INTRODUCTION:

In spite of the development of modern medicines all over the world, still the maximum population in developing countries rely on the traditional medicines which have great demand and are used extensively. The herbal medicines are derived from various parts of the plants like leaves, roots, stems, flowers and seeds. The World Health Organisation (WHO) defines herbal medicines as the aerial or underground plant parts or other plant material that contains an active ingredient as finished labelled medicinal product and is classified as: raw plant material, processed plant materials and Medicinal herbal products. The different types of traditional system of medicines are followed in India, China, Korea and Africa. The critical aspects in the quality standards of the herbal medicines includes the adulteration, heavy metals contamination, raw material harvesting seasons, processing and storage¹. The herbal medicines, concentrates more on treating the chronic conditions and this differs completely from conventional medicines (A system which treats the symptoms and diseases using drugs, radiation or surgery by the medical doctors and other health care professionals).

The plants are the main source for many of the conventional medicines like aspirin from willow bark, morphine from the opium poppy etc. The herbal medicines are highly toxic and have high risk of adverse effects and interactions². The popularity of the herbal medicines is more in developing countries than in developed countries like US, Germany, France and Italy, also follow appropriate guidelines. The regulatory process and the laws differ from one country to another, and the reason is that the scientific study for the herbal medicines are rare, thus the safety and efficacy tests are carried out for certain herbal preparations³. The WHO has prepared the pharmacopoeia monograph and set the evaluation guidelines for the quality, safety and efficacy of the herbal medicine also provides guidance in selecting the cultivation site, collection, plant identification, adulterants differentiation, post-harvest operations, which will be helpful for the manufacturers and regulatory authorities⁴. The herbal products internationally are classified as; complementary medicines, supplements, traditional herbal medicine, natural health products, OTC and prescription medicines with different regulatory requirements⁵.

Regulatory Aspects of Herbal Medicines in India:

The Drug and Cosmetic Act (D and C) 1940 and Rules 1945 regulate the herbal medicines and the regulatory authority is the Department of AYUSH and a manufacturing license is must to manufacture or market the herbal medicines⁶. Schedule T (Chapter IV-A), of the D and C Act provides the Good Manufacturing Practice (GMP) for herbal medicine manufacturers⁷. The Ministry of AYUSH (9^thNovember 2014) focused on the development of AYUSH health care system, which was known as the Department of Indian system of medicine and homeopathy (March1995) earlier and was renamed as the Department of Ayurveda, Yoga and Naturopathy, Unani, Siddha and Homeopathy. The information on the manufacture, registration, sale, license, GMP certificate and penalties are in Section 33C to 33O. The availability of the manufacturing and expiry date on the product label was made mandatory from 2017⁸. The duration for the approval of clinical trials in India takes about three months⁹.

Table – 1 Guidelines for the Ayurveda, Siddha, Unani Drugs

Quality control methods for medicinal plant material¹⁰	WHO, 1998
General methodologies and research evaluation traditional medicines ¹¹	WHO, 2000
OECD Guidelines¹²	2001
Protocol for testing of ASU medicines¹³	PLIM, 2007
Quality control manual for ASU medicine Pharmacopoeial laboratory for Indian medicine¹⁴	PLIM, 2008
Laboratory manual for the analysis of Ayurveda and siddha formulations¹⁵	CCRAS, 2010
Quality control methods for herbal materials¹⁶	WHO, 2011
GCP guidelines for ASU medicines, Ministry of AYUSH¹⁷	2013
General guidelines for safety, toxicity evaluation of ayurvedic formulation¹⁸	CCRAS, 2016
General guidelines for drug development of ayurvedic formulation¹⁹	CCRAS, 2016
General guidelines for clinical evaluation of ayurvedic interventions²⁰	CCRAS, 2016

The manufacturers can obtain the GMP certificate according to the D and C Act (Section 157) and the flow of the process is given below²¹.

