Herbal drugs: Standards and regulation

Fitoterapia 81 (2010) 462–471 Contents lists available at ScienceDirect Fitoterapia j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / f i t o t e Review Herbal drugs: Standards and regulation Niharika Sahoo a, Padmavati Manchikanti a,⁎, Satyahari Dey b a b Rajiv Gandhi School of Intellectual Property Law, IIT Kharagpur, Kharagpur-721302, West Bengal, India Department of Biotechnology, IIT Kharagpur, Kharagpur-721302, West Bengal, India a r t i c l e i n f o Article history: Received 18 September 2009 Accepted in revised form 2 February 2010 Available online 13 February 2010 Keywords: Herbal drug Drug regulation Traditional medicine Herbal drug harmonization a b s t r a c t The use of herbal drugs for the prevention and treatment of various health ailments has been in practice from time immemorial. Generally it is believed that the risk associated with herbal drugs is very less, but reports on serious reactions are indicating to the need for development of effective marker systems for isolation and identification of the individual components. Standards for herbal drugs are being developed worldwide but as yet there is no common consensus as to how these should be adopted. Standardization, stability and quality control for herbal drugs are feasible, but difficult to accomplish. Further, the regulation of these drugs is not uniform across countries. There are variations in the methods used across medicine systems and countries in achieving stability and quality control. The present study attempts to identify the evolution of technical standards in manufacturing and the regulatory guideline development for commercialization of herbal drugs. © 2010 Elsevier B.V. All rights reserved. Contents 1. 2. 3. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Effect of herbal drugs on human health: adulteration, heavy metal, pesticide and microbial contamination Standardization of herbal drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Complexity and characterization: marker based analysis of herbal drugs . . . . . . . . . . . . . 3.2. Quality control of herbal drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4. Regulatory norms development for herbal drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . 5. International harmonization. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflict of interest statement. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1. Introduction The use of plants, parts of plants and isolated phytochemicals for the prevention and treatment of various health ailments has been in practice from time immemorial. It is ⁎ Corresponding author. Tel.: + 91 3222 281736; fax: + 91 3222 282238. E-mail addresses: [email protected], [email protected] (P. Manchikanti). 0367-326X/$ – see front matter © 2010 Elsevier B.V. All rights reserved. doi:10.1016/j.fitote.2010.02.001 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 462 463 465 465 466 467 469 470 470 470 estimated that about 25% of the drugs prescribed worldwide are derived from plants and 121 such active compounds are in use. Of the total 252 drugs in WHO's essential medicine list, 11% is exclusively of plant origin [1]. Nearly 80% of African and Asian population depends on traditional medicines for their primary healthcare [2]. In India, about 80% of the rural population uses medicinal herbs or indigenous systems of medicine [3]. About 960 plant species are used by the Indian herbal industry of which 178 are of high volume exceeding N. Sahoo et al. / Fitoterapia 81 (2010) 462–471 100 metric tonnes a year [4]. Indian herbal market is registering a significant growth and is likely to reach Rs 145,000 million by 2012 and exports to Rs 90,000 million with a CAGR of 20% and 25% respectively (ASSOCHAM, 2008). Based on nature of the active metabolites herbal drugs are of three types. Drugs used in crude form are the first category. The active constituents isolated after the processing of plant extracts represent the second category of herbal drugs. These are pure molecules and generally pharmacologically more active. The third type of herbal drugs for which data on acute and chronic toxicity studies in animals is available [5]. In 2003, a classification system for herbal drugs was recommended in the regional workshop on the regulation of the herbal medicines, organized by WHO regional office for South East Asia. Herbal drugs have been broadly categorized into four groups such as indigenous herbal medicines, herbal medicines in systems, modified herbal medicines and imported products with an herbal medicine base [6]. Indigenous herbal medicines are well known in terms of their composition, treatment and dosage due to their age old use in a local community. Herbal medicines in systems (Ayurveda, Unani and Siddha) have been in use for a long time and therefore, for local use assessments of efficacy are not required. Modified herbal medicines represent modification of the form of indigenous herbal medicine or herbal medicine in systems either in shape or dosage form, mode of