinical trials involving human subjects.

 Good Laboratory Practice (GLP):

It specifically refers to a quality system of management controls for research laboratories

and organizations to try to ensure the uniformity, consistency, reliability, reproducibility,
quality, and integrity of chemical (including pharmaceuticals) safety and efficacy tests.
CONCLUSION AND SCOPE OF WORK
CONCLUSION:-

Many in the Regulatory Affairs Profession believe the New Approach to regulation will
eventually be adopted for all healthcare products as it represents the best model for
delivering new healthcare advances to market in a reasonable time with acceptable
safety.

Regulatory Affairs department is constantly evolving and growing and is the one which
is least impacted during the Acquisition and Merger, and also during recession.
Regulatory Affairs departments are growing within companies. Due to the changing
resources necessary to fulfill the regulatory requirements, some companies also choose
to outsource or out task regulatory affairs to external service providers.

In today’s competitive environment the reduction of the time taken to reach the market
is critical to a product’s and hence the company’s success. The proper conduct of its
Regulatory Affairs activities is therefore of considerable economic importance for the
company.

SCOPE OF WORK:-

Locally the F.D.A. (Foods & Drugs Control Administration) is the main regulatory
body governing and implementing the rules and regulations for the Drug & Pharma
industry. The F.D.A. has state branches and sub-branches all over the country. With
globalization process reaching out to India, the geographical barriers have become
obsolete. Any country will have to compete and trade globally in order to progress and
survive in the years to come. The major drugs and pharma. Companies have realized
this fact and have stepped into the global area of competitive trade. If an Indian
manufacturer wants to sell his drug or formulation to a foreign country it is mandatory
that he has to fulfill all the statutory requirements laid by the regulatory authorities of
that country. Also, his product needs to be perfectly as per the specifications laid down
by the concerned regulatory authority. Thus, in order to enter into trade with the foreign
countries it is mandatory to get the necessary approvals and sanctions as per the formats
given by local regulatory authorities. E.g. Approvals to be obtained from U.S.F.D.A. for
U.S.A, T.G.A. for Australia & New Zealand, M.C.A and M.C.M. for U.K. & European
countries and ICH guidelines going to be uniform for international levels.
Since, the business involved is worth multibillion dollars; this branch has assumed
tremendous significance and is bound to grow enormously, in the Post-GATT era.
Many big players in the drugs & pharma field has already established separate
Regulatory Affairs Departments in their companies. Regulatory experts are thus in great
demand. Since, the field is highly technical Pharmacy professionals again fit in these
positions.
REFERENCES
 References:-

1. Philip S., Philip A.; The scope of regulatory affairs in the pharmaceutical industry;
Hygeia. J.D .Med; 2010; vol.2(1); 1-6.

2. Kolla C .P., Prabodh M., Rastrapal D., Suthakaran R.; The Purview of Regulatory
Affairs in the Pharmaceutical Industry; Asian Journal of Pharmaceutical Technology &
Innovation;2014; vol.02 (06); 1-6.

3. Douglas J. P., David S.M.; Text book of FDA Regulatory Affairs a Guide for
Prescription Drugs, Medical Devices, and Biologics; 2008; vol.2; 351-368

4. Gopinath E., Bhadauria R.S., Gunjan J., Insha Z.; International Journal of Advanced
Research in Pharmaceutical & Bio Sciences ; 2012; vol.2 (2); 292-301.

5. Kumar S., Panwar R., Singh U.; Regulatory Affairs in the Pharmacy Curriculum
International Journal of Research and Development in Pharmacy and Life Sciences;
2013; Vol.2(6); 690-698
6. Fierce Pharma; FDA halts Ranbaxy India imports; September 17, 2008.

Available at: http://www.fiercepharma.com/story/fda-halts-ranbaxy-india-

imports/2008-09-17; Accessed on 28 April 2015
7. Fierce Pharma; FDA slaps Apotex with import ban; September 9, 2009.
Available at: http://www.fiercepharma.com/story/fda-slaps-apotex-import-ban/2009-09-
09; Accessed on 28 April 2015
8. Business World; Wockhardt Plunges After FDA Ban On Another Plant; 27 Nov,
2013.

Available at: http://www.businessworld.in/news/business/pharma/wockhardt-plunges-

after-fda-ban-on-another-plant/1168724/page-1.html; Accessed on 28 April 2015

9. The Economic Times; USFDA warns Cadila Pharma over drug production processes;
12 Nov, 2014.

Available at:
http://economictimes.indiatimes.com/industry/healthcare/biotech/pharmaceuticals/usfda
-warns-cadila-pharma-over-drug-production-processes/articleshow/45120353.cms;
Accessed on 28 April 2015
10. Business Standards; Sun Pharma hit by US FDA ban on Gujarat plant; March 14,
2014
Available at: http://www.business-standard.com/article/companies/sun-pharma-hit-by-
us-fda-ban-on-gujarat-plant-114031400021_1.html; Accessed on 28 April 2015
11. Reuters; Ipca hit by FDA ban over Ratlam plant production violations; Jan 23, 2015

