Strategic archetype of Herbal Medicine Product (HMP) in Regulated and Emerging Market

Swagat Tripathy¹*, PN Murthy², BP Patra³, Vikram⁴, Sumit Sanduria⁴ , Harish Dureja⁴*

¹Dr. Reddy’s. Laboratories, Hyderabad, Telangana, India – 500034.

²Royal College of Pharmacy and Health Sciences, Berhampur, India – 760002.

³XIMB, Xavier Square, Jayadev Vihar, Bhubaneswar, Odisha, India – 751013.

⁴Department of Pharmaceutical Sciences, Maharshi Dayanand University, Rohtak, India – 124001.

*Corresponding Author E-mail: swagat.tripathy7@gmail.com

ABSTRACT:

Herbal Medicine Products (HMPs) are ever-present and demand still keeps on the rise, despite of fact that modern medicines are well developed. So, regulative intervention and attempts by various regulatory bodies across the globe to ensure the safety, quality, and efficacy of HMPs have been a real-time challenge.  While Allopathic medicines principally depict chemical substances, and those interactions had been well-known, validated also, proper regulatory standard then relevant measures are put into action. HMPs, instead by and large consisting numerous ingredients holding multifaceted combinations along with plant constituents then frequently likewise comprise of roughly anonymous complexes, therefore, building affecting regulatory framework toward measure affecting worth about those drugs is more tricky. So, through this manuscript efforts have been made to summarize definitions, basis of formulating policies and measures pertaining on registration and regulation of herbal medicinal products (HMPs) for both regulated and emerging markets i.e., United States, India, China, Japan, and Europe. 

KEYWORDS: WHO, Herbal Medicines Products, USFDA, EMA, AYUSH, NMPA, PMDA.

1. INTRODUCTION:

Historical information suggests that therapeutic plant utilization goes back to the Palaeolithic period, around 60,000 years ago;^1,2 in twenty-first centuries, contamination, an unwanted existence, and pollutants in the atmosphere are a threat to diseases. Additionally, symptoms and misuse/abuse of allopathic medicines remain a significant worry.³ As a result, herbal medications are in high demand in both emerging and developed countries due to their efficacy, safety, and lack of adverse effects when compared to synthetic compounds⁴. The World Health Organization published "The WHO Conventional Medication Approach 2014-2023" in 2013, emphasizing the integration of traditional and reciprocal drugs to improve overall social insurance and guarantee the quality, safety, and adequacy of these drugs.³ Herbal drugs also playing a vital role in Diabetes mellitus,^5,6 and current covid-19 situation.⁷

The global pharmaceutical companies has been modifying profoundly in the last decade.⁸ Approximately 80% consisting affecting overall populace remains estimated can put faith in traditional medicines (TM) along with those fundamental medical maintenance requirements.⁹ Herbal Medicines are significant portion of the most essential medical care frameworks around the globe.¹⁰

The interest in Herbal has been expanded among the nineteenth to twenty-first centuries when affecting cutting-edge arrangement of medication neglected to address testing sicknesses like malignancy, psoriasis, tuberculosis, osteoarthritis, and so forth.¹¹

As per World Health Organization (WHO), HM are characterized as "Aerial or underground plant parts or other plant material containing an active ingredient as a finished labeled medicinal product.”¹²

1.1 The WHO has classified Herbal Medicines into different four categories:

Category 1:  Native HMPs, this classification of herbal medicinal products is traditionally used in a particular community or area and is well known in terms of its structure, care, and dosage by the local people over long periods of use.

Category 2: This category of medications has been about since a prolonged period then are well-known and recognized by countries with their special theories and principles. Ayurveda, Unani, and Siddha, for instance, will fall under the TM range.

Category 3: HM has been tweaked Apart from whatever shape or form, including portion, measurement structure, way of organization, HM therapeutic fixings, preparedness techniques, and clinical indicators, these are HM prescriptions as defined in Categories 1 and 2. They have to comply with the national safety and effectiveness regulatory criteria for herbal medicines.

