|Year : 2014 | Volume
| Issue : 4 | Page : 363-371
Approaches in fostering quality parameters for medicinal botanicals in the Indian context
Pooja D Gupta, Poonam G Daswani, Tannaz J Birdi
The Foundation for Medical Research, 84A, RG Thadani Marg, Worli, Mumbai, Maharashtra, India
|Date of Submission||01-Oct-2013|
|Date of Decision||09-Feb-2014|
|Date of Acceptance||04-Apr-2014|
|Date of Web Publication||4-Jul-2014|
Tannaz J Birdi
The Foundation for Medical Research, 84A, RG Thadani Marg, Worli, Mumbai, Maharashtra
Source of Support: The Corpus grant from Jamsetji Tata Trust to FMR
supported the authors during compilation of this review and part of its
experimental studies., Conflict of Interest: None
India is among the important megabiodiversity centers of the world with nearly 45,000 known plant species. This diversity coupled with a rich heritage of traditional knowledge has made India a home to several important time-honored systems of health care such as Ayurveda, Siddha and Unani. Herbal medicines, however, are associated with a number of shortcomings including uniform efficacy and lack of appropriate quality control measures at various stages of product development. The review intends to outline the importance of fostering quality parameters towards standardization and manufacturing of botanicals for India to emerge as a leader in global market of herbal products. Literature survey was carried out on important parameters for processing and manufacturing of botanicals. The review highlights that there have been constant efforts for developing state of the art technologies in the field of herbal research. It also reflects that Government authorities have also taken a number of initiatives to formulate appropriate guidelines from standardization of raw materials to obtaining botanical products. However, in the Indian context, there exist certain lacunae in the current regulatory mechanisms which need to be strengthened and stringently implemented to ensure safety, purity and efficacy of herbal medicines. Towards this the approaches being developed globally can be adopted. Based on the literature reviewed, in our opinion, four areas viz., benefit sharing, investment by industry, standardization and national/international networking structure need immediate attention for strengthening Traditional Systems of Medicine in India.
Keywords: India, quality control, regulations, standardization, traditional medicine
|How to cite this article:|
Gupta PD, Daswani PG, Birdi TJ. Approaches in fostering quality parameters for medicinal botanicals in the Indian context. Indian J Pharmacol 2014;46:363-71
|How to cite this URL:|
Gupta PD, Daswani PG, Birdi TJ. Approaches in fostering quality parameters for medicinal botanicals in the Indian context. Indian J Pharmacol [serial online] 2014 [cited 2023 Jun 9];46:363-71. Available from: https://www.ijp-online.com/text.asp?2014/46/4/363/135946
| » Introduction|| |
The continuing search for new drugs has seen researchers looking to the natural world for potential products. WHO estimates that about 80% of the population of developing countries relies on herbal medicines (HM) for their primary health care. They have been an important source of precursors and products used in a variety of industries, such as pharmaceuticals, food, cosmetics and agrochemicals. Traditional medicines (TM) are enjoying an upsurge in popularity because of their perceived low toxicity. Additional species are being gradually added to the Materia Medica and the standards for purity and identification do not always keep pace with this expansion. 
India is among the important mega biodiversity centers of the world with nearly 45,000 known plant species.  This diversity coupled with a rich heritage of traditional knowledge (TK) has made India home to several important health care systems viz., Ayurveda, Siddha and Unani. Whilst there is increasing demand for Indian TM globally, it is only for products validated by modern scientific research. Indian exports of around $100 million are relatively low compared to Chinese figures of $3 billion. Report by Group-II of Task Force on "Pharmaceuticals and Knowledge Based Industries" 1999 states that Indian exports of herbal products are low due to several factors, quality being most important.  To be a strong player in global herbal market, it is critical that India develops appropriate quality control systems for standardization of raw materials and finished products and to strengthen the regulatory mechanism. Therefore, it is extremely important to foster quality parameters for processing and manufacturing of botanicals by undertaking in-depth investigations on quality control at all levels viz., collection of information and harvesting of raw material, cultivation/storage, efficacy and safety evaluation through preclinical studies, phytochemical standardization, toxicity studies, in vivo assays, etc. In this review, each of these parameters has been discussed with examples of various approaches adopted and updated globally. These approaches can be implemented for modernization of botanicals in India. Additionally, the paper includes recommendations which in our opinion need immediate attention for strengthening TM in India.
