Regulatory Problems That Require Solution
Table of Contents:
Monitoring of A.Y.U.S.H. G.C.P. Guidelines
Putting into practice the new A.Y.U.S.H. G.C.P. guidelines, in fact, stirs up a hornet’s nest. For example, existing regulatory and licensing authority in Ayurveda is not competent to monitor the implementation of A.Y.U.S.H. G.C.P. guidelines because of a lack of infrastructure and human resources. Authorizing a Western medicine regulatory authority for this purpose is unscientific and unethical. A competent regulatory authority for quality assurance of ayurvedic product development needs to be formed with an advisory board comprising ayurvedic experts from various sectors like Ayurveda research and practice, drug manufacturing and marketing experts and members from administrative and academic sectors of government departments and ayurvedic institutions. This should be developed over a time period of 3-5 years.
Product development, according to A.Y.U.S.H. G.M.P. guidelines, calls for the investment of huge amounts of money and time which will not be affordable to most of the manufacturers of ayurvedic medicine. Lack of infrastructure, non-availability of clinical research experts in the Ayurveda sector and small market volume compared to Western medicine are deterrents.
Before formulating a better set of guidelines, the Department of A.Y.U.S.H. should conduct workshops in different parts of India involving experienced physicians from clinical practice, clinical research, Ayurvedic medicine manufacturing and medicine marketing. The new guidelines should be implemented step by step in a phased manner over a span of 8-10 years. The pertinent question here is: Why should we strive to formulate new products when there are numerous formulae in Ayurveda classical texts not requiring clinical trials? Classical texts describing such formulae should be included in the First Schedule.
Revision of First Schedule
An approved list of classical ayurvedic texts (First Schedule) does not cover important texts like Vaidyamandrama, Ydgdmrtam, Cikitsamanjari and so on which have been widely used by Ayurveda exponents for many generations. As these texts are not included in the First Schedule, formulations from these texts are considered to be proprietary medicines according to A.Y.U.S.H. G.C.P. guidelines. A.Y.U.S.H. G.C.P. guidelines state that clinical trials are required for formulae outside the First Schedule, even if they are in traditional dosage forms like kvatha, arista, cfmja or avaleha. The First Schedule should, therefore, be revised in consultation with physicians, manufacturers and academics before implementing new quality assurance rules for Ayurvedic proprietary medicines.
Interest in Ayurveda has been growing all over the world ever since the World Health Organization (WHO) convened the International Conference on Primary Health Care (6—12 September 1978) at Alma Ata, in the former Soviet Republic of Kazakhstan (Kumar 2016). This interest arises primarily from the belief that Ayurveda is a form of natural medicine utilizing herbs. Nevertheless, when one gets closer to Ayurveda, it becomes apparent that heavy metal-containing preparations are also freely employed. The First Schedule of Drugs and Cosmetics Act, 1940, lists 54 classical texts, out of which many deal with rasasastra or the art of treating diseases using mercurials. This is a self- contradiction. To erase the stigma attached to Ayurveda following the report of Saper et al. (2004), these rasasastra texts should be replaced with Sanskrit texts dealing with herbal Ayurveda. This calls for revision of the First Schedule.
Regulation of Change in Dosage Form
Ayurvedic practitioners traditionally used to prepare the same formula in different dosage forms for different conditions of the disease, even though the original formula might have been mentioned in only one dosage form in classical texts. An example is Indukantam kvatha, the original formula described as a ghrta in the text (Vaidyan and Pillai 1985). A.Y.U.S.H. guidelines limit the privilege of the physician or the manufacturer who manufactures the medicine for the physician by making clinical trials mandatory for any change in dosage form or dose. Ayurvedic medicines with the same formula, but in a different dosage form, should be considered under the classical medicine category only.
Regulation of Complementary Products
These days ayurvedic soaps are widely manufactured to protect the skin from dirt and germs. Chandrika, Medimix, Margo Neem Soap, Hamam Tulsi Soap and Himalaya Herbal Soap are some of them. They are considered proprietary ayurvedic products and their licensing, therefore, requires clinical trial reports, according to A.Y.U.S.H. G.C.P. guidelines. Even for the renewal of a license, phase 3 and 4 clinical trials are essential. In the larger interest of Ayurveda, such complementary products should be exempted from the ambit of A.Y.U.S.H. G.C.P. guidelines, and if necessary, only a pilot safety study should be insisted upon.
