A Brief Introduction of Indian Drug Quality Supervision System

JIN Yu, SHAO Rong

(1.School of International Pharmaceutical Business of CPU, China Pharmaceutical University, Nanjing 211198, China; 2.The Research Center of National Drug Policy & Ecosystem, China Pharmaceutical University, Nanjing 211198, China)

A Brief Introduction of Indian Drug Quality Supervision System

JIN Yu1, SHAO Rong2

(1.School of International Pharmaceutical Business of CPU, China Pharmaceutical University, Nanjing 211198, China; 2.The Research Center of National Drug Policy & Ecosystem, China Pharmaceutical University, Nanjing 211198, China)

Objective To give a brief introduction of Indian drug quality supervision system, and to provide references for the development of drug quality supervision in China. Methods Indian drug quality supervision system was fully expounded in the following aspects: pre-quality supervision; in-quality supervision and post-quality supervision. Results and Conclusion Indian pharmaceutical industry develops rapidly in recent years and has a well-organized quality control and supervision system, which may provide references for the perfection of drug quality supervision system in China.

India; drug; quality supervision

India’s pharmaceutical industry plays an important role in the global drug market. In the 1970s, India almost relied on imported drugs, but now, India has become a big medicine manufacturing country. The development of India’s pharmaceutical industry is a perfect model for the developing countries. Although India’s economic development is slower than China, its international competiveness of pharmaceutical industry is ahead of China. It is characterized by large scale, strong research abilities and high internationalization. India’s pharmaceutical industries get much more COS Certifications and DMF files than China. In addition, India has the largest number of FDA approved pharmaceutical factories outside the United States. India actively set up the International Contract Research Organizations (CRO). By taking part in the international contract research, India developed its quality control and regulation system gradually. India’s drug quality has been recognized by both domestic and foreign customers and it is one of the reasons for India’s large proportion of exports drugs. This relies on its well-organized pharmaceutical quality control system. We will introduce India’s pharmaceutical quality system from aspects of regulatory agencies, legislation and the three stages of drug production. We can provide a reference for China’s pharmaceutical regulatory system.

1 Introduction of the pharmaceutical regulatory system and legal system

1.1 Pharmaceutical regulatory bodies

India’s pharmaceutical regulatory system can be divided into national level and the state’s level. The major national drug regulatory bodies include Central Drugs Standard Control Organization (CDSCO, which belongs to Ministry of Health and Family Welfare), National Pharmaceutical Pricing Authority (NPAA, which belongs to Ministry of Chemicals & Petrochemicals), Department of Chemicals & Petrochemicals (DCP, which also belongs to Ministry of Chemicals & Petrochemicals) and Genetic Engineering Approval Committee (GEAC, which belongs to Ministry of Environment & Forests). Apart from CDSCO, MOHFW also takes charge of pharmaceutical industry. India’s Pharmacopoeia Commission is an independent body belongs to MOHFW, and it is in charge of making the standards for pharmaceutical industry. The Central Drug Research Institute supervises the quality of imported drugs and domestic cosmetics and offers suggestions for standard making. The function of Central Drugs Standard Control Organization is similar to China’s Food and Drug Administration. CDSCO takes charge of the approval for marketing of drugs, cosmetics and medical devices, production license for special drugs, GMP certification, adverse reaction monitoring, making regulations rules, drug testing, supervising clinical trials and evaluating export drugs. The Department of Chemicals and Petrochemicals and the National Pharmaceutical Pricing Authority takes charge of making pharmaceutical industry rules and controlling drug prices, which is similar to China’sNational Development and Reform Commission. NPAA is responsible for the implementation of the Drugs Price Control Order to control the price of drugs. Apart from the regulatory authorities at national level, there are 35 food and drug regulatory bodies at state level in India. The state authorities are responsible for product registration, authorizing pharmaceutical plants and controlling the quality. India, as one of the Commonwealth countries, has gained much drug supervision experience from western countries and developed a well-organized pharmaceutical quality and regulation control system.