Figure. 1 – Approval process of herbal drugs

A manufacturing premises should consist of a manufacturing area, office, workers room, raw material store, finished products store, quarantine room, packaging material store, bottle washing and drying room, packaging and labelling room and QC laboratory ²²

Documents required for the approval of premises:

Table 2 – Documents required for the approval of premises

· Forwarding letter

· Application form filled and signed by the authorized person

· The firm details filled and signed by the authorized person

· Original challan for license and fee as per the requirement

· 1 copy of the premises plan – original

· Possession of the premises

· Constitution of the firm

· 4 copies – list of products

· 3 copies – draft table of each product

· 1 copy – List of machines, equipment’s and laboratory equipment’s

· 4 copies – Technical persons (with details)

· Raw materials and analysis methods details

· Consent letter of public testing laboratories

· Standard Operating Procedure (SOP) list

· Master Formula Record (MFR) of all products

· Product ingredient reference book (Xerox copy)

The grant or rejection for license is done in form 25D and is valid for 5 years and in case of any addition to the existing constitution, a new license should be obtained²³.

AYUSH Guidelines for COVID-19:

The Ministry of AYUSH is working for the development of herbal drugs for the prevention and treatment of the novel corona virus disease and has set a number of guidelines which is available in the website https://ayush.gov.in/ and the following guidelines are given below²⁴.

Table 3 – AYUSH Guidelines for COVID-19

Guidelines for Practitioners

Naturopathy Guidelines

Siddha Guidelines

Homeopathy Guidelines

Unani Guidelines

Ayurveda Guidelines

Yoga Guidelines

Integrated AYUSH guidelines for public health and health care practitioners for COVID-19

Guidelines for AYUSH clinical studies in COVID-19 recommended by interdisciplinary AYUSH R and D task force

Clinical protocol guidelines documents and annexures

Guidelines for Research

Guidelines of clinical evaluation

Guidelines of drug development

Guidelines of safety toxicity

Good Clinical Practice Guidelines for clinical trials of ASU medicines

Global Herbal Regulation:

United States of America:

In USA, the herbal products are categorized as dietary supplement or food or drug and in 1994 “Dietary Supplement Health and Education Act” regulates the herbal medicines and evaluation is not done by the FDA ²⁵.

United Kingdom:

The licensing requirements in the UK are, set in the section 12 of the Medicine Act which is governed by the Medicine Control Agency (MCA). The Traditional herb registration (THR) (Directorate 2004/24/EC) or market authorization (Directorate 2001/83/EC) helps the products to get registered in UK and companies registering under this scheme should provide the quality data as per the GMP, safety and efficacy based on long traditional use of overall 30 years and 15 years in EU. The product label should contain the THR certificate mark with the statement “exclusively based in long term use”²⁶.

Association of South East Asian Nations (ASEAN):

The ASEAN regulations (8^thAugust 1967) established in Bangkok by the five member countries, Indonesia, Malaysia, Philippines, Singapore, Thailand followed by inclusion of Brunei, Darussalam, Vietnam, Laos and Myanmar, Cambodia which is covered by the Health Science Authority (HAS). The herbal medicines are being classified as Indigenous herbal medicine, herbal medicines in system, modified herbal medicines and imported products with herbal medicine base²⁷.

Table 4 – Herbal regulations in ASEAN countries

Malaysia	The registration is done with the Suruhanjaya Syarikat Malaysia or the Malaysian registrar of business under the traditional products or health supplements.
Singapore	In Singapore, a Chinese Proprietary Medicine (CPM) refers to a medicinal product that: Is in the form of a finished product, such as a capsule or tablet, and Contains one or more active ingredients from any plant, mineral, or any combination of sources and there is no registration requirement for the herbal medicines.
Philippines	The herbal medicine registration for the manufacture, import and marketing are regulated by the Bureau of Food and Drugs (BFAD).
Thailand	The herbal medicines are classified as products to sell/ import/ order and it is required for the distributors of the medicinal products to obtain permission from the Food and Drug Administration.
Indonesia	The GMP of the Traditional drugs is regulated by the directorate of the Ministry of Health (MOH).

Saudi Arabia:

In 1996, the herbal medicine regulation was established with a separate law for the herbal medicines. The manufacturing requirements are the same as the GMP rules for conventional pharmaceuticals and WHO GMP. The pharmacopoeial and non-pharmacopoeial evidence for the traditional products are considered as the supporting data.