Category 4: Imported herbal medicinal products this category includes all herbal medicinalproducts imported, inventory of raw materials and components. Introduced HM should be licensed and put into the market. The information on protection and effectiveness must be sent to the national import authority.¹³

1.2 Global Market Scenario of Herbal Medicine:

The ageing population, more consumer knowledge, reduced or no adverse effects, providing advancements, and the FDA's issue about CGMP (current good manufacturing practice) toward DS(dietary supplements) are all driving forces in the USA Traditional Medicine industry. Other causes include rising pricing, health budget considerations, and a shift in consumers toward herbal treatment systems that are cost-effective, economical, and safe. Taking all of these variables into account, by the end of 2023, the market for traditional medicine is expected to reach $115 billion, with a CAGR of 7.2 percent from 2017 to 2023.¹⁴

In 2020, the HPMC market in the EU will be worth USD 4.6 billion. Between 2021 and 2026, the market is anticipated to increase at a CAGR of 3%, reaching USD 5.5 billion by 2026.¹⁵

The market for herbal medicinal goods in India was valued Rs. 4.2 billion (US$ 56.6 million) in 2019, and is expected to grow at a CAGR of 38.5 percent to Rs. 14 billion (US$ 188.6 million) by 2026. At the moment, the worldwide herbal trade is worth US$ 120 billion.

Traditional and complementary medicine markets in China and Japan range depending on the source, the amount ranges from US$6 billion to US$20 billion.¹⁴

2. Regulations of Herbal Medicinal Product in Regulated Market:

2.1. HMPs regulation in United States America (USA):

Under the "Federal Food, Drug, and Cosmetic Act (FD&C Act)," a botanical product can be categorized as a food (containing dietary supplements), medicine, medical device, or therapy. The intended purpose about an article determines whether it is a, medication, medical device, or cosmetic, however for some product classifications, additional considerations must also be considered.¹⁷ A botanical product intended for use in diagnosing, restoring, modifying, or treating illness fulfills the definition of medicine under section 201(g)(1)(B) of the FD&C Act and is therefore subject to the regulations.¹⁸ Under FDA guidelines for HMPs published by the “Center for Drug Evaluation and Research,” herbal medication products are divided into two categories: those sold over the counter (OTC) and those that require a New Drug Application (NDA).^12,16

Approval process HMPs in USA:

To request the addition of a botanical drug product to an OTC pharmaceutical monograph, a resident appeal under 21 CFR 10.30(a) 12 or TEA (Time and extent application) under 21 CFR 330.14 is used.¹⁹ A botanical medicine substance should remain documented cutting-edge therefore authoritative USP-NF (US pharmacopeia and national formulary) monographs on a medicine establishes the requirements for character, durability, high quality, then immaculateness for an OTC medication monograph.²⁰ Therefore, a solicitation to remember a botanical drug substance for an OTC medication monograph ought to contain direct link toward the relevant USPNF pharmaceutical assessment. Without a USP-NF drug monograph, the solicitation ought to contain a recommended specification aimed at incorporation with a publication that will be perceived cutting-edge and authority USPNF pharmaceutical assessment, by way of given popular 21 CFR 330.10(a)(2).¹⁸ After publishing the final OTC drug monograph of a herbal drug product for a specific indication, any individual can sell that product, the only need is that he supplies the labeling and additional active components (if present) under all relevant monographs and other applicable requirements. Even if patent protection is not available, the USFDA grants the drug developer 5 years of market exclusivity from the time of approval for a new drug entity if it has been authorized under an NDA. Under 314.108, a new herbal medication that comprises several chemical ingredients may be considered as another synthetic compound (a). During the period of selection of a herbal medicine product, if another producer qualifies his product as another synthetic compound for the same indication, the FDA won't support it, or in certain circumstances even consider it, until the second manufacturer submits a 505 application (b).⁹ As a result, if the manufacturer would like to sell a HMPs that is excluded from the current OTC medication monograph, he should seek approval of an NDA after demonstrating the safety and effectiveness of his product rather than requesting the competent authority to change a monograph. Furthermore, a document containing a schematic description of alternative regulatory methods, such as an OTC drug monograph and NDA procedures, can assist in the marketing of HMPs in the USA. AHPA published the GACP (Good Agriculture and Collection Practices) guideline in the American Herbal Pharmacopoeia to assure a high level of security and viability of HMPs, as well as QC (Quality control) requirements throughout the manufacture of herbal supplements and medications.¹²