At present, China’s pharmaceutical regulatory agency is the China Food and Drug Administration (CFDA). The restructuring of departments under the State Council in 2013 changed the former State Food and Drug Administration (SFDA) into China Food and Drug Administration (CFDA). As the State Comprehensive institution, it is responsible for the supervision of food, health care products, cosmetics and medicines (including herbal medicines, Chinese medicine, chemical raw materials and their preparations, antibiotics, biochemical drugs, biological products, diagnostic drugs, radioactive drugs, narcotics, toxic drugs, psychotropic drugs, medical devices and health materials, etc.) It is also responsible for investigation concerning medical accident. Nowadays Drug agency cancels the vertical management and implements local management. The reform of local grading weakens the independent supervision of the pharmaceutical sector, and it is vulnerable to be influenced by local interests. In addition, the existing regulatory system makes quality supervision of medicines under several different sectors, such as the Ministry of Health, National Development and Reform Commission and, the Industrial and Commercial Administrative Departments which results in the unstable drug quality monitoring. China’s existing regulatory system should be clearly defined its regulatory functions in the legal premise and establish a modern supervision system based on laws so that regulatory agencies must be in accordance with the laws to supervise the quality of drugs. Through the information disclosure and review mechanisms, it can improve their efficiency to ensure the safety of drugs.

1.2 Rules and laws

The legal basis for India’s drug supervision is “1940 Drug and Cosmetic Act” and its purpose was to regulate the import, standard of drug manufacturing, distribution and sale of the drugs. Base on this law, India made the“1945 Drug and Cosmetic Act”, and the two laws have been revised several times since then. Now they are the core of India’s pharmaceutical and cosmetic legal system. The other laws concerning drugs include “1948 Pharmaceutical Law”, which regulated the pharmaceutical industry and was revised in 1959, 1976 and 1984. In 1954, India made the “Law of Drug Advertisements”, which regulated the advertisements of drugs. This law regulated advertisements concerning drugs and the punishments for violating the rules. In 1958, India made the “Narcotic Drugs and Psychotropic Substances Act”, which regulated the supervision of narcotic drugs and psychotropic substances.“Drug Price Control Order” was released in 1995 to control the price of drugs.

Except for the basic laws and acts, there are other laws concerning the manufacturing, distribution and retail of the drugs. They are: “Industry Act” in 1951, “Trade and Trademark Law” in 1958 and “Indian Patents and Designs Act” in 1970[1]. These laws and acts witnessed the establishment and development of pharmaceutical regulatory system.

China’s drug regulation is based on “The Drug Administration Law, coupled with a series of supporting administrative rules. The relevant laws include “Drug Implementation Regulations”, “Provisions for Drug Registration”, “Measures for the Supervision and Administration of Pharmaceutical Production”, “Measures for the Supervision and Administration of Pharmaceutical Circulation” and “Drug Pricing Method ” etc. While India’s regulatory system is based on “1940 Drug and Cosmetic Act” and other relevant laws. China should continue making more specific laws on drug supervision based on “the Drug Administration Law” to supervise the whole process of drugs from research and development, production, circulation to the use. India’s law-making focuses on encouraging the development of industry, by offering certain preferential policies to enterprises that can meet the requirement of the government. However, the focus of regulation in China is to supervise drug quality. We can concentrate on encouraging the development of pharmaceutical industries as well.

2 Regulations in advance (drug market access system)

2.1 Drug approval

Importing or manufacturing a new drug must be approved by Indian Drug Administration. India follows the American mode of drug approval and all the drugsregistration documents must be declared in the CTD format from 2008. When approved by the IND, the clinical test can be conducted according to the “1940 Drug and Cosmetic Act”.

