Regulatory affairs - Industrial Pharmacy II B. Pharma 7th semester PDF Notes

Regulatory affairs


• Introduction

• Historical overview of regulatory affairs

• Regulatory authorities

• Role of regulatory affairs department

• Responsibility of regulatory affairs professionals

Learning objectives

• At the end of this lecture, student will be able to:

– Explain the role/significance of regulatory affairs in pharmaceutical industry

– Explain the various regulatory authorities

– Explain the responsibility of regulatory affairs professional 

What is Regulatory affairs?

• As a discipline, regulatory affairs covers a broad range of specific skills and occupations.

• Under the best of circumstances, it is composed of a group of people who act as a liaison between the potentially conflicting worlds of government, industry, and consumers to help make sure that marketed products are safe and effective when used as advertised.

• People who work in regulatory affairs negotiate the interaction between the regulators (the government), the regulated (industry), and the market (consumers) to get good products to the market and to keep them there while preventing bad products from being sold.

• The range of products covered is enormous, including foods and agricultural products, veterinary products, surgical equipment and medical devices, in vitro and in vivo diagnostic tools and tests, and drugs (which range from small molecules to proteins).

• The range of issues addressed is huge, such as manufacturing and analytical testing, preliminary safety and efficacy testing, clinical trials, and post-marketing follow-up.

• Advertising issues, with a healthy dose of data management, document preparation, project management, budgeting, issue negotiation, and conflict resolution, are thrown in the mix.

• On the industry side, people in regulatory affairs work with research scientists, clinicians, manufacturing groups, and sales and marketing groups to make sure that the government has the information it needs to judge a product.

• On the government side, people in regulatory affairs work to interpret and implement laws that Congress establishes to help protect the public. Evaluate a given drug, biologic, and/or device with respect to safety and efficacy. Decide whether the product should be on the market—and if so, how it should be marketed and sold.

• On the consumer side, people in regulatory affairs help keep the other two groups honest, and provide stimulus for Congress to enact laws                               

• Regulatory Affairs (RA), also called 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


• 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).


• The early 18th century, chemical manufacturing factories had started the first large scale manufacturing of glycerine during 1818-1840.

• Medicines - compounded by Pharmacists and Doctors at Pharmacy laboratories. Crude drugs i.e. opium were extracted from natural plants by pharmacists and progressed further for identifying isolating active ingredients from the crude drug.

• In USA, the root of modern pharmaceutical industry was borne during Mexican- American war (1846-1848) American troops had suffered due to import of spurious medication for Malaria, Cholera, Dysentery, and Yellow Fever - federal government into action for creation of Custom Laboratories.

• The first law which controlled import of medicines was Import Drugs Act of 1848.  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.

• The objective - creating system for standards, quality control and national formulary.

• At the start of 19th century, new legislations for medicines control started 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.

• Diphtheria antitoxin developed by City Health Department of St.  Louis was contaminated by tetanus causing bacteria - death of 14 children in November 1901. Simultaneously, smallpox vaccine administered was found contaminated and resulted into 9 more death in 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 labeling in terms of manufacturer’s name, address, license number, identification of product and expiry date.

• Further federal government took steps for controlling adulteration/misbranding of foods, drugs, medicines, liquors - prohibited interstate transport of adulterated food/drugs.

• Toxic colors 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).

• Earlier 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.

• In 1938, Sulfanilamide Elixir tragedy raised concern about the safety of drug products - more than 100 people 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.

• Pre-marketing approval of all new drugs was made mandatory and proof for scientific safety study was asked by FDA, directions for safe use.

• Categorising medicines as Over-The-Counter (OTC) drugs and Prescription drugs which was not in place earlier.

• 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 labeling 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 5 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 9100 employees of varied category i.e. physicians, pharmacologists, chemists, microbiologists, pharmacists, veterinarian and lawyers.


• The drug industry in India was at very primitive stage till 20th Century.

• Drugs were imported from foreign countries.

• Post First World War, the demand for drugs increased which led to the cheap & substandard drugs into the market, as like in USA post Mexican American war.

a)   1900-1960:

• To control cheap drugs in market – The Poisons Act 1919 was passed -regulated possession of substance/sale of substances as specified as poison, specifies the safe custody of the poisons, labeling/packaging of poisons, maximum quantity to be sold and inspection/examination of the poison sold.

• It was followed by The Dangerous Drugs Act 1930 regulated opium plant cultivation/manufacture/possession of opium, its import, export, tranship and sell of opium.

The Narcotics and Psychotropic Substances Act in 1985 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

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 a 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: 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.

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 TRIPS, manufacturer can market this product post 2005 without infringing product patent.

