1. Why Do We Have Drug Regulations?

Structures of drug regulation that exist today i.e., drug laws, drug regulatory agencies, drug evaluation boards, quality control laboratories, drug information centers, etc., have evolved over time in response both to increasingly sophisticated pharma sector, and to apparent needs of society.

In some countries, passing of comprehensive drug laws was result of crisis-led change, when public demand led to adoption of more restrictive legislations to provide stronger safeguards.

While drug laws provide basis for drug regulation, regulatory tools such as standards and guidelines, and drug regulatory authorities provide practical means of implementing those laws. Though world pharma regulations are in continuous process of harmonization, they can still be divided into four major categories based on region, development strategy, regulations and marketing interest:

Based on Economy & Control:
Regulated Markets = US, EU, Japan, ANZ (Australia, New Zealand) – Well defined, stringent guidelines, high data requirements.
Emerging Markets = ROW excluding ANZ – Includes Brazil, Mexico, Tanzania, Russia, Hong Kong, GCC, India, ASEAN – Evolving regulations, price sensitive, faster growth but needs local knowledge.

2. United States of America – The Gold Standard

Authority: Food and Drug Administration (FDA) within U.S. Department of Health and Human Services. Main center for drugs is Center for Drug Evaluation and Research (CDER) – one of six product centers.

USA is major market for pharma. USA has evolved from no regulations in 18th century to one of highly regulated and admired regulatory authority in world. Indeed, way this country regulates drugs typically has been born out of adversity, out of events that have killed and injured thousands. Evolution of current system in USA is recognized globally as gold standard for drug safety and efficacy.

During 1990, FDA began work to develop standards for exchange of electronic information critical to agency’s mission. This recognized inefficiency of paper for transferring mass quantities of data and need to develop harmonized format that would be usable by FDA as well as counterparts in EU and Japan. Consequently, firms are now able to submit paperless product applications (eCTD) and related material to world regulatory agencies more efficiently, while each review authority maintains its own high standards.

Because all drugs have some risk, FDA task force advised agency to make more systematic use of principles of risk management in way FDA oversees drug development and marketing. Today – ANDA for generics (505j), NDA for innovators (505b1/b2), DMF system for API, eCTD mandatory, ICH QbD expected.

US Terminology: NDA, ANDA, DMF, RLD, Orange Book, Paragraph I-IV Certification, 505(b)(2), eCTD, CDER, USFDA Inspection, BE – Bioequivalence

3. European Union – 27 Countries, One System but Multiple Procedures

Authority: European Medicines Agency (EMA, formerly EMEA) + National Competent Authorities.

EU has one of most highly regarded regulatory systems in world. System comprises European Parliament, Council of Ministers, and European Commission. EU consists of 27 member states: Austria, Belgium, Bulgaria, Cyprus, Czech Republic, Denmark, Estonia, Finland, France, Germany, Greece, Hungary, Ireland, Italy, Latvia, Lithuania, Luxemburg, Malta, Netherlands, Poland, Portugal, Romania, Slovakia, Slovenia, Spain, Sweden, and United Kingdom and 3 countries which are member of European Free Trade Agreement (EFTA) Iceland, Norway, and Liechtenstein.

Eligibility and requirements are set in Commission Regulation (EC) No 726/2004 and defined in articles 8 and 10 of Directive 2001/83/EC.

To market generic medicinal product in European Economic Area (EEA) which consists of 27 member states + 3 EFTA, marketing authorization has to be issued.

Procedures for EU Filing:

• Centralised Procedure: Mandatory for new drug products, biotech, oncology – Single application to EMA, valid in all EEA
• Decentralised Procedure (DCP): Generally followed for generic drug products – Simultaneous submission in multiple member states, one RMS (Reference Member State)
• Mutual Recognition Procedure (MRP): Product already approved in one member state, then recognition in other states
• National Procedure: For filing in single country only

EU Terminology: MAA – Marketing Authorization Application, DCP, MRP, Centralised, SmPC, PIL, CEP – Certificate of Suitability (EDQM), ASMF – Active Substance Master File (EU DMF), RMS/CMS

4. Brazil (LATAM) – Gateway to Latin America

Authority: ANVISA – Agência Nacional De Vigilância Sanitária (National Health Surveillance Agency) – Established in 1999.

Brazil’s pharmaceutical market is 11th largest in world and second in Latin America after Mexico since devaluation of 2001. Brazil’s market is clearly key market to drive global development of any pharma company with international ambitions and may have located regional headquarters in country. Regulatory framework is considerably improved and makes Brazil preferred gateway to other Latin American markets.

The 1999 Law (The Generics Law) and ANVISA regulate implementation of generic pharmaceuticals policy in Brazil, establishes technical standards and defines concepts of bioavailability, bioequivalent drugs, innovators, reference drugs, and similar.

According to Brazilian legislation, all pharmaceutical products must be registered with ANVISA before coming to market in Brazil. Product registration in Brazil is laborious exercise, and is to be requested by local Brazilian based office of foreign company or its distributor in Brazil. Registration is valid for 5 years and can be renewed continuously for same period. Law must complete registration process within 90 days after registration is requested, or denied.

ANVISA Classifies: New Product, Similar Product, Generic Product. Needs GMP certification by ANVISA – they will audit your plant in India before approval. Dossier in Portuguese, stability Zone IVb (30°C/75% RH).

Brazil Terminology: ANVISA, Generic Law, Similar Product, Reference Drug (RDC 51), GMP Certificate (CBPF), Dossier – Portuguese, Zone IVb, 5-year validity

5. Tanzania (AFRICA) – WHO Based System

Authority: Tanzania Medicines and Medical Devices Authority (TMDA, formerly TFDA – Tanzania Food and Drugs Authority)

African medicines regulatory authorities (MRAs) role is to ensure pharma products that are needed, are registered in their country. This process is called “registration,” “marketing approval,” “marketing authorization” or “product licensing”, and involves assessment of product information submitted by manufacturer (product dossier) to make sure it is safe and effective for use by local patients.