After registration, the drugs can be manufactured in the factory. Drug production in India requires licenses, such as factory license, packaging and labeling licenses etc. All these licenses should be updated regularly. The sale license is issued by the Food and Drug Administration in each state of India. The requirements for the sales license mainly include the marketing space and the quality of the employees of the company. The supplier must get the financial credit memos which record the name of retailer, address, license number, memo number and the name and quantity of drugs in the store[2]. After getting the production and sales license, all the manufacturers, distributers and retailers should obtain drug registration certificate.

Generics are well-developed drugs in India’s market. As for the registration of the generics, each of the 28 states has the right to issue a permit for the enterprise and it will take several months for registration. India has a loose policy for generics. Drugs approved in the United States can be produced in India without clinical trials if the India’s manufacturer can make the same drugs (i.e. the products should have the same ingredient as the ones on the US market). Other requirement for generic drugs in Indian is that the first generic manufacturer should have clinical test and bioequivalence test on the sample drug from the original factory. For the other generic manufacturers, only bioequivalence test is required. To sum up, India attaches importance to the quality of the generics and some data or tests can be avoided if the former papers or articles can be provided.

Drugs listed in China should have a marketing authorization and production license, namely, a drug approval number will be issued to the manufacturer who has a “drug production licenses”. Companies must obtain“Pharmaceutical Production License” and “Pharmaceutical Trading License”, then SFDA will review drug safety, effectiveness, quality, controllability based on the applicant's drugs, and decide whether to issue a permit or not. This system, to some extent, restricts the development of China's pharmaceutical industry. China should gradually separate trading licenses and production licenses in accordance with the specific national conditions to promote China’s pharmaceutical industry.

2.2 Registration and importing approval for imported drugs

Starting from Jan 1st 2003, all the imported drugs must have registration license and sales license. To get these licenses, the pharmaceutical companies should send an application to the DCGI and get the new drug approval (NDA), then (or without finishing part 1) send an application to DCGI to get an imported drug registration certificate. Finally they can get an import license. The second step and the third step should be conducted based on the rule 21 to 30 from “1945 Drug and Cosmetic Act”. The import license can be applied once a time or several drugs can use one license. Only the imported drugs manufactured in the same factory can be covered by one import license. Drugs manufactured in different places (even by the same company) must have different import license[3]. After getting a registration license, the company can apply for the import license. According to the current Indian law, all kinds of drugs, including the ingredients, vaccine and some special pharmaceutical devices must have an import license, rather than the drugs listed in the “1940 Drug and Cosmetic Act”. Before giving out the import license, Indian authorities authorize some agencies to check the manufacturer and factory of the imported drug. If a manufacturer produces one drug in two different factories, two different import licenses is needed. Finally, the imported drugs can be sold in India’s market.

3 Quality control system

3.1 GLP, GCP and GMP system

The Good Laboratory Practice was made by India’s Ministry of Science and Technology, and the specific requirements of GLP were included in Schedule L from “1940 Drug and Cosmetic Act”. The contents and requirements of GLP are the same with the WHO version, but there are some minor differences in the scope of application, documentation and the suppliers’evaluation. Indian government attaches importance to the implementation of GLP. In 2003, India became the temporary member of the Organization of Economic Cooperation and Development (OECD). OECD has 34 member countries and after joining the OECD, India’s GLP data will be accepted by the other 33 member countries. At present India has 18 labs which have comprehensive GMP certifications and its laboratory test has met the international requirements.

Good Clinical Practice (GCP) standardizes the experiment process that can ensure the safety of the volunteers. The GCP requires that the manufacturers shouldprovide the chemical and pharmaceutical information and the molecular formula of the drugs before the clinical test. A rigorous and complete test plan is also needed which contains the information of the test, such as the purpose, ethics, design, safety evaluation, data analysis and management, quality control and assurance, etc. Apart from this, the reparation for accidents must be included. India’s GCP became effective in Nov. 2001, and it revised the “Y Project” from the “1940 Drug and Cosmetic Act”to ensure the safety of patients. The GCP regulates the clinical experiments should be in line with the international standard.