2.2. HMPs regulation in European Union (EU): HMPs, marketing permission issued under European directive 2001/83/EC based on the findings about reliability, security, or effectiveness studies and experiments. The key characteristics about directive 2001/83/EC include the definition of traditional herbal medicine, provisions for a common list of herbal compounds and community herbal monographs, and a streamlined registration procedure.²⁰ The Committee on herbal medicinal products (HMPC) of EMA was established in September 2004 in accordance with regulation (EC) No.726/2004 and directive 2004/24/EC. The European directive 2004/24/EC streamlines the registration procedure aimed at herbal pharmaceuticals, as many firms struggle towards meet the standards of directive 2001/83/EC, notably in regards as for effectiveness with THMPs. The HMPC's key duties include the evaluation of medicinal goods, the simplification of registration, approval among the HMPs, the development of community herbal monographs and the compilation of a list of herbal components or formulations²¹ Herbal medical products, herbal medication compounds, and herbal products have been identified. in directive 2004/24/EC as follows:²²

Herbal Substances:

Herbal compounds are unprocessed, typically dried whole plants, plant parts, cut plants, mushrooms, algae, lichen, and certain exudates of plants in their natural state. The binomial method is used to classify and recognize medicinal compounds, which are classified and perceived based on the plant section and botanical name.

Herbal formulations (HFs):

Concentrates, fundamental oils, communicated juices, powdered HM substances, colors, and refined exudates are created from natural substances that have gone through different cycles like extraction, articulation, refining, fractionation, cleaning, fixation, or maturation. The following three types of herbal medicinal products are available: 1. A conventional HMPs with appropriate safety evidence and probable effectiveness, as well as a customary utilization enlistment (worked on enrollment technique) gave by a Member State. 2. In relation to proven clinical usage conditions, an herbal medicinal product may be sold (all around established use). This is shown by ample protection and efficacy evidence. As a result, the herbal substance may be approved for sale in certain instances, by EMA or member state. 3. An advertising approval request containing solitary "precise protection then effectiveness details of the substance" can be authorized for an herbal product (full dossier). Following that, if all conditions are met, the HM substance is allowed a promoting grant by the Agency or a Member State by means of the incorporated cycle.²³

The approval process of HMPs in EU:

Most herbal medicinal products are granted marketing permission by individual European Union member states; however, knowledge about the products and their approval is synchronized in the EU. Following that, if all conditions are met, the HM substance is allowed a promoting grant by the Agency or a Member State by means of the incorporated cycle. The HMPC produces local area monograph on herbs focused happening empirical proof in terms of protection and effectiveness of HM and their clinical uses. In addition to non-clinical and clinical statistics, the HMPC keeps track of all scientific evaluations of herbal products' long-term use and practice in the community. Established utilization and traditionalistic usage are affecting two categories of community monographs (marketing authorization). The conventional usage segment is focused on appropriate safety data and possible effectiveness, while the well-established use segment is based on safety and efficacy data. A typical usage registry or marketing permit claimant may use the final group monograph as reference material for their submission. The Community catalog of herbal ingredients, formulations, and varieties, as well as the Community herbal monographs, are lawfully adhered to by qualified authorities and applicants in the Member States as follows:

1. It is not required for an inquirer to have verifications of the safe and traditional utilization of an herbal medicine therapeutic item that he is looking for a conventional usage enlistment uncertainty he validates so affecting suggested natural therapeutic item then connected cases according to application adhere to the terms set out cutting-edge affecting gathering timeline.

2. knowledgeable officials don’t possess the right along seek extra details via ascertain the product's conventional use and protection.²⁴

The ‘Community list' is steadily built up by list entries. Since the Committee has included an herbal drug or commodity in a draught list, it is made available for public comment for three months on the committee's website. The HPMC does a research paper review prior submitting a list entry to the European Commission for endorsement. The “European Commission (EC)” then releases the group list as a result of this authorization.²⁴

The following information is contained in the list entry document:

1) In both EU languages, the generic name of the herbal drug, as well as its scientific/botanical name.

2) The effectiveness and dosage of an herbal drug.

3) The drug type and administration path.