• 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.

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).


• Main objective of keeping unsafe products out of marketplace in addition to ensuring Quality, Safety and Efficacy,

Ethical considerations: To avoid unethical and unsafe clinical trials - 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: Major revolution of drug regulations started post Thalidomide tragedy. In late 1950s, a German company was marketing new sedative pills reduced nausea in pregnant women- 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.

• However, this changed with formation of European Economic Commission (EEC) in 1957 (Currently 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, labeling and promotion directives were came into effect

• Early 1990s in UK, Creuthfeldt-Jacob disease cases were started increasing. Bovine Spongiform Encephalopathy (BSE), commonly known as “mad cow disease”.

• It was applicable to all ingredients derived from bovine materials i.e. lactose, magnesium stearate, gelatin.

• Free availability of information: Any information about medicine is available almost to everyone due to wide spread use of media and internet. 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.  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.

• Changes in market structure: Healthcare regulations were required due to creation of single EU market by removing trade barrier. A common regulatory framework was required. Since the market was open, the quality concern for imported products led to the development of new regulations.

Pharmaceutical legislation

• Currently, the EU legislation on medicinal products consists basically of

• Directives must be transferred into national law by the member countries prior to becoming effectives.

• Regulations apply directly in all member states.

• Decisions & Recommendations.

• Notice to applicants: Under this section, detailed requirements and understanding about marketing authorisation procedure (Evaluation process, query response and timeline) as well as dossier preparation and its content (CTD and eCTD) and related guidelines are available. This is non-binding texts to help applicants fulfils regulatory approval obligations to place drug products in market.

• Regulatory guidelines: Under this section, regulatory guidelines i.e. Quality and Biotechnology, Safety, environment and information, as well as efficacy guidelines to support product development are available.

• Detailed drug monitoring guide: Under this section, guidelines pertaining to drug monitoring (pharmacovigilance) for the medicinal products already approved are available.

Regulatory authorities

Country             Regulatory body

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

Japan                 Ministry of Health, Labour & Welfare (MHLW)

Country wise Regulatory agency



Orange book:


Home page: Guidelines page:


Home page: Guidelines page:                  


International conference on harmonization (ICH)

www.ich.orgGuidelines page:


www.hc-sc.gc.cah ld/index-eng.php

Role of Regulatory affairs Department

• Keep in touch with international legislation, guidelines and customer practices

• Keep up to the date with a company’s product range

• Ensure that a company’s products comply with the current regulations.

• The Regulatory Affairs professional’s job is to keep track of the ever-changing legislation in all the regions in which the company wishes to distribute its products.

  They  also  advise  on  the  legal  and  scientific  restraints  and requirements, and collect, collate, and evaluate the scientific data that their research and development colleagues are generating.

• Formulate regulatory strategy for all appropriate regulatory submissions for domestic, international and/or contract projects.

• Coordinate, prepare and review all appropriate documents for example dossier and submit them to regulatory authorities within a specified time frame in conjugation with the organization.

• Prepare and review of SOPs related to RA. Review of BMR, MFR, change control and other relevant documents.

• Monitor the progress of all registration submission.

• Maintain approved applications and the record of registration fees paid against submission of DMF’s and other documents.

• Respond   to   queries   as   they   arise,   and   ensure   that registration/ approvalare granted without delay.

• Impart training to R&D, Pilot plant, ADl and RA. Team members on current regulatory requirements.

• Advising their companies on the regulatory aspects and climate that would affect proposed activities. I.e. describing the "regulatory climate" around issues such as the promotion of prescription drugs and Sarbanes-Oxley compliance.

• Manage review audit reports and compliance, regulatory and customer inspections.

• Regulatory Affairs professionals help the company avoid problems caused by badly kept records, inappropriate scientific thinking or poor presentation of data. In most product areas where regulatory requirements are imposed, restrictions are also placed upon the claims which can be made for the product on labelling or in advertising.

• Have a duty to provide physicians and other healthcare professionals with accurate and complete information about the quality, safety and effectiveness of the product.

Responsibility of Regulatory Affairs Professional

• The Regulatory Affairs professional’s job is to keep track of the ever-changing legislation in all the regions in which the company wishes to distribute its products.

• They also advise on the legal and scientific restraints and requirements, and collect, collate, and evaluate the scientific data that their research and development colleagues are generating.

• They are responsible for the presentation of registration documents to regulatory agencies, and carry out all the subsequent negotiations necessary to maintain marketing authorization for the products concerned.

• They give strategic and technical advice at the highest level in their companies, right from the beginning of the development of a product, making an important contribution both commercially and scientifically to the success of a development program and the company as a whole.

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