The manufactures must satisfy the requirements of Good Manufacturing Practices (GMP), which is defined in Schedule M from the “1940 Drug and Cosmetic Act”. Part one of Schedule M gives specific requirements of the buildings and materials and Part two regulates the Good Manufacturing Practice for devices and factory buildings. India establishes WHO GMP office in drug regulation authorities and the big pharmaceutical company may apply for GMP certification from WHO, while the smaller ones can apply for domestic GMP certification and sell the products in domestic market. Indian pharmaceutical companies actively apply for the international GMP certifications and India has the second largest number of pharmaceutical factories which have the GMP certifications from FDA. Some India’s companies apply for the cGMP certifications, which meet European and American standards. In addition to investing in original research, India’s pharmaceutical companies update their factories and devices to meet the cGMP standard. Now, many Indian pharmaceutical companies have the international certifications to ensure the quality of drugs.

Compared with India, China’s target market is different from India. India’s target is the international market and it applies for the international standard of GLP, GCP and GMP, while China’s target is domestic market and it is low internationalized. Therefore, India’s way of implementing GLP, GCP and GMP has a good inspiration for Chinese pharmaceutical companies to broaden overseas market.

3.2 Drug quality certification system

To ensure the quality and safety of the drugs, India launched product certification system to standardize the control and requirements of the drugs. The certification includes the chemical drugs. The certification systems consist of Compulsory Certification and Voluntary Certification. For the products required for compulsory certification, a certificate is needed before drugs are sold on the market. The agency that issues the certification is the Bureau of Indian Standards and it is the only drug certification agency in India. And the Technology Committee makes the standard for certification. The laws guiding the certification include the “1986 Bureau of Indian Standards Act”, “1987 Bureau of Indian Standards Rules” and “1988 Bureau of Indian Standards (Certification) Rules”. Besides, India encourages the pharmaceutical company to get the foreign certification, and Indian companies get much more COS certification and DMF articles than the Chinese. Since this certification is the passport to the international market, Indian’s pharmaceutical industry has much advance than ours.

3.3 Drug price control

Indian government knows that formulating a reasonable price can ensure sufficient drug supply on the market, and the quality of health services can be guaranteed. National Pharmaceutical Pricing Authority (NPPA) takes charge of drug pricing In 1970, India issued the first drug price control act, the “1970 Drugs Prices Control Order” (DPCO). It was revised in 1979, 1987 and 1995 respectively. These acts ensure the availability of the drugs. But for the development of pharmaceutical industry, India minimizes the field of regulation and gives more freedom to the market. In 1970, 500 types of common drugs and their ingredients’ price were controlled by the DPCO. The number of drugs decreased to 370, 143 and 74 in 1979, 1987 and 1995 respectively. In 2005, this number dropped to 28. And in 2006, India decided to free the prices of nonlist drugs, which consist of 65 percent of drugs on the Indian market[3]. We can see that the price control is decreasing and the market is playing a more important role. In 2006, India established a series of drug regulatory organizations including the price of drugs monitoring systems. Then the cost, profit, wholesale price, retail price and other factors will be taken into consideration to determine a reasonable price. This shows that India has established a set of more comprehensive and accurate drug price control mechanism.

Because the development of new drugs is a highly professional job, NPAA, the special department in India can control the drug price more scientifically. In China, the price department at all levels and National Development and Reform Commission are responsible for drug pricing. It covers the drugs on the national medical insurance catalog, narcotic drugs, psychoactive drugs, contraceptives andimmune medicines. Other drugs prices can be determined by the enterprises themselves. Due to the lack of the professional knowledge and human resources, drug pricing in China is not reasonable. Therefore, China should establish its own drug price control agency in the future.

3.4 Drug bidding

Drug bidding system mainly focuses on the basic drugs. India takes the Delhi model as the example in the designing of the pharmaceutical bidding system. In order to implement the basic drug bidding system, the Delhi state government established the centralized pharmaceutical bidding agency (CPA), and a special committee is responsible for the bidding system and redistribution system. The hospitals submit their drug demand to the CPA in every 4 months and CPA orders the drugs. The vendors must supply directly to every hospital within 35 days[4]. This agency also has a thorough feedback system. By monitoring the hospital status, CPA corrects the imbalance in drug using and ensures the availability of drugs in 24 hours. Besides, India takes a active part in the international procurement, and India will form a professional team to ensure the quality of the international procurement.