| » Literature Survey|| |
In the e-era, internet resources are easily accessible and Winker et al., 2000 has highlighted the possibility of incomplete and/or misleading information being available in the field of medicine.  Hence, in this review an attempt has been made to compile relevant information mainly from published data in peer reviewed journals. The search engines accessed were Pubmed, Scidirect and google scholar. The key words used for retrieval were a combination of broad as well as section specific. Apart from the above mentioned search engines, websites on bioprospecting and biopiracy were referred and cited wherever relevant. Websites on TM hosted by Government of India (GOI) and WHO guidelines have been referred to as per their applicability. Specific examples have also been quoted from scidev.com, zebrin.com, Medicinal Plant Names Index and Information Service (MPNI).
| » Parameters for Processing and Manufacturing of Botanicals|| |
An ethnobotanical survey requires a multidisciplinary team consisting of a botanist for taxonomical and botanical characterization and a medical practitioner to identify the disease condition (e.g. differentiate between muscle pain and arthritis) and help in understanding whether a treatment is curative, alleviating only the symptoms or a mere placebo effect. Even if rapid assessment is undertaken initially it needs to be followed up with a detailed survey.
Ethnomedical information is available from ancient texts of different systems of medicines such as Kampo, Ayurveda, Unani and traditional Chinese medicine (TCM). However, while using these texts, a fact to be considered is that plants may have evolved over time resulting in changes in phytochemical composition and hence medicinal properties and therefore confirmation of efficacy is required. Nevertheless, the success rates of the ethno-based approaches are substantially higher than those of random screening.
Frequency of quote of plants by the community is a key indicator of its efficacy. However, this information may not be reliable. A particular plant may be quoted more often based on its easy availability and recognition and/or its resemblance to a certain feature of a disease e.g. seeds of Bixa orellana, that have a bright red arillus are used in herbal mixtures used for treating bloody diarrhoea.  People may also quote plants about which they have gained information from personal communication or books. Additionally, publications on medicinal plants are often compilations from other texts and seldom from personal experience, making evaluation difficult.
Consistency in data constitutes the basis for scientific evidence and evidence-based practice. This includes information about the plant name, part used, collection data, post harvest processing, storage, chemical analysis, criteria for selection, significance of in vitro and in vivo assays to traditional use, as well as the appropriateness of the techniques used to analyze the data and the robustness of the output. Development of methods to store, retrieve, share and update information is also essential. These procedures are vital in producing a precise and useful information resource which can be utilized for reproducibility of experiments and registration of evidence-based herbal therapeutics.
An in-depth identification and specification of the material used is a pre-requisite for any research to be undertaken on TM. Globally researchers face challenges in interpreting local medicinal plant names. A project at the Royal Botanic Gardens Kew, UK, aims to provide a new resource for clarity in the use and interpretation of medicinal plant names (http://www.kew.org/science/directory/projects/MPNI.html, accessed on July 11, 2013).
Complete taxonomical information is important during selection as it can play a vital role in its biological activity. Chan et al., reported the significance of identification of Chinese Materia Medica to ensure scientific accuracy in publications and their safe use.  Utilization of these principles could also be applicable to TM in India. Recording of various environmental conditions and vegetation at the collection site is required. Information regarding the geographical distribution, its abundance, threatened or endangered, shrub/fast growing tree, the botanical identity, scientific name including family, genus, species, subspecies or variety of the plant needs to be recorded. If available, the local name should also be verified. It is of immense importance that a voucher specimen be deposited in a national or regional herbarium for authentication and further consultation by other researchers. However, the herbarium specimens are often stored in a manner that makes them hard to access and are of limited use to the public. Moreover, the herbarium sheets disintegrate and fade with time. This necessitates the creation of digital repositories of fresh plants. Accessibility would become easier through digitization of the collections and reduce the need for and risk in physical handling of specimens. 
A recent thrust in the field of ethnobotany is to embrace molecular techniques and genetic identification to distinguish plant material, or to merely differentiate between several species.  A number of molecular approaches have been designed to overcome the problem of identification. Effective use of DNA fingerprinting for supporting morphological data, DNA bar-coding and the sequence divergence of parts of genes or spacer regions has been demonstrated. It is a relatively new concept aiming to provide rapid, accurate and automatic identification by using a standardized DNA region as a tag. Bar-coding does not have to displace taxonomy but can serve as a first attempt to roughly identify species in taxonomic analyses when variation within species is complex. It is still not developed entirely and is expensive, but several groups are trying to develop an operating method and interest in this field is growing. ,
Metabolomics, an emerging field, has also been used for inter/intra differentiation of plant species. Bharti et al. demonstrated the use of metabolic profiling by HR-MAS NMR spectroscopy on four chemotypes of Withania somnifera. Variations in primary metabolites among the chemotypes using multivariate principal component analysis has been reported. 