Assessment of generic drugs is relatively simple: 1) Generic is bioequivalent to and thus therapeutically interchangeable with comparator product. 2) Product meets comparable sustainable quality standards to innovator.

Every country of African region has its own regulatory framework. Drug product registration was gradually introduced in Tanzania under Tanzania Food, Drugs and Cosmetics Act 2003, to have smooth transition, beginning with 1-year provisional registration taken as notification from 1998. This gave ample time for Pharmacy Board to prepare guidelines. Following preparation of guidelines, first application was received in 1997 and first product was registered in April 1999.

All documents shall be in Kiswahili or English. Applications that do not comply to requirements prescribed will be rejected and returned at applicant’s own cost. All ingredients used in formulation of generic medicinal products must comply with specifications prescribed in USP, BP, EP, International or Japanese pharmacopoeia. In-house specifications shall only be accepted if limits are tighter than those in pharmacopoeias.

Africa Terminology: TFDA/TMDA, Provisional Registration, WHO-CTD, Zone IVb stability, English/Kiswahili dossier, BE against WHO comparator

6. Russia (CIS) – Emerging Power Market

Authority: Ministry of Health of Russian Federation – Roszdravnadzor + Ministry within CIS (Commonwealth of Independent States – founded 1991, former Soviet Republics after dissolution of USSR).

According to some estimates, Russia is poised to be among top five Global pharma markets in terms of value in next five years. Russia stands at threshold of becoming major force in global pharma market.

Regulatory processes in CIS countries are led and supervised by Regulatory Agencies closely collaborating with or operating within respective Ministries of Health. Each CIS country has established individual registration guidelines. Registration in RUSSIA is national procedure. Estimated duration up to 24 months. Documentation in Russian language in format compliant with Russian requirements.

Original and generic products pass same stages of registration. Original products must pass through all registration procedures while generic products are exempted from some. For example, original product must undergo clinical trials in Russia. For generic products, bio-equivalence studies can be conducted in any other countries and not only in Russia, but recommended submission of BE study carried out in certified research organizations within Russian Federation’s territory.

CIS Terminology: National Procedure, Russian language dossier, 24 months timeline, Roszdravnadzor, Clinical trials exemption for generics, BE in certified centers

7. Hong Kong (ASIA) – Conservative but Strategic

Authority: Pharmacy and Poisons Board (PPB) + Department of Health (DOH), Hospital Authority (HA) Drug Formulary

Pharma regulatory agency in Hong Kong remains conservative in outlook but facing challenge from pharma sector. HA’s adoption of purchasing policy favoring use of bulk contract and generic substitution has undercut market for multinational pharma companies represented by Hong Kong Association of Pharmaceutical Industry (HKAPI).

Difficulties: Difficulty of listing new drugs in HA Drug Formulary, delay in new drug registration application submitted to PPB, Intellectual property rights issues, have provoked outcries about deterioration in business environment. Hong Kong’s regulatory body and business sector evidently lag behind international developments. PPB has not gained membership of Pharmaceutical Inspection Cooperation Scheme (PICS) that facilitates signing of Mutual Recognition Agreement with regulatory bodies in developed countries. This lack of international harmonization of GMP standard makes it difficult for local manufacturers to become exporters.

8. Japan – Second Largest Market

Authority: Ministry of Health, Labour and Welfare (MHLW) + Pharmaceutical and Medical Devices Agency (PMDA, KIKO)

Japan is world’s second largest market next to US. MHLW is in charge of pharmaceutical regulatory affairs and PMDA undertakes main duties: handles clinical studies, approval reviews and post-marketing safety measures i.e. approvals and licensing. Japan requires Japanese language dossier (J-CTD), Japan-specific stability, and bridging studies for many products. PMDA consultation (Omagari?) is crucial before filing. DMF system exists (MF – Master File).

Japan Terminology: MHLW, PMDA, J-CTD, Japanese language, MF, Bridging Study, Sakigake Designation, PMDA Consultation

9. Quick Comparison – Regulated vs Emerging: What Actually Differs?

Conclusion

World covers more than 100 countries, where most have established pharmaceutical legislations. For worldwide dossier submissions, it is pre-requisite to have knowledge of country-specific guidelines and norms.

Regulated markets (US, EU, Japan, ANZ) give high value but need high quality data, eCTD, QbD, DMF/CEP, and strict BE. Emerging markets (LATAM, Africa, CIS, GCC, Asia) give volume growth but need local language, Zone IVb stability, local GMP certificate, and local distributor office (e.g., Brazil needs local Brazilian office).

Best strategy for Indian pharma: Develop product once as per most stringent market (US/EU) + Zone IVb stability + Do BE against US & EU RLD. Then use same data to file in ROW with local Module 1 adaptation. This avoids major surprises after submission.

Regulatory guidelines provide basis for implementation of laws, whereas laws provide legal basis for drug control. Analyze differences and commonness before you start development – That’s true regulatory strategy.

– Mahummed Asif

About the Author

Mahummed Asif is a experienced pharmaceutical Quality Assurance professional and publisher of Pharmashare. He has worked with leading Pharmaceutical organizations and has developed extensive expertise in Quality Assurance, deviation management, investigations, CAPA, QMS, Product Life Cycle Management, change control, risk management, validation, product complaints, product recalls, and regulatory compliance. He is passionate about sharing practical pharmaceutical knowledge with professionals, students, and quality practitioners across the industry.