administration, herbal medicinal ingredients, methods of preparation and medical indications. These should meet the national regulatory requirements of safety and efficacy. Preclinical data and clinical data may or may not be required depending on the modification(s). Imported herbal medicines (that include raw materials and products) must be registered and marketed in the countries of origin. Safety and efficacy data have to be submitted to the national authority of the importing country. Good manufacturing practices (GMP) compliance of the last two categories of herbal drugs is more critical. Apart from standardized herbal extract and raw material India is known to export herbal medicines in system such as ayurvedic drugs to different parts of the world. While there is increased usage of herbal drugs throughout the world, reports on side effects and adulteration of herbal drugs have raised concerns on their wide use and are affecting their commercialization. Further, regulatory procedures of these drugs are also not uniform across different countries. The present study attempts to identify development of technical standards in herbal drug manufacturing as well as the regulatory framework for commercialization of these drugs. 2. Effect of herbal drugs on human health: adulteration, heavy metal, pesticide and microbial contamination Herbal products are not completely free from side effects. Well-controlled randomized clinical trials have revealed that undesirable side effects are possible in the use of herbal drugs. Cardiovascular problems with use of ephedra, hepatotoxicity by kava-kava consumption, anticholinergic effects leading to reduced visceral activity associated with asthma medicine containing Datura metel, water retention by liquorice are few examples of herbal drug side effects [7,8]. Due to increased reports on adverse effects regulatory/monitoring agencies in many countries have brought out alerts on herbal drugs. In 463 1993, the American Herbal Products Association (AHPA) issued an alert to restrict the use of comfrey, a herbal medicine that contains pyrrolizidine alkaloids (PAs) for external applications. In 2001, hepatotoxicity reported from use of comfrey led US Food and Drug Administration (USFDA) to recall it from all dietary supplements. Cardiovascular events reported with the use of Chinese herb containing ephedra used to promote weight loss in the US led to its ban by USFDA in 2004. In 2007, the Medicines and Healthcare Products Regulatory Agency (MHRA) of the UK advised all herbal interest groups to withdraw all unlicensed proprietary products that may contain hepatotoxic PAs from Senecio species. The use of three herbal medicines that contain aristolochic acids (AAs), namely Radix Aristolochiae Fangchi (Guangfangji), Caulis Aristolochiae Manshuriensis (Guanmutong) and Radix Aristolochiae (Qingmuxiang), has been banned in China since 2004 due to the potential risk of nephrotoxicity [9]. The WHO database has over sixteen thousand suspected herbal case reports. The most commonly reported adverse reactions are hypertension, hepatitis, face oedema, angiodema, convulsions, thrombocytopenia, dermatitis and death [10]. In 1992, a list of about 33 herbal drugs with serious risks prepared by the Committee for Proprietary Medicinal Products (CPMP) was published by the European Commission. This list included some plants such as Aconitum (all species), Aristolochia (all species), Claviceps purpurea (FR) TULASNE, Convovulus scamonia L., Ocimum basilicum L., Strychnus nux-vomica L., Vinca minor L. etc. [11]. In the UK, certain potentially hazardous plant species are restricted to use by medical practitioners by the Prescription Only Medicines (Products Other than Veterinary Drugs) Order 1997. The Medicines (Retail Sale or Supply of Herbal Remedies) Order 1977 lists 25 plants which can be supplied only via a pharmacy and includes toxic species such as Areca, Crotalaria, Dryopteris and Strophanthus. Following reports of serious cases of renal toxicity and evidence of substitution of certain ingredients in traditional Chinese medicines (TCM), ‘The Medicines (Aristolochia and Mu Tong etc) (Prohibition) Order 2001’ was enacted to prohibit unlicensed medicines of Aristolochia species and a number of other herbal ingredients which can be confused with Aristolochia [12]. The effects of herbal drugs on metabolism have been studied predominantly for ginkgo, kava and St. John's wort [13]. Components of a number of commonly used herbal products inhibit human drug metabolizing enzymes in vitro. Constituents of Ginkgo biloba (ginkgolic acids I and II), kava (desmethoxyyangonin, dihydromethysticin, and methysticin), garlic (allicin), evening primrose oil (cis-linoleic acid) and St. John's wort (hyperforin and quercetin) could potentially inhibit the metabolism of co-administered medications whose primary route of elimination is via cytochrome P450 [14]. Undeclared chemical or synthetic substances or other active ingredients are the adulterants which are common in raw material trade of medicinal plants. Adverse