Brazil:

The regulatory framework for the herbal medicines in Brazil has been in existence since 1967. The manufacturing requirements are similar to the information in the pharmacopoeia and monographs. More than 1000 herbal medicines are registered in Brazil²⁸.

European Union:

The European Directive 2004/24/EC was adopted and the term traditional herbal medicine product (THMP) was established. The bibliographic evidence and the preclinical safety data are required for the marketing authorization of traditional medicines. The EU member states were asked about the regulatory status of herbal medicines and it was found that majority of the countries do not have regulations for herbal medicines²⁹.

Canada:

In 1986, the herbal medicines are being defined as the folk medicine. The assessment of the herbal system is constituent with the WHO guidelines. It is the responsibility of the license holder to monitor the adverse reactions occurring due to their products and also to report the serious adverse to the Health Canada. The Natural Health Product directorate of the Health Product and Food Branch (1999) managed by the Ministry of Health (MOH), the Natural Health Products (NHP) from 2004 regulated the herbal remedies and traditional medicines. Prior approval is required to market the herbal products in Canada and it follows the standards as per the US Pharmacopoeia, British Herbal Pharmacopoeia, European Cooperation on Phytotherapy (ESCOP) and WHO.

Australia:

Therapeutic Goods Administration (TGA) regulates the herbal medicines and the product should be registered in the Australian Registrar of Therapeutic Goods (ARTG). The registered medicines are found to have high level of risk, listed medicine having low risk. The registration application may be rejected, get conditional acceptance or it can be accepted. The registration is done in the CTD format.

Russia:

In 1991, the National policy was issued and in 1993, the laws and regulations were framed same as the prescription medicines, OTC medicines or dietary supplements and the GMP rules are the same used for the conventional pharmaceuticals ³⁰.

South Africa:

The Herbal medicines are regulated in accordance with the Medicine and Related substance act, 1965 and herbal medicines are known as complementary medicines. The registration applications should be submitted in the South African CTD and the approval process in lengthy³¹.

Nigeria:

The National Agency for Food and Drug Administration and Control (NAFDAC) regulates the herbal medicines and also the registration and licensing³².

China:

The Traditional Chinese Medicines are in existence since 4000 years and the documentations are done in the Chinese Materia Medica. In China there are special requirements for the marketing, with the proper quality dossier, evaluation of safety and efficacy³³.

Challenges regarding the herbal drug regulations:

Before the entry of any drug into the market the quality control and other standardisation tests are necessary to confirm the quality and safety. But it is found that many national drug regulatory agencies do not have proper knowledge regarding the herbal regulations. In order to overcome these challenges the WHO has set the guidelines for the herbal medicines which will be useful for the regulatory agencies³⁴.

CONCLUSION:

The Herbal Medicines are found to have a promising future as there is large number of plants worldwide and the modern medicines are also produced indirectly from medicinal plants. Based on the studies on herbal medicine regulation it is found that the lack of proper regulatory guidelines for the herbal medicines there is an issue with the quality. The Indian herbal drug regulation are governed by the AYUSH department and some of the flaws in the regulations include difficulties in standardization due to the polyherbal nature, lack of the post-harvest facility, raw material testing laboratories, product traceability. Globally there are herbal regulations, but not in a structured manner. It has been found that there is a lack of harmonization in the regulatory requirements of herbal products internationally.

ACKNOWLEDGEMENT:

The authors would like to thank the Department of Science and Technology – Fund for Improvement of Science and Technology Infrastructure in Universities and Higher Educational Institutions (DST-FIST), New Delhi for their infrastructure support to our department.

CONFLICT OF INTEREST:

No conflict of interest in the present study.

REFERENCE:

1. Paul C. Chikezie and Okey A. Ojiako. Herbal Medicine: Yesterday, Today and Tomorrow. Alternative and Integrative Medicine. 2015; 4(3): 2-5. Available from: URL:www.researchgate.net/publication/282837248.