There is now wider recognition of the role of local knowledge systems (LKS) in conservation and sustainable utilization of natural resources.  However it lacks official support.  Remarkable approaches and efforts have been taken by grassroot community groups and Non Government Organizations (NGO) in revitalizing and promoting LKS of medicine.  The local communities should be acknowledged and should receive benefits for their involvement. The clauses of a benefit sharing agreement should be mutually agreed by the pertinent parties. The general rule could be of fair and unbiased sharing of benefits.  Benefits may be monetary and/or non-monetary.  Designing of a suitable modality for benefit sharing thus poses a challenge.
A research-based company, HG&H Pharmaceuticals (Pvt) Ltd, developed Zembrin®, a patented South African botanical product. It is an extract of a cultivated elite selection of the Namaqualand plant Sceletium tortuosum, used for centuries. The villagers' participation on use of plants, doses and addiction study was essential for the preliminary research and development on Zembrin®. The founders of Zembrin® are the first local developmental entrepreneurs to sign Africa's foremost "prior informed consent benefit-sharing agreement" with an indigenous community (www.zembrin.com). In India, through 'Jeevani', an example of equitable sharing of benefits with indigenous communities has been demonstrated. The Tropical Botanic Garden and Research Institute (TBGRI), located in South India, developed an innovative anti-fatigue product 'Jeevani' from the plant Trichopus zeylanicus discovered by the locals of the Kani tribe. The agreement between TBGRI and the manufacturer included sharing 2% royalty (ex-factory sales price) with the tribals. 
Lack of legal protection given to the indigenous knowledge is one of the salient features of divergence between traditional and modern medicines. On the other hand, modern medicine has stringent intellectual property laws and a highly evolved patenting system. With the realization that TM holds immense wealth of knowledge, many scientists have begun searching indigenous sources for newer drugs, hence emerged the field of bioprospecting (http://www.hillargic.ac.in/edu/covas/vpharma, accessed on September 5, 2013).
The easy accessibility of TK has led to biopiracy where there is indiscriminate use of indigenous resources without permission from and with little or no compensation or recognition to the indigenous people. Biopiracy is an example of the challenges being faced in efforts to bring the TM into mainstream (http://www.thefreedictionary.com/biopiracy, accessed on May 11, 2013). Patents for medicinal components that have been used for centuries in treating diseases have been sought. For instance, in 1995, WR Grace and Company and US Department of Agriculture (USDA) were granted a patent by the European Patent Office (EPO) on an anti-fungal derivative of neem. Use of neem in Indian TM is common. Though, the GOI convinced the EPO to revoke the patent on the basis of prior use, it took five years and millions of dollars (http://www.scidev.net/global/disease/feature/integrating-modern-and-traditional-medicine -facts-and-figures.html, accessed on August 4, 2013).
Uniquely, GOI established a programme for the documentation of TK, which is already available in the public domain. The political goal is to protect the sovereignty of TK and to defend it from being misused in patenting of non-patentable inventions. The Traditional Knowledge Digital Library (TKDL) is an original proprietary database, which is fully protected under national and international laws of Intellectual Property Rights (IPR) and is maintained and developed by GOI. TKDL permits automatic conversion of information from Sanskrit into different languages.  Additionally, agreements with leading offices globally viz., United Kingdom Trademark and Patent Office (UKPTO), EPO and the United States Patent and Trademark Office have been signed. This could protect TK from biopiracy by allowing patent examiners to access databases for patent search and examination purposes (http://pib.nic.in/newsite/erelease.aspx?relid=61122; www.livemint.com, accessed on June 6, 2013). However, unfortunately the database is not available to Indian researchers.
| » Source of Plant Material|| |
Kala et al. asserted that of the 17,000 higher plants to be found in India, 7500 are known to possess medicinal uses, with Ayurvedic medicine claiming to use 2000 of them, most of which are obtained from the wild.  Over 60 species are in great demand and the tribal belt of India is abundant in these plants. The tribal population mainly depends on the trade of these plants for their livelihoods. In Nepal, more than 300,000 households are engaged in the collection of medicinal plants. Most of the industrial requirement of these plants is met through wild collection.  Uncontrolled collection and trading of large quantities of plant material from the forest has led to devastation of many forest plants, particularly the endemic species that have a restricted geographical distribution. For example, plants like Curcuma caesia, Rauwolfia serpentina were reported to occur abundantly in central India.  However, due to their growing economic importance and rampant harvesting, they have been categorized as critically endangered.  The current deteriorating state of botanicals in forests demands immediate attention to conservation and propagation. Through habitat management, countries can guard their biodiversity of medicinal plants by collaborating with industry to monitor and maintain restricted non-destructive harvesting. Cultivation of medicinal plants seems to be a commercially attractive option to industries as they can have a greater control over supply of the material and it is easier control for post-harvest treatment.  In addition, it could decrease the reliance on collection of plants from the wild, potentially protecting them and conserving their genetic diversity.