4) Some other details needed for the herbal drug or preparation, such as contraindications, warnings, and safeguards.

The process, SOPs, structure, and framework for revising and planning community list entries and community monographs on the EMEA website, they have been made available. The HPMC created a system for collecting scientific evidence and information on HMPs from the public. This instruction will be utilized by the Committee throughout the production of local area list entries and Company monographs. Logical supporting proof might be submitted to the board in paper design (two duplicates through post or fax) or electronic arrangement (email or CD-ROM) during the 2-month term following the distribution date in light of a solicitation for the accommodation of logical information. The HMPC has made all under planning monographs and finalized group monographs on the EMEA website, you'll find it.

The Community pharmacy regulation had established an enforceable association structure that could be used in supposing recommendations. In particular recommendations result in the Commission giving a single preference directed at altogether member states, this was accounted aimed at data in relation to applicants before holders of advertising authorizations. Regardless of these references, as illustrated in articles 29, 30, 31, 35, and 36 of directive 2001/83/EC, community drug guideline has likewise settled an instrument by which member states can allude such THMP matters to the Agency's HMPC without requiring a local area strategy. These situations are probably going to emerge in: "Competence about proof of constant usage recommendation" is specified in “Article 16c (1)(c) of Directive 2001/83/EC”. 2. Article 16c (4) of Directive 2001/83/EC ("Traditional usage for less than 15 years ").²⁵

2.3 HMPs regulation in Japan:

Herbal medicine products developed from natural sources are known as traditional herbal remedies in Japan. There are two types of crude medicine products: Kampo products and non-Kampo crude medicine products.²⁶ Kampo medicines play an important part in Japanese healthcare. Internal assignments on the review for approval of OTC Kampo products was issued by the MHLW (Ministry of health, labor and welfare).²⁷

The approval process of HMPs in Japan:

The OTC Kampo product approval requirements address appropriate raw medication segment ratios, dose or delivery, as well as an indicator for every formulation. There are presently 294 formulas recorded. These Kampo formulations have been used for a long time, then no pre-clinical or clinical evidence remains required according to the approval criteria.²⁶ Table (1) shows information needed during OTC Kampo product request according to their approval criteria.²⁶

Table 1: Data required for approval of Kampo products.²⁶

Information provided during submission	Under the application instructions, OTC non-Kampo crude medicinal products	Under the approval requirements, OTC Kampo products	For gaining ethical standing, new non-Kampo crude drug products are needed.
A. The context of discovery, as well as the circumstances of usage in other nations i. The discovery's origins and context ii. Usage conditions in other countries iii. The clinical category, a comparative to other medicines, and other relevant data	×       × Օ	×       × օ	օ օ օ
B. Techniques of manufacture, regulations, and testing i. Physical and chemical characteristics, chemical composition, and associated data ii. Developing approaches iii. Techniques of evaluating or grading	× × Օ	× × օ	օ օ օ
C. Constancy i. Preservation for a long time ii. Experiment in harsh environment iii. Enhanced assessment	∆      ×      ∆	∆      ×      ∆	օ օ օ
D. Pharmacologic achievement i. Prime addictive ii. Subordinate addictive, Security pharmacokinetics iii. Additional pharmacologic achievement	×      × ×	×  × ×	օ օ  ∆
E. Preoccupation, circulation, digestion then evacuation i. Preoccupation ii. Circulation iii. Breakdown iv. Evacuation v. Bioequivalence vi. Additional ADME	×      ×      ×      ×      × ×	×      ×      ×      ×      ×    ×	օ օ օ օ     ×     ∆
F. Cytotoxicity, mutagenicity, or other types of toxicity (acute, subacute, and chronic), toxicity, and other types of toxicity i. Toxicology of a single dosage ii. Toxicology of repeated dosage iii. Experiment iv. Carcinogenicity v. Toxicology to the reproductive system vi. Irritation in a local area vii. Toxicology in another way	×     ×     ×     ×     ×     ×     ×	×      ×      ×      ×      ×      ×      ×	օ օ օ      ∆ օ      ∆      ∆
G. Clinical trails i. Results of clinical trails	×	×	օ