2. Niharika Sahoo Bhattacharya. Recent developments in herbal drug standard in India. International Journal of Complementary and Alternative Medicine. 2019; 12(5): 186-188. Available from: URL: https://medcraveonline.com/.

3. Refaz Ahmad Dar, Mohd Shahnawaz, Parvaiz Hassan Qazi. General overview of medicinal plants: A review. The Journal of Phytopharmacology. 2017; 6(6): 349-351. Available from: URL: www.phytopharmjournal.com.

4. Stephen Bent. Herbal Medicine in the United States: Review of Efficacy, Safety and Regulation. J Gen Intern Med. 2008; 23(6):854–859. Available from: URL: www.ncbi.nlm.nih.gov/pmc/articles/PMC2517879.

5. Sanjay Sharma. Current status of herbal product: Regulatory Overview. J Pharm Bioall Sci 2015; 7(4):293-296. Available from: URL: http://www.jpbsonline.org.

6. Davyson de L. Moreira, et al. Traditional use and safety of herbal medicines. Rev Bras Farmacogn. 2014; 24: 248-257. Available from: URL: https://www.sciencedirect.com/science/article/pii/S0102695X1400012X.

7. Vijay Kumar. Herbal medicines: Overview on regulations in India and South Africa. World Journal of Pharmaceutical Research. 2017; 6(8): 690-698. Available from: URL: https://www.researchgate.net/publication/318815842.

8. Darshan Shankar and Bhushan Patwardhan. AYUSH for New India: Vision and strategy. Journal of Ayurveda and Integrative Medicine. 2017; 8: 137-139. Available from: URL: http://elsevier.com/locate/jaim.

9. Shrivastava Alankar, et al. Clinical trial of herbal drugs and products in India: Past and current status and critical issues. Research J. Pharm. and Tech. 2008; 1(2): 69-74.

10. World Health Organization (WHO). Quality control methods for medicinal plant materials. Geneva: WHO. 1998; 1-127. Available from: URL: https://www.who.int/.

11. World Health Organization (WHO). General guidelines for Methodologies on research and evaluation of Traditional medicines. Geneva: WHO. 2000; 1-80. Available from: URL: https://www.who.int/.

12. OECD guidelines for testing of chemicals: Acute oral toxicity-acute toxic class method. 2001. Pharmacopoeia Commission for Indian Medicine and Homoeopathy. Available from: URL: ttps://www.academia.edu/3780435/OECD_Guideline_for_Testing_of_Chemicals_Acute_Oral_Toxicity_Acute_Toxic_Class_Method.

13. Quality Control Manual for Ayurvedic, Siddha and Unani Medicine. India: Pharmacopoeial Laboratory for Indian Medicine. 2008. Available from: URL: https://www.researchgate.net/publication/224944102_Quality_control_manual_for_Ayurvedic siddha_and_Unani_Medicines.

14. Lavekar, Padhia EE, Pant P, et al. Laboratory Manual for the Analysis of Ayurveda and Siddha formulations. India: Central Council for Research in Ayurvedic Sciences. Ministry of AYUSH; 2010. Available from: URL: https://www.worldcat.org/title/laboratory-guide-for-the-analysis-of-ayurveda-and-siddha-formulations/oclc/660089454.

15. World Health Organization (WHO). Quality control methods for herbal materials. Geneva: WHO. 2011; 1–187. Available from: URL: https://www.who.int/.

16. GCP Guidelines for ASU Medicines. India: Ministry of AYUSH. 2013; 1–114. Available from: URL: https://www.jli.edu.in/blog/good-clinical-practice-gcp-guidelines-to-provide-new-direction-for-asu-trials/.

17. General Guidelines of Safety/Toxicity Evaluation of Ayurvedic Formulations (CCRAS, 2016). India: Central Council for Research in Ayurvedic Sciences. Ministry of AYUSH. 2018; 1–94.

18. General Guidelines For Drug Development Of Ayurvedic Formulations (CCRAS, 2016). India: Central Council for Research in Ayurvedic Sciences. Ministry of AYUSH. 2016; 1–123.