Climatic conditions also influence the physiochemical and biological qualities of medicinal plants. The water and temperature stress related increase in the content of active constituents such as the total phenolic compounds was shown by Nacif de Abreu and Mazzafera in Hypericum brasilience.  Hence, the best conditions for cultivation should be determined based on biological activity rather than their vegetative yield. In addition, the cultivation conditions should be such that undesirable factors such as pesticide residues, heavy metals, aflatoxins and microbial load are within acceptable limits. 
Cultivation of medicinal plants may be more difficult than usually suggested in the scientific literature. Alam and Belt state that local companies could provide advice and support to farmers on growing techniques including the correct use of fertilizers and pesticides with the support of academic institutions and NGOs.  By paying an agreed price the buyer can anticipate to have control over the collection, drying and storage. This could be a rational and pragmatic approach to satisfy both the demands of international trade and the need to assure consistency and stability in price structures.
For rural workers this may appear as a win-win situation. However, there is a counter argument: by exploiting the farmers and workers, the companies are the key benefiters. The workers in turn have few options than to subjugate themselves to companies.  They are increasingly dependent on a wide range of external inputs ranging from seeds to fertilizers to pesticides.  The relative bargaining power of producers is weak compared to the processors and retailers who control both the price paid for the raw materials and the vital inputs required in manufacturing economically viable yields. 
The physical appearance and chemical quality of plant materials is influenced by duration and conditions of its storage. Often, a considerable time lapse exists after the collection of the plant material till its transportation to the manufacturing unit. WHO has provided detailed guidelines on Good Manufacturing Practices (GMP) to be adopted for all aspects of storage of HM. 
| » In Vitro Screening and Confirmation of Efficacy|| |
In vitro screening is important to establish the therapeutic efficacy of the medicinal plants and to confirm their historical utilization by traditional practitioners. This is significant as the plants may have evolved over a period of time leading to changes in their chemical composition and thus the biological activity. The advantage of these studies is that one can easily study and compare the efficacy of different plants in a cost effective manner and design rational drug combinations. However, the choice of screening assays is paramount. Assays employed in screening can be either cell-based or biochemical. The current trend in drug discovery is shifting towards cell-based assays as they can provide biologically more relevant information on the nature of the activity. 
Two common approaches used for assessing the pharmacological effects of herbals are: screening multiple plants using a single bioassay and studying the action of a single plant with multiple bioassays. Screening medicinal plants for infectious diseases are unfortunately often restricted to testing antimicrobial activity which is not always appropriate. Plants could act against infectious diseases by mechanisms other than antimicrobial activity. Similarly, when screening plants for immune-enhancing properties, often synthetic antigens and immunological assays are used which do not have any biological relevance to disease(s) in question.
The importance of using relevant and where necessary multiple bioassays for screening medicinal plants for infectious diseases has been highlighted in our previous studies. Decoctions of two plants viz., Zingiber officinale and Pongamia pinnata were evaluated for their antidiarrhoeal activity. , The assays in addition to the antimicrobial action screened the plants for colonization (adherence and invasion) and enterotoxins - the two most important features of diarrhoeal pathogenicity. It was observed that though both plants did not have marked antimicrobial action, they were effective antidiarrhoeal agents with different mechanism(s) of action. P. pinnata inhibited cholera toxin binding but not the adherence of enteropathogenic E. coli (EPEC) to epithelial cells whereas Z. officinale inhibited EPEC adherence to epithelial cells but not cholera toxin binding. These results showed that the antidiarrhoeal activity of the plant could be due to its action on various parameters. Besides, confirmation of activity of plants listed during ethnobotanical surveys, in vitro screening also plays a vital role in (i) standardization of extract
(ii) determination of shelf life/stability of the botanical and the formulation developed from it (iii) establish conditions for cultivation for obtaining maximum medicinal activity.
Despite several advantages, the in vitro testing has certain limitations. The lack of a positive result in a screening assay does not always mean the absence of bioactive constituents, this may occur due to (a) the assay employed may not be appropriate, (b) in vitro assays do not screen for active principles that are generated as metabolized products in vivo, (c) the crude extracts may contain insufficient quantities of the active component(s) resulting in extracts being ineffective at the doses tested. Alternatively, if the active principle is present in abundance, presence of other components could exert antagonistic effects, negating its positive effects.  Moreover, extrapolation of in vitro dose to in vivo animal models and humans is difficult.