Instead in theory, օ this indicates that the specified information is necessary. this indicates that the specified information is not required. ∆ Indicate that the specified data is required on a case-by-case basis. In terms of surveys, comic PMDA (Pharmaceuticals and medical devices agency), a Japanese administrative office that collaborates with MHLW, should ensure that the dynamic fixings, substance, dose, and organization, as well as the norms and test procedures used to ensure item quality, all meet the endorsement guidelines.²⁷

3. Regulations of Herbal Medicinal Product in Emerging market:

3.1. HMPs regulation in India:

Herbal medicinal products (HMP) have been produced and sold in India since ancient times under the names Ayurveda, Siddha, Unani, and others.²⁸ HM are directed in India by the joint effort of Central Council of Indian Medicine Act, the "Exploration Councils (ICMR and CSIR)", the Division of AYUSH, and the Drug and Cosmetics Act 1940" (Amendment) under the management of the Drug Controller General of India (DCGI).²⁹ The Ministry of AYUSH regulates product licensing, composition, and formulation, as well as ensures product manufacturing, labeling, packing, and quality under Schedule" for good manufacturing practice (GMP) and monitors the export about ASU products²⁹ then also published GCP rules for clinical preliminaries.³⁸ "ASU medication" is characterized as "all prescriptions proposed for inner or outer use for or in the finding, treatment, alleviation, or counteraction of infection or aggravation in people or creatures just under the formulae depicted in approved books."³²

The approval process of HMPs in India:

Herbal Medicinal products are regulated in India as stated by Drug and Cosmetic Act (D and C) 1940 and Rules 1945which explicitly spell out the administrative arrangements for ASU medication in Chapter IV-A. From section 33C to section 33 O, there are 18 distinct sections. These sections cover all aspects of ASU drug legislation, including manufacturing, selling, registering, obtaining a GMP certificate, licensing, and fines have been tabulated in Table 2.

Table 2: Different sections of the ASU drug regulation.⁴⁰

Components	Title
33C	Technical Advisory Board for ASU Drugs.
33D	The Consultative Committee on ASU Drugs.
33E	Drugs those are mislabeled.
33EE	Adulterated drugs.
33EEA	Illegal drugs.
33EEB	Ayurvedic, Siddha, and Unani medicines are manufactured and sold under strict regulations.
33EEC	Certain ASU medicines are prohibited from being manufactured or sold.
33EED	In the public interest, the Central Government has the authority to ban the manufacturing of Ayurvedic, Siddha, or Unani medicines, among other things.
33F	Analysts for the government.
33G	Inspectors are on the job.
33H	Sections 22, 23, 24, and 25 are all used in this case.
33I	Manufacturing, selling or distributing ASU medicines over violation this chapter's is punishable.
33J	Punishment during later misconduct.
33K	Seizure is a legal term that refers to the taking of something
33L	Government departments are subject to the clauses.
33M	Recognizance of wrongdoing.
33N	The ability of the central government to enact legislation.
33O	The need to change the First Schedule.

Ayush updates the ASU drug rules regularly. There were previously no criteria for conducting clinical studies, but in March 2013, Ayush announced new GCP aspects of clinical studies on “ASU” medicines. The guidelines aim to create two cardinal principles: the security of human subjects' privileges and the veracity of ASU medication clinical preliminary information. The CDSCO demonstrate GCP regulations aimed at pharmaceutical product clinical trials serves as the foundation for these suggestions.³¹ They should be pursued for all ASU medicine studies in India at all levels of drug improvement, including when item enlistment in India. From 2017 onwards, it's also mandatory that there must be expiry and manufacturing date present on the product label.³¹

3.2. HMPs regulation in China:

On April 24, 2015, the standing committee of China's National People's Congress revised the People's Republic of China's Food Safety Law of 2009. The new legislation took effect on October 1, 2015. The China Food and Drug Administration (CFDA) issued suggested changes in relation to food safety legislation applying regulation for public comment on December 9, 2015.³⁴ Under the National Medical Products Administration, a new unified structure was created (NMPA).³⁵ The NMPA is the main regulatory agency liable for drug enlistment the executives, formulation of drug registration standards, and evaluation and approval of drug registrations. Medication clinical preliminary applications, drug promoting approval applications, additional applications, and medication re-enrollment applications for foreign manufactured medicines are all reviewed by the NMPA's Drug Evaluation Center (CDE).³⁶ Traditional Chinese medicine products are classified as either "classified as supplements" or "classified as medicines" under the Chinese Food Safety Law. "Classified as Medicines" ingredients consume a large appearance cutting-edge China then are widely mentioned toward as TCM.³⁷