event reports are often due to the presence of unintended herbs and this has affected the promotion of herbal products. Adulteration of herbal drugs with one or more synthetic drugs is reported from different parts of the world. Forty-one products out of 3320 Chinese Proprietary Medicines (CPM) screened by 464 N. Sahoo et al. / Fitoterapia 81 (2010) 462–471 Health Science Authority (HSA) Singapore, between 1990 and 2001were found to contain nineteen synthetic drugs. In twelve out of nineteen CPM manufactured in China claimed to be tonics for the treatment of sexual dysfunction in males had sildenafil as adulterant and other such over the counter (OTC) drug products were found to be adulterated with sildenafil, tadalafil, vardenafil and their structurally modified analogues [15,16]. “Tung Shueh Pills” from Taiwan that caused acute renal failure was found to be adulterated. “Tung ShuehWan”, used for pain relief sampled from Singapore market was found to contain the four undeclared drugs, caffeine, diazepam, indomethacin and prednisolone, which have potential to cause mental depression, bone loss, spontaneous fractures, intestinal bleeding and even coma. “Gu Ben Wan” used for the treatment of dry cough was found to contain six undeclared drugs. “Wonder Pills” used for reducing fats from body was found to contain phenformin, a drug banned in Singapore since 1977 [16]. Substitution involves intentional replacement with another plant species or intentional addition of a foreign substance to increase the weight or potency of the product or to decrease its cost. The use of fake or wrong herbs has generated serious questions about the safety and efficacy of herbal products. Many popular and expensive Chinese herbs are in short supply and inferior substitutes or fake crude herbs have been found in the UK market [17]. Substitution of Aristolochia fangchi instead of the Chinese herb Stephania tetrandra was found to lead to nephritis. It was subsequently discovered in 1994 that one of the herbs which should have been from the Stephania genus was unintentionally replaced with an herb of Aristolochia genus, as both shared the transliterated name of Fangchi [17]. Cases of substitution are reported in Indian traditional system of medicine. In Ayurveda, ‘Parpatta’ refers to Fumaria parviflora. In Siddha ‘Parpadagam’ refers to Mollugo pentaphylla. These two herbs are often interchanged or substituted as they are similar sounding. Shankhapushpi is equated with Canscora decussata, Evolvulus alsinoides and Clitoria ternate in specific regions of India. Lack of knowledge about the authentic plant can also lead to unintentional adulteration. Mesua ferrea is available throughout the Western Ghats and parts of Himalayas and is an authentic source of ‘Nagakesar’. Samples are adulterated with flowers of Calophyllum inophyllum due to lack of knowledge as well as restriction on collection. Hypericum perforatum is cultivated and sold extensively in European markets. Due to limited availability the species H. patulum is sold in the name of H. perforatum. It is reported that similarity in morphology and or aroma is the reason for unintended adulteration of Mucuna prurien with M. utilis (sold as white variety) and M. deeringiana (sold as bigger variety), M. cochinchinensis, Canavalia virosa and C. ensiformis. Parmelia perforate, P. cirrhata and Usnea sp. are found to be admixed in samples of Parmelia perlata commonly used in Ayurveda, Unani and Siddha [18]. American ginseng and Asian ginseng that have contrasting properties are morphologically similar. Cases of misidentification of ginsengs based on traditional methods of authentication via morphology have been documented [19]. The replacements of roots of Cholorophytum borivilianum with Asparagus racemosus, gum resin of Commiphora wightii with gum of Acacia arabica and Boswellia serrata, Swertia chirata substituted with Andrographis paniculata, American ginseng (Radix Panacis Quinquefolii) with ginseng (Radix Ginseng) are some of examples of substitution of high priced material with a cheaper plant material [20]. Another common problem with use of herbal medicines is the intentional or accidental presence of toxic heavy metals in more than the permissible limit set by national regulatory authorities. Toxic contaminants are reported at all steps beginning from collection of raw materials to manufacturing [17,21]. The first published case of heavy metal poisoning related to ayurvedic medicines was in 1978 in UK. So far there are over 50 published reports on heavy metal poisoning from different areas in the world including the Indian subcontinent, North America, the Middle East, Western Europe and Australasia [22]. Lead, mercury, copper and arsenic are the predominant contaminants. Thirty-one ayurvedic formulations were analyzed for their mercury content. It was found that with the exception of one remedy, all exceeded the legal limits of 1 ppm mercury and 16 preparations exceeded the limits by more than two orders magnitude. Huge variability of mercury content was also observed