| » Extract Standardization|| |
Standardization and quality assurance of botanicals is a major problem. Batch-to-batch variations may occur in their efficacies due to natural and genetic modifications, seasonal variations, differences in soil and nutritional status of the medicinal plant.  Thus, standardization is important for the establishment of consistent biological activity, chemical profile and a quality assurance program for production and manufacturing of herbal drugs. The reference standards for micro and macroscopic characteristics, Thin layer Chromatography (TLC) fingerprint and permissible limits for heavy metals, purity and strength of plant extracts are mentioned in the Indian Pharmacopoeia (IP). However, these standards need to be updated regularly using modern technologies. Bioassays can play an important role in the standardization of extracts and quality control but they can be cumbersome and time consuming in absence of high throughput assays. Thus, the development of analytical methods that can reliably profile the phytochemical composition that includes quantifying the marker/bioactive compounds and other major constituents, is a challenge to researchers. Phytochemistry helps in standardizing the HM so as to get the optimal concentrations of active constituents (if known) and preserve their activities. This can be undertaken through finger printing (FP). Chemical FP through chromatographic techniques such as High performance Liquid Chromatography (HPLC) and High performance Thin Layer Chromatography (HPTLC) is commonly used for standardization and is obtained in terms of one or more marker compounds which may be the active component and frequently when no active marker is known analytical markers without known clinical relevance are used as surrogates. However, surrogate markers should not be generally recommended to guide the optimization of an extract. The advantages and disadvantages of these methods with regard to suitable target metabolites, reproducibility of signal intensities and positions, sensitivity, resolution and sample preparation efforts have been comprehensively discussed earlier. 
Recent advances in standardization
Due to limitations of the conventional methods, a systems biology approach (metabolomics) is now being applied to link the biochemical components of plant extracts to their biological activity. Standardization through metabolite profiling could have an advantage over the conventional chromatographic methods as it gives a FP of many molecules simultaneously and is not limited by the need to know which chemical components are involved in efficacy. It can help in development of a robust analytical method to establish extracts with consistent biological activity and chemical profile which are requisites for therapeutic consistency. Metabolomics, including both targeted and global metabolite profiling strategies, is being preferred across a wide range of sciences.  Various research institutes in India are exploring this newer paradigm of analytical strategy to study metabolite profiles of bioactive compounds from Pseudomonas sp., profiling of primary and secondary metabolites in medicinally important plants, etc. ,
The metabolomes of medicinal plants are particularly a valuable natural resource for the evidence-based development of new phytotherapeutics and nutraceuticals. Comparative metabolomics platforms are developing into novel technologies for monitoring development of disease, chemical toxicology and drug metabolism. A competent multidisciplinary marriage of the emerging techniques of metabolomics with agricultural biotechnology will benefit both basic and applied medical research.  Novel standardization methods could raise the medicinal potency and quality of herbal drugs. Developing cutting-edge gene-chip based applications could also assure standardization of botanicals.  Newer analytical and bioinformatics technologies are being created or optimized continuously. Recent advancement in vibrational spectroscopy (VS) such as Fourier transform infrared (FT-IR) and Near Infrared (NIR) has also opened new avenues of application in biological samples. VS, a non-destructive and rapid technique, requires both minimal sample preparation and minimum amount of analyte.  FT-IR is routinely used in quality control of food, pharmaceuticals, nutraceuticals and microbiological samples in order to perform quicker quality checks of incoming raw materials and continuous controlling of quality parameters.  Research on use of taste sensor for the quality control of medicinal plants is being actively explored.  An artificial taste sensor was used by Kataoka et al., to assess bitter and/or astringent tasting botanicals including Chinese medicines. 
| » Stability|| |
Stability is aimed at assuring that the drug/product remains within the specifications established to ensure its identity, strength, purity and quality. Environmental factors can affect stability. In addition, factors such as pH, particle size, properties of water/solvents used, nature of container and presence of other chemicals resulting from contamination or from the intentional mixing of different products can influence stability. Extracts are complex mixtures of different components where each component has not only variable shelf-life and activity but also different concentration and consistency. Due to this, problems arise in determining storage conditions as it is difficult to establish the stability of final product based on the activity and stability of a single component.  Each ingredient, whether therapeutically active or inactive, can affect stability. Degradation of these components may be unsafe and result in adverse events. Extensive chemical degradation may lead to a substantial loss of potency i.e. dissolution/bioavailability or changes in physical appearance leading to product failure. Hence, ensuring adequate stability for long-term storage and safety for consumption by the patients is crucial. 
| » In Vivo Screening for Evaluation of Efficacy and Toxicity|| |
Preclinical in vivo biological screening is important since some extracts may show in vivo activity due to metabolism of inactive compounds into active forms and vice versa. 
In vivo experiments can help in evaluating efficacy and safety data before performing clinical trials. Authentication and preclinical screening of botanicals involves documentation and testing of their pharmacological efficacy in in vivo models and studies of toxicology, specificity, biopharmaceutical properties and drug interactions. Animals are useful to ascertain the pharmacological or toxicological data generated in vitro.