The approval process of HMPs in China:

The marketing authorization holder can submit applications for drug clinical trials, drug marketing authorization, re-registration, and supplemental applications. After completing the pre-clinical and clinical research that supports the drug registration, the applicant must submit the drug marketing authorization application in accordance with the rules. If the application materials pass a formal assessment and fulfill the standards, approval will be granted. The Drug Evaluation Center (CDE) gathers pharmacy, technological and health care specialists via assesses applications for drug showcasing approval that have been accepted. After the entire review is completed, certificate of drug registration is issued. The application is disapproved if the complete review's result is not passed. The review process for marketing authorization is shown in figure 1.³⁸

Figure: Process flow for market authorization(China).³⁸

Table 3: Similarities and differences in regulatory aspects of herbal medicine products.^{39, 40}

	USA	European Union	India	China	Japan
Regulatory body	Food and drug administration (FDA)	European medical agency (EMA)	Central drug standard control organization (CDSCO)	China food and drug administration (CFDA)	Ministry of Health, Labor, and Welfare (MHLW)
Terminology used for HM	Botanical drugs	Herbal medicinal product	Traditional herbal medicine	Traditional Chinese medicine	Kampo medicine
Pre-market approval	Yes	Yes	Yes	Yes	Yes
Clinical data	Yes	Yes	Yes	Yes	Yes
Application submitted to	ODS (office of dietary supplements)	EMA	AYUSH	NMPA	PMDA
Therapies	Medicine only	Medicine Homeopathy	Medicine ASU (Ayurvedic, Siddha, and Unani)	Medicine and procedure	Medicine and procedure
Reported adverse/reaction	Yes	Yes	Yes	Yes	Yes
Historical usage	Yes	Yes	Yes	Yes	Yes
Format of Application submission	eCTD	eCTD	Paper submission	eCTD	eCTD
Validity Period (In year)	5	5	5	5	5

The medication enrollment declaration of a medication Marketing Authorization Holder (MAH) is substantial for a very long time. During the legitimacy time frame, the MAH is obligated for the recorded medications' security, viability, and condition controllability, or should apply for drug re-enlistment a half year before the legitimacy time frame terminates.

4. COMPARISON OF HMPS REGULATION:

Each regulatory agency has its process for approving herbal medicines. The various similarities and differences of HMP regulatory process in regulated and emerging markets is tabulated in Table 3.

5. CONCLUSION:

The monumental growth of the Pharma industry has not lessened the importance of HMPs in society. On the other hand, the needs and demands HMPs have been improved due to population growth. Regulations across the globe about the purpose of assessing the reliability, effectiveness, or security about HMPs, and affecting meticulous efforts about governing agencies for formulating the guidelines in this field, have been extremely supportive in strengthening quality embedded HMPs. When we dip dived regulations and practices followed for HMPs, we understood that the rules and regulations for herbal medicine are fully and consistently applied and controlled in the USA and the European Union. However, Indian regulations are in its infancy in comparison of the EU and USA and this area is emerging too. Because Clinical studies for herbal medicines have begun in India. However, no systematic process has been seen in India. In a similar line, we may infer that there is no adequate or unique framework for regulating herbal medication, even in China and Japan, and they intend to follow the regulations of the European Union and the United States. We aspire to believe that further fine-tuning of regulatory guidelines in India, China and Japan by referring to US and EU’s regulatory insights could turn out to be the foundation for more qualitative evaluative studies to check, safety, efficacy, and potential use of HMPs in health care systems in different parts of the world.

6. CONFLICT OF INTEREST:

No conflict of interest, financial or otherwise.

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Received on 22.07.2021           Modified on 18.08.2021

Accepted on 03.09.2021         © RJPT All right reserved

Research J. Pharm. and Tech. 2022; 15(5):1973-1980.

DOI: 10.52711/0974-360X.2022.00328