As to the implementation of the basic drug system, there are several agencies, such as the agency for drug bidding, the agencies for selecting the basic drugs and agencies controlling drugs quality. China should build such agencies to make sure that the essential drug system can be well conducted.

Ensuring the quality and safety of essential medicines is one of the important goals of China’s basic drug system. Since the implementation of the basic drug system, some results have been achieved. But there are still some issues that can impact drug safety, such as the current directory can not fully meet the medication needs, the bid price bidding mode has been questioned and there are difficulties in the distribution of essential medicines to remote areas. Therefore, China should improve the organization and learn from India’s drug procurement system.

4 India’s pharmaceutical alert system

WHO defines pharmaceutical alert as the scientific activity or research relevant to discovery, estimation, understanding or prevention of adverse reactions and other accidents. India’s pharmaceutical industry is developed, but the system of drug adverse reaction is still in its infancy India proposed to establish the ADR monitoring system in 1986 and it cooperated with the WHO to build up 3 ADR monitoring centre in 1997. In 2004, India issued the national pharmaceutical alert plan (NPP) and it came to effect on Jan 1st, 2005. It changed is name into the Pharmaceutical Alert Program of India in 2007 (PvPI) to ensure the safety of drug usage for public. PvPI is made by the Central Drugs Standard Control Organization to monitor the adverse reactions and to support the decisions from the CDSCO. Now, India has formed a clear pharmaceutical alert reporting system, which includes the adverse reaction report system (ADR) and periodic safety update reports (PSUR). The adverse reporting channel includes the ADR monitor centre reports, the company’s ADR reports and clinical test safety report[5].

Although India’s PvPI still has some problems, we can see India attached great importance to pharmacovigilance system from the establishment of PvPI and adverse reactions reporting system.. In general, India has established a set of pharmacovigilance system based on its national conditions. At present, China has established the adverse reaction monitoring system consisting of National Adverse Drug Reaction Monitoring Center and provincial Adverse Drug Reaction Monitoring Center, The number of municipal adverse drug reaction monitoring agencies is more than 200. China will establish PvPI based on the current reaction system. We can refer to Indian experience due to the similar national conditions between the two countries.

5 Summaries

We can conclude that India’s profound drug regulation system and law system promotes the development of pharmaceutical industry. In the stage of research, production and redistribution, India uses the international standards as its goal to ensure the quality of drugs. India’s drug price controlling system and the pharmacovigilance system give a good example for the development of China’s pharmaceutical industry. To sum up, China has a similar situation to the India and can learn from India’s drug regulation system to perfect drug quality control system as well as the regulation system.

[1] AI Liang-hua. The Regulators in India and Their Related Regulations [J]. Shanghai Food and Drug Supervision Information Research, 2009, (96): 1-3.

[2] DONG Zuo-jun, ZHANG Ling. Analysis of Drug Circulation Admittance System [J]. Qi Lu Pharmaceutical Affars, 2006, 26 (9):521-523.

[3] TIAN Yun, YANG Shi-min. Implications of Indian Drug Price Control System for China [J]. China Pharmacy, 2007, 18 (28): 2167-2170.

[4] LI Ying. Research on Pharmaceutical Policy of India Based on the Delhi Model Case Study [J]. Hospital Directors’ Forum, 2011, 9 (5): 59-63.

[5] LU Yu-mei. Overview of Pharmacovigilane Systems in India [J]. Chinese Journal of Pharmacovigilance, 2012, 9 (7): 413-417.

Author’s information: SHAO Rong, Professor. Major research area: Social pharmacy. Tel: 025-86185038, E-mail: shaorong118@163.com