Toxicological studies on herbals are often neglected. This is mainly due to the belief that it's prolonged and apparently uneventful utilization is an indication of its safety. Traditional usage however does not ensure safety as traditional practitioners may not be able to monitor delayed effects (e.g. mutagenicity), adverse and rare adverse effects due to long-term use of these plants.  Toxicological studies should include tests such as acute, chronic, sub-chronic and special toxicology that are impossible to detect clinically such as genotoxicity, immunotoxicity, reproductive toxicity and carcinogenicity.  These tests help in the identification of the toxic symptoms and the possible organ(s) involved. Special toxicological assays such as carcinogenesis are required if known mutagenic or carcinogenic compounds are present in the plants. 
| » Pharmacokinetics and Bioavailability|| |
Pharmacokinetics of botanicals is always taxing due to their complexity, unavailability of standards and methods. A dearth of pharmacokinetic studies is one of the biggest hindrances in the modernization of TM as there is no way to measure their bioequivalence. 
Though evidence-based verification of the efficacy of botanicals is lacking, attempts are being made to assure availability of data on assessment of toxicity and therapeutic efficacy. The advances in state-of-the-art technology have led to detection of many new active components from botanicals. Few medicinal plants viz., Allium sativum, Artemesia annua, Ephedra sinica, Ginkgo biloba have been investigated for pharmacokinetics using marker compounds.  However, establishing their pharmacological basis for efficacy remains a constant challenge. Failure of drug regimens is attributed to lack of efficacy and is governed by pharmacokinetics. Pharmacokinetics can be used to link in vitro assays and clinical studies. It can help in obtaining the information on bioavailability of the active constituents. It is important to evaluate the bioavailability as it often determines the therapeutic efficacy of that product. Elucidation of metabolic pathways and evaluation of elimination routes and their kinetics are of equal importance and can be studied using pharmacokinetics. Additionally, pharmacokinetics can be used to study herb-drug interaction. Several clinically important botanical-drug interactions have been reported leading to altered efficacy and/or toxicity and life threatening adverse reactions.  The evidence of interactions is often based on presumed pharmacologic activity, data from in vitro or animal studies, or single case reports and to a lesser extent from well-designed clinical studies. For example, tamarind, an ingredient of ayuverdic medicine and a food flavouring agent, has been reported to significantly enhance the extent of absorption of a single 600mg dose of aspirin, posing potential danger if excess of aspirin is ingested along with it. 
Thus, a better understanding of pharmacokinetics and bioavailability of phytopharmaceuticals could help in designing safe and rational dosage regimens and hence ensure more rational use of HM.
| » Clinical Trials|| |
One of the major issues in modernizing TM is measurement of its efficacy. User surveys, case studies and anecdotal information regarding TM are not accepted by many clinical practitioners. They claim that without clinical trials (CT), the efficacy and safety of HM cannot be demonstrated and insist on implementation of methods and guidelines used for clinical validation of modern medicines on herbal products. Different types of CT viz., observational, interventional or adaptive could be adopted for HM. Observational cohort studies (observational, drug monitoring studies) could be an alternative or precede interventional trials.  Whilst randomized controlled trials (RCT) are widely used, placebo RCT, considered the gold standard, are more difficult to undertake due to the requirement of designing suitable placebos. Development of a method to allow placebo controls for changing and individualizing therapies is required to facilitate comparison between TMS and western medicine. The approach demonstrated by Furst et al., shows that double-blind, placebo, RCT are possible when testing classic Ayurvedic versus allopathic medications.  However, the systematic and controlled setting used in RCT may not always present the complex and dynamic real world of clinical practice.  Selecting and controlling certain variables may mean exclusion of others that could be influential. Considering the fact that HM is individualized and offers a holistic approach, adaptive CT to retain the therapeutic relationship is required. A detailed and extensive database of case studies may be considered.
| » Regulations for Traditional Medicines|| |
Countries face challenges in development and implementation of regulations for HM. These challenges are associated with regulations, assessment of safety and efficacy, quality control and lack of knowledge on TM/CAM within national drug regulatory authorities. In order to meet these challenges, the WHO TM Strategy was developed, with four primary objectives: Policy framing; enhancing safety, efficacy and quality; ascertaining access; and promotion of rational use. Resolution WHA56.31 on TM, adopted in 2003, requested WHO to support Member States by providing internationally acceptable guidelines and technical standards and also evidence based information to assist Member States in formulating policy and regulations to control the safety, efficacy and quality of TM. 