19. General Guidelines for Clinical Evaluation of Ayurvedic Interventions (CCRAS, 2016). India: Central Council for Research in Ayurvedic Sciences. Ministry of AYUSH. 201; 1–123.

20. Niharika Sahoo and Padmavati Manchikanti. Herbal Drug Regulation and Commercialization: An Indian Industry Perspective. The Journal of alternative and complementary medicine. 2013; 19(12): 957-963. Available from: URL: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3868382/.

21. Nitin Verma. Herbal Medicines: Regulation and Practice in Europe, United States and India. International Journal of Herbal Medicine 2013; 1 (4): 1-5. Available from: URL: www.florajournal.com.

22. Regulatory requirements for registration of Nutritional supplements and Herbal products in India: A case study. Journal of Analytical and Bioanalytical Techniques. 2011; 2(6): 6-53. Available from: URL: www.wjpr.net.

23. Ministry of AYUSH Official Website. Available from URL: https://www.ayush.gov.in/ .

24. Budhwar Vikaas, Yadav Sunita, et al. A comprehension study on regulation of herbal drugs in USA, European Union and India. International Journal of Drug Regulatory Affairs; 2017; 5(4): 8-17. Available from URL: https://www.researchgate.net/publication/235393678.

25. Chaduvu Ramakrishna, Jayachandra Reddy. P, Alagusundaram. M. Current Regulations for Herbal Products. International Journal of Advance Research, Ideas and Innovations in Technology. 2017; 3(3): 1597-1604. Available from URL: www.ijariit.com/manuscripts/v3i3/V3I3-1637.pdf.

26. Rudra Prasad Giri, et al. Regulation on herbal product used as medicine around the world: a review. International Research Journal of Engineering and Technology. 2018; 5(10): 217-223. Available from URL: https://www.irjet.net/archives/V5/i10/IRJET-V5I1037.pdf.

27. Malathi Seshasayee Konda Ramadoss and Kailasam Koumaravelou. Regulatory compliance of herbal medicines – A review. International journal of research in pharmaceutical sciences. 2019; 10(4): 3132-3135. Available from URL: www.irjet.net.

28. Ruiz-Poveda OMP. Regulation of Herbal (Traditional) Medicinal Products in the European Union. Pharmaceutical Regulatory Affairs: Open Access. 2015; 4(2): 1-5. Available from URL: www.pharmascope.org/ijrps.

29. Khushboo Mayurbhai Vora, et al. Regulatory Requirements for Registration of Herbal Medicinal Products in European Union and Australia. International Journal of Pharmaceutical Sciences Review and Research. 2015; 31(1): 147-153. Available from URL: https://www.hilarispublisher.com

30. Avdhesh Kumar, et al. Regulations And Challenges Of Herbal Medicines In Russia. International Journal of Ayurvedic and Herbal Medicine. 2016; 6(1): 2149-2161. Available from URL: www.globalresearchonline.net.

31. Ngcobo, M, et al. Recommendations for the development of regulatory guidelines for registration of traditional medicines in South Africa. Afr J Tradit Complement Altern Med. 2012; 9(1):59‐66. Available from URL: https://pubmed.ncbi.nlm.nih.gov/23983321/.

32. Rakesh K Sindhu and Parneet Kaur. Regulatory Requirements and stability testing of Ethnomedical Plant Products. Research J. Pharm. and Tech 2020; 13(3):1538-1542. Available from URL: https://rjptonline.org/.

33. Tripti Jain, et al. Regulatory Status of Traditional Medicines in Different Countries: An Overview. Research J. Pharm. and Tech. 2011; 4(7):1007-1015. Available from URL: https://rjptonline.org/.

34. Nishith. M.C, M.P. Venkatesh. Herbal Drug Regulatory Landscape: Key comparison between Russia and India. Research J. Pharm. and Tech. 2019; 12(12): 6153-6156. Available from URL: https://rjptonline.org/AbstractView.aspx?PID=2019-12-12-92.

Received on 22.07.2020 Modified on 13.09.2020

Research J. Pharm.and Tech 2022; 15(3):1348-1352.

DOI: 10.52711/0974-360X.2022.00225