Available at: http://in.reuters.com/article/2015/01/23/ipca-labs-fda

idINKBN0KW0AP20150123; Accessed on 28 April 2015

12. Rahalkar H.; Historical Overview of Pharmaceutical Industry and Drug Regulatory
Affairs. Pharmaceutical Regulatory Affairs; 2012; 2167-7689

13. T. Rakesh.; Role of regulatory affairs in a pharmaceutical industry; International

Journal of Pharmacy Review & Research; 2014; vol.4; 127-131

14. Sudhakar Y, Jayaveera K.N.; Novel drug delivery system and regulatory affairs;
2014; vol.2; 315-344

15. Clin Page; A quick history; India’s Regulation Timeline; 2009; June 19

16. Lumley C, Walker S; improving the Regulatory Review Process -Industry and
Regulatory Initiatives; Dordrecht: Kluwer Academic Publishers; 1996; 13-19

17. Baeyens AJ, Lacombe D. Regulatory issues for clinical trials at EORTC: The way
forward. European Journal of Cancer; 2002; 38

18. Soderlund N., and Tangcharoensathien V.; Health Sector Regulation –

Understanding the Range of Responses from Government. Health Policy and Planning;
2000; 347-348.

19. Donald J., Wright D.J.; The Drug Bargaining Game: Pharmaceutical Regulation in
Australia. Journal of Health Economics; 2004; 785–813

20. Danzon P., Chao L.; Does regulation drive out competition in pharmaceutical
markets? Journal of Law and Economics; 2000; 311–357

21. Van Boxtel C.J., Santoso B., Edwards I.R.; Drug Benefits and Risks International
Textbook of Clinical Pharmacology; 2008; vol.2; 65-66

22. Santoso B.; Drug Benefits and Risks: International Textbook of Clinical
Pharmacology; Chapter-6 ―Drug Regulation: History, Present and Future; 2008; vol.2
;66-76
23. Jeffery R., Santhosh M.; Architecture of Drug Regulation in India- What are the
Barriers to Regulatory Reform? ; Journal of Health Studies; 2009; vol.2; 13-32

24. Sarda R. R.., Ladkat N.B., Khodade R.B., Chaudhari P.M., Kasture P.V.; The
Indian Pharmaceutical Industry; Evolution of Regulatory System and Present Scenario;
International Research Journal of Pharmacy; 2012; vol.3(6); 49-55

25. Langar E.; Biologics Regulation in India- India is restructuring its regulation of
biopharmaceuticals to help the country’s industry compete internationally; India Today;
March 2008; Vol.21(3)

26. Khurana G, Jaipuriar N, Indian Pharmaceutical Market, Indian law offices.

Available at: www.indialawoffices.com ; Accessed on 15 April 2015
27. Danzon.; Cross-National Price Differences for Pharmaceuticals: How Large and
Why? Journal of Health Economics; 2000; vol.19 (2); 159-95

28. Andrea T.; The History and Contemporary Challenges of US-FDA. Clinical
Therapeutics; 2007; vol.29(1):1-16.

29. Pisano D.J., Mantus D.S.; FDA Regulatory Affairs: A Guide for Prescription drugs,
medical devices and biologics; 2008; vol.2; 54-60

30. Casper S., Matraves C.; Institutional Frameworks and Innovation in the German and
UK Pharmaceutical Industry. Research Policy ;2003 ;1865–1879

31. Ramesh T.; Regulatory Perspective for Entering Global Pharma Markets. Pharma
Times; 2011; vol.43(09);15-19.

32. Ceci A, FelisiM, CatapanoM, Baiardi P, Cipollina L, Ravera S;. Medicines for
Children Licensed by the European Agency for the Evaluation of Medicinal Products.
Eur J ClinPharmaco ;2002 ; vol.58; 495-500

33. European Medicines Agency. Better medicines for children. EMEA 2008.
Available at: http://www.emea.europa.eu/htms/human/paediatrics/regulation.htm ;
Accessed on 12 April 2015

34. Hayakawa T.; New drug approval process in Japan. Current opinion in
biotechnology; 1999; vol.10; 307-311
35. Uyama Y.; Successful bridging strategy based on ICH E5 guideline for drugs
approval in Japan. Clin. Pharmacol. Ther; 2005; vol.78; 102–113.

36. Bareilles M.; Chapter 5- Japanese regulations. Global Clinical trials ;2011; 63-85

37. DiMasi JA., Manocchia M.; Initiatives to Speed New Drug Development and
Regulatory Review: The Impact of FDA-Sponsor Conferences. Drug Inf J; 1997;
vol.31; 771 – 88

38. FDA (U.S Food and Drug Administration); drugs;

Available at:
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedand
Approved/ApprovalApplications/InvestigationalNewDrugINDApplication/default.htm;
Accessed on 26 March 2015
39. FDA (U.S Food and Drug Administration); drugs;
Available at:
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedand
Approved/ApprovalApplicati ons/NewDrugApplicationNDA/default.htm; Accessed on
20 March 2015