The legal status and the practice of use of HM vary significantly amongst countries. Central Council of Indian Medicine Act, Research Councils Indian Council of medical Research (ICMR) and Council of Scientific and Industrial Research (CSIR), Department of AYUSH and Drugs and Cosmetics Act 1940 (Amendment) regulate HM in India. Botanicals to be incorporated in allopathy have to follow the regulations of Drug Controller General of India (DCGI). 
The Ayurvedic Pharmacopoeia Committee has laid down standards for single drugs based on experimental data worked out at the Pharmacopoeial Laboratory of Indian Medicines (PLIM) and in units of the Central Council for Research in Ayurveda and Siddha (CCRAS). Although scanty, published scientific literature on the subject has also been collected and included after due verification. 
Indian Pharmacopoiea Commission (IPC), an autonomous Institution of the Ministry of Health and Family Welfare, GOI, publishes official documents for improving quality of medicines by way of adding new and updating existing monographs in the form of IP. IP covers overall Quality Control and Assurance of pharmaceutical products marketed in India. However, as per the policy of IPC, IP monographs are not framed to detect all possible impurities. While the monographs in IP primarily focus on the standardized raw material, equal importance needs to be given to documentation of monographs of standardized plant extracts and herbal formulations (http://www.ipc.gov.in/, accessed on February 14, 2013).
Good Clinical Practice (GCP) guidelines pertaining to TM have been published by ICMR. Department of AYUSH, ICMR and CSIR are working together in order to achieve safe and effective AYUSH products. The objectives of AYUSH include controlling of drug quality, laying down pharmacopoeial standards, overseeing functioning of PLIM and Indian Medicine Pharmaceutical Company Limited and coordinate with the Quality Council of India. AYUSH also emphasizes implementation of GMP and appropriate Drug Quality Controls and establishment of common facilities following the Cluster approach. Good Agriculture and Field Collection Practices (GAFCPs) developed by the WHO in 2003 and Good Agricultural Practices (GAPs) enunciated by the GLOBALGAP Secretariat are being implemented in over 80 countries. Using this as a reference the National Medicinal Plants Board and Department of AYUSH have prepared specific guidelines for GAPs in India. 
China has a longer history of cultivating and marketing medicinal plants compared to India. According to Warude and Patwardhan, India should take the lead from China in developing a more quality driven ethos towards medicinal plant production.  Through government sponsored GAP's and GMP's, China has been continuously and vigorously modernizing its TM.
The Chinese Government has promoted the internationalization of TCM in recent years. Announced in 2006, the Development Plan on Standardization of TCM (2006-2010) planned to draft/revise 500 standards implemented in China, sponsor 3 to 4 international standards and participate in drafting at least 20 international standards.  Good practice in traditional Chinese medicine research (GP-TCM) in the post-genomic era is the first EU funded 7 th Framework Programme (FP7) Coordination action aiming to inform the best practice and harmonize research into TCM. Hundred and seven partner institutions from 24 countries are members of this consortium. It comprises of 10 interactive Work Packages. The primary aim of the consortium was to develop a European-Chinese network collaborating on TCM research, with an emphasis on the application of omics technologies. 
An increase of 24% on TCM market was reported in 2010, amounting to RMB317.2 billion (about €36.8 billion). It is estimated that this will further rise to €96, 2 billion by 2025 (http://www.hkc22.com/chinesemedicine.html, accessed on February 25, 2013). Though presently India contributes less than 1% to the global herbal market; it is fast emerging as a key supplier across the globe. The increased demand of HM has led to a sudden increase in herbal manufacturing units. According to Polshettiwar, in India there are about 20 well-recognized manufactures of herbal drugs and 140 medium or small-scale manufactures.  Additionally, several vaidyas (traditional healers) have their own miniature manufacturing facilities. On record there are about 1200 licensed small manufactures in India. A number of initiatives have been taken by the GOI to refurbish the small scale units to ensure quality control in manufacturing. A number of research centers in the public and private sector have been engaged in this area either individually or through private public partnerships (PPP) to meet the challenges of global markets. The importance of registration of Evidence Based Medicine and TM and its complexity thus demands extensive collaboration, discussion and implementation by all stakeholders viz., the government, industry, scientists from the academia and industrial research, practicing clinicians and ayurvedic practitioners.
| » Concluding Remarks - Recommendations|| |
Whilst individual aspects have been addressed above, four major aspects that in our opinion need immediate attention for strengthening traditional systems of medicine (TSM) are:
Dr. Zafar Mirza, coordinator, WHO Department of Public Health, Innovation and Intellectual Property stated "The WHO has acknowledged and embraced TM as part of health care systems worldwide for many years and developed its first official TM strategy in 2002. Any new protection system should not only provide protection for the owners of TK but also allow the development of new treatments based on TM and more broadly allow innovation for public health and the sharing of any benefits arising from commercialization of resulting products and therapies" (http://www.ip-watch.org/2012/04/18/divergences-clarified-on-protection-of-traditional- knowledge-at-wipo/, accessed on March 2, 2013).