Labeling of Products
Bhalerao et al. (2010) carried out an interesting survey on the labeling information on 190 labels (101 classical and 89 proprietary formulations) of three ayurvedic pharmacies. The information given in them was checked against a set of quality criteria given in the Drugs and Cosmetics Act, 1940. The results were expressed as percentages. References to authoritative books as specified in the First Schedule of the Act were mentioned on only 90% of labels of the 101 classical formulations surveyed. 55% of labels of classical drugs and 88% of labels of proprietary drugs listed the ingredients. Only 20% of classical formulations’ and 15% of proprietary formulations’ labels mentioned warnings.
The authors observed that majority of the labels did not fulfill all the requirements that were mandatory as per the Act, and there was not even a single label which fulfilled all ten requirements specified by the Drugs and Cosmetics Act, 1940. The survey showed that nearly 45% of the classical formulations and 12% of proprietary formulations did not list the ingredients (Bhalerao et al. 2010). Similar findings were also reported by Mallick et al. (2012).
The Drugs and Cosmetics Act, 1940, states that mentioning the expiry date of a product is mandatory only in the case of ayurvedic medicines exported from the country (Anonymous 2002). It implies that it is not compulsory for the expiry date to be printed on containers of products marketed in India. This can be construed as permission to keep and use ayurvedic products for any number of years without a loss in quality. Nevertheless, Sarngadhara Samhita clearly specifies that all ayurvedic drugs should have an expiry date (Bhalerao et al. 2010). According to it every ayurvedic formulation has a specific savTryata avadhi. It means that the medicinal constituents in the formulation are active only for a given period of time and that keeping those formulations beyond that period can render them ineffective. For example, a ciirna has a savTryata avadhi of only four months, and if used beyond that period, the formulation may be ineffective (Bhalerao et al. 2010). Therefore, the printing of expiry date on labels should be made mandatory even for ayurvedic medicines sold inside the country.
The Drugs and Cosmetics Act, 1940, does not insist on processing details of Bhasmas. There are several methods for the preparation of one bhasma in ayurvedic texts (Anonymous 2003). Therefore, it is necessary to specify which method was used in the manufacture of the formulation in question. Considering the reports on the presence of heavy metals in Bhasmas (Saper et al. 2004, 2008; Kales and Saper 2009), it will be appropriate to also mention the heavy metals content on the product labels.
None of the labels specified potential interactions with food and synthetic medicine, as providing these details for ayurvedic drugs is not mandatory according to the Drugs and Cosmetics Act, 1940. It is widely believed that ayurvedic medicines are safe, as they are “natural”. However, now it is known that many herbs have the ability to affect the CYP450 enzyme system. The most notable among them is St John’s Wort (Hypericum perforatum), which reduces the plasma concentration of many drugs such as amitriptyline, digoxin, theophylline, non-steroidal anti-inflammatory drugs (N.S.A.I.D.s), and oral contraceptives (Izzo and Ernst 2001). St John’s Wort also increases the activity of multidrug transporter P-glycoprotein efflux pumps in the duodenum. This mechanism has been implicated in its interactions with indinavir, digoxin, and cyclosporin. It also increases the metabolism of protease inhibitor indinavir, resulting in therapeutic failure. It has also been implicated in reducing the bioavailability of cyclosporine, an immunosuppressive agent given to transplant recipient patients (Mai et al. 2000; Milic et al. 2014; Bhadra et al. 2015).
Serious adverse effects have been encountered with warfarin due to herb-induced inhibition of its metabolizing enzymes. These effects include spontaneous post-operative bleeding, hematomas, hematemesis, melena, subarachnoid hemorrhage, subdural hematomas and thrombosis. The herbs that can cause such adverse reactions include Allium sativum, Areca catechu, Boswellia serrata, Camellia sinensis (tea), Hibiscus sabdariffa and Zingiber officinale (Milic et al. 2014; Bhadra et al. 2015; Izzo 2012; Izzo et al. 2016).
The common ayurvedic herb licorice (Glycyrrhiza glabra) contains glycyrrhizin and glycyr- rhetinic acid. These phytocompounds are potent inhibitors of ll-(3 hydroxy steroid dehydrogenase, causing raised cortisol and increased mineralocorticoid activity, leading to hypertension and suppression of the renin-angiotensin aldosterone system. Licorice also interacts with some antihypertensives and antiarrhythmics (Serra et al. 2002). Therefore, manufacturers of ayurvedic medicines should also provide some information about the safety of the formulations (including dosage schedule and drug storage conditions) on the drug labels. The drug control department should enforce the laws pertaining to the marketing of ayurvedic medicines. These measures will prevent the irrational use of ayurvedic medicines.