within one identical remedy manufactured by different companies indicating to the lack of product uniformity and the associated risks [23]. Accumulation of heavy metals namely Pb, Cd, Cu and Zn was found in Indian herbal drugs derived from nine plants beyond the WHO permissible limits [24]. In 2003, a study from US on heavy metal content of ayurvedic drugs manufactured in India and Pakistan reported that nearly 20% of the herbal drugs contained high concentration of lead, arsenic and mercury than the prescribed limit by US Pharmacopeia. It is not yet confirmed whether the contamination is intentional [25]. Another study published in 2008 also reported 21% of ayurvedic medicines manufactured and distributed by US and Indian companies via the internet contained high concentration of lead, mercury or arsenic [26]. Ten Chinese crude herbal drugs marketed in Italy were analyzed for foreign matter, total ash, microbial and heavy metal contamination. The level of ash was found to be higher than the permissible limit in three samples. For one sample, lead and total viable aerobic count were found to be higher than the limits set by the European or Italian Pharmacopoeias. Of these only Rhizoma coptidis showed an amount of lead three times higher than the maximum level allowed. Parasite contamination was found in two samples [21]. Out of 3320 CPM marketed from 1990 to 2001 in Singapore, 138 were found to contain toxic heavy metals in amounts exceeding the limits set by Singapore Medicines Order, 1995. Of the 138 CPM products tested, 51.4% was detected to contain mercury in excess, 34.8% with arsenic, 14.5% with lead and 0.7% with copper [16]. In Malaysia, when a total of 100 different Eugenia dyeriana herbal preparations were analyzed for lead contamination using atomic absorption spectrophotometry, 22% of the products showed 10.15– 13.20 ppm of lead (10 ppm being the maximum permissible limit) [27]. The permissible limit for some heavy metals in different regulatory systems is shown in Table 1. The presence of pesticide residues in herbal materials has seriously affected the development and process of internationalization of traditional herbal medicine. Contamination of crude medicinal plants as well as their products/preparation (infusion, decoctions, tinctures and essential oils) has 465 N. Sahoo et al. / Fitoterapia 81 (2010) 462–471 Table 1 Permissible limit for some heavy metal in herbal drugs. Test for heavy/toxic metals WHO US Food and Drug Administration (FDA) Department of Ayurveda, Unani, Sidhha and Homoeopathy (AYUSH) India Health Science Authority (HSA) Singapore Lead Mercury Arsenic 10.0 ppm 1.00 ppm 10.0 ppm 10.0 ppm 1.00 ppm 10.0 ppm 10.0 ppm 1.00 ppm 10.0 ppm 20 ppm 0.5 ppm 5 ppm increasingly been reported. A study with 280 samples of 30 different TCMs for pesticides residues showed that 75.8% of samples contained at least one organochlorine pesticides (OCPs) such as PCNB, aldrin, BHC or DDT [28]. Another study with 300 kinds of TCMs revealed that all the samples had hexachlorocyclohexanes (HCH) residues [29]. Similarly isomers of HCH were found in all the 40 samples of single crude drugs of Dashmoola, a popular herbal formulation with immunomodulator and febrifugal properties [30]. OCPs such as DDT has been restricted or even banned in many countries due to their persistence in humans and their effects. The use of pesticides in medicinal plants is regulated in many countries. The WHO has established maximum residue limit (MRL) for these pesticides in cultivated or wild medicinal plants as well as appropriate methodologies for their detection [31]. Pharmacopoeias of different nations have assay methods and residual limits for the organochlorine pesticides. Use of highly sensitive analytical methods for qualitative and quantitative determinations of multiple pesticide residues is needed to ensure safety of herbal medicines. GC, HPLC, GC/MS, HPLC/MS, SFC, capillary electrophoresis (CE), and enzyme linked immunosorbent assay (ELISA) are the basic analytical methods used for determination of pesticide residues. Due to the complex compositions of herbal medicines and diversity in the types of pesticide residues it is quite difficult to find a method for the removal of pesticide residues in herbal medicines without loss of active ingredients and without secondary pollution caused by the organic solvent. Practices used in harvesting, handling, storage, production and distribution can result in contamination by various fungi. Evaluation of ninety-one medicated herbal samples for the presence of predominant mycoflora and the extent of fungal contamination showed that 54.9% of the samples exceeded the limit determined by the US Pharmacopoeia (2 × 102 CFU/g of the product is the maximum fungal contamination limit). The genus Aspergillus was the most dominant genus recovered (179 isolates) followed by Penicillium (44 isolates) and these two genera were found in 90.1% and 39.6% of the samples analyzed. Most of the identified moulds have been reported to have ability to produce mycotoxins [32]. Wide and