In India, although the majority of the population still relies on LKS to meet their health needs, the official policies and nationalized support structures need to be strengthened for TSM and folk medicine.  NGOs have demonstrated that community-based approaches can provide a platform on which holders of local medicinal plant knowledge systems (both folk and TSM) can interact with the holders of formal knowledge (e.g. botanists and other scientists). The outcomes of such initiatives have shown a way to achieve the larger goals of equity and empowerment. In order to make these goals more durable and widespread, similar community-based approaches need to be encouraged with supportive policy and legislative measures at the national and the global level. The supportive policies should encourage organizations to contribute the knowledge into the public domain there by permitting active research into its validation whilst safe guarding the interests of local communities.
Investment by industry
Adequate protection of TK and Biological Resources is available in Indian law. The unique provision under Section 3 (p) of Indian Patents Act states "an invention which, in effect, is TK or which is an aggregation or duplication of known properties of traditionally known component or components is not an invention and hence, not patentable, within the meaning of the Patents Act." (http://www.ipindia.nic.in/iponew/TK_Guidelines_18December2012.pdf Accessed on August 8, 2013).
The Indian herbal industry faces daunting challenges as it is failing to attract investors. The manufacturing companies find the process of filing for registration of their products costly, cumbersome and time-consuming. The investors argue that profits do not justify the high cost of moving a herbal product through the standard FDA approval process. As it is not possible to patent most herbal products, it further inhibits their willingness to make large investments in clinical trials and product development. This has resulted in labeling of products as food supplements which is not advisable to shortcut the process. This outlook also results in the lack of in-depth research into development of HM. However, some leading herbal industries in India have succeeded in obtaining patents globally on herbal products (mentioned in the codified systems of medicine) through modifications either in combinations or extraction method.
Another aspect as discussed under the heading 'Benefit sharing' wherein the company has shared its profits with communities from whom TK was obtained could be considered.
A modus operandi needs to be worked out wherein the industry and the local community would benefit from integration of TK into the modern drug development process.
Often TSM falls into disrepute due to lack of standardization of extracts resulting in variability in efficacy. This is because plant preparations are chemically complex and contain compounds that may act together to produce synergism. The composition of these compounds in a plant may vary due to environmental factors making it necessary to standardize the crude extract.  Standardization has been traditionally carried out either by bioactivity guided fractionation or by obtaining chemical FP through HPTLC/HPLC.
Difficulties in standardization arise due to: (i) often the active principle is unknown; (ii) synergy between two or more compounds;  (iii) a common approach is to standardize extracts on the basis of the quantitative presence of one or more marker compounds. However, presence of marker compounds alone may not assure consistency in the biological activities as non reproducibility results from variations in the unknown active principle.  Although in vitro assays are necessary for pre-clinical screening they are not ideal for routine quality control as they are laborious, time consuming and expensive since high throughput assays are not always suitable. Thus, a rapid and comparatively economical technology needs to be developed. Metabolite profiling of plant extracts using LC-MS and 1 H NMR spectroscopic techniques has an advantage over the conventional chromatographic methods as it gives a FP of many molecules simultaneously and is not limited by the need to know which components are indicators of efficacy.  Its use in standardization after being sufficiently demonstrated needs to be widely adopted. Alternatively the bioelectronic tongue that is able to biologically and chemically standardize without dependence on identification of a single active component or mechanism of action can be used to aid evaluation of quality control parameters of botanicals such as batch to batch variation etc.  Another non-destructive and rapid technique such as VS can also be adopted for standardization and quality assessment of medicinal plants as it requires minimal sample preparation.  Integration of these state-of-the-art technologies could thus be applied to ensure modernization of TM.
needs to consider quality and selective national and international networking structure not only to disseminate and increase acceptance of TM but more importantly to develop newer paradigms in this field to ensure modernization of TM. A classic example of international collaboration on GP-TCM has been discussed in the section 'Regulation on TM'.
| » Acknowledgments|| |
We deeply appreciate the suggestions given by Padmashri Dr. RA. Mashelkar and Prof. R Roy Chaudhury. The efforts and inputs of Dr. NF. Mistry, Director, The Foundation for Medical Research (FMR) are sincerely acknowledged.
We would like to thank our funding agencies viz., Department of Science and Technology, Department of Biotechnology, Indian Council of Medical Research, Sir Dorabji Tata Trust.
The Corpus grant from Jamsetji Tata Trust to FMR supported the authors during compilation of this review and part of its experimental studies.
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