Revision of Schedule E1
A list of potentially toxic ingredients including heavy metals has already been classified under Schedule El of the drugs and cosmetic rules as a special category (Anonymous 2016a). Nevertheless, it includes only 21 drugs from Ayurveda and has not been amended since 2010. In 2010 certain ingredients like red oxide of lead were also removed from the list, which previously contained 25 entries. The Drugs and Cosmetics Act, 1940, needs to be amended appropriately to include potentially toxic drugs in Schedule El. This can be achieved with the help of an expert committee that can review the available recent literature and formulate the list of such ingredients to be appended to the list. Additionally, a separate document for the appropriate detoxification-cum-potentiation protocols for toxic drugs in recommended media is also required (Ilanchezhian et al. 2010). This is all the more important, as sodhana procedures enhance the medicinal value of the herb in addition to removing toxic phytocompounds (Singh et al. 1985; Mitra et al. 2012; Acharya 2014).
Effective Implementation of the Act
Sahoo and Manchikanti (2013) carried out a questionnaire-based survey to assess the constraints faced by the Indian herbal medicine industry. Responses were collected from 150 companies through email, telephone and personal interviews. Insufficient regulatory guidelines, particularly guidelines for G.M.R; non-implementation of good agricultural and collection practices; and weak implementation of the Drugs and Cosmetics Act, 1940 were mentioned as major impediments to the industry. The implementation of G.M.P. is decisive for the quality of herbal medicines. Most of the respondents suggested that apart from Schedule T, separate guidelines on quality control and quality assurance should be developed and that greater emphasis should be laid on documentation.
A major drawback of the Indian herbal industry is the implementation of the Drugs and Cosmetics Act, 1940, and its regulation. The survey revealed that only 107 of the 150 surveyed companies were G.M.P. compliant, even though G.M.P. compliance as per Schedule T of the Act has been mandatory since 2006. Further, survey responses revealed that the drug licensing authorities in various states of India interpret the Drugs and Cosmetics Act, 1940 differently. Consequently, the same medicine that is not permitted in one state is allowed to be manufactured in another state. The survey also identified non-uniformity in the drug registration timeline across states as a major problem. Development of unified protocols, defined timelines and specific guidelines defining the meetings with regulators may remove the anomalies related to state licensing authorities and establishing a unified system in the country (Sahoo and Manchikanti 2013).
In addition to the brhatrayi (greater triad) and laghutrayi (lesser triad), many Ayurveda texts have become popular over the centuries. Vaidyamandrama, Ydgdmrtam and Cikitsamanjari are three such texts that are immensely popular in Kerala. Many unique and potent formulae unavailable in other texts are described in these works. Considering their inherent value, these and similar texts need to be included in First Schedule.
The fine prescribed for many violations of provisions of Drugs and Cosmetics Act, 1940, is very nominal. For example, if an Inspector commits offences like searching any place, vehicle or vessel without reasonable ground, or vexatiously and unnecessarily seizes any drug or cosmetic, or any substance or article, or any record, register, document or other material object, he shall be punishable with fine which may extend to 1000 rupees. Similarly, whoever manufactures for sale or for distribution, or sells, or stocks or exhibits or offers for sale any cosmetic other than a cosmetic referred to in clause (i) in contravention of any provision of Chapter 4 or any Rule made thereunder, shall be punishable with imprisonment for one year or with fine of 1000 rupees or with both. The penalty for non-disclosure of the name of the manufacturer is imprisonment for one year, or with a fine of 1000 rupees or with both (Anonymous 2016a). The levying of the fine is intended to act as a deterrent to violations. One thousand rupees is not a large sum in contemporary India. Therefore, the amounts of fine prescribed for many of the violations of the Act need to be revised for its implementation.
Insufficient regulatory guidelines and weak implementation of the Drugs and Cosmetics Act, 1940, are often mentioned as major impediments to Ayurveda industry. The existing regulatory and licensing authority in Ayurveda is not competent to monitor the implementation of A.Y.U.S.H. G.C.R guidelines because of the lack of infrastructure and human resources. Entrusting this responsibility to the Western medicine regulatory authority is unscientific and unethical. A competent regulatory authority needs to be formed with an advisory board comprising ayurvedic experts, marketing experts, administrators and academics. According to industry sources, apart from Schedule T, separate guidelines on quality control and quality assurance should be developed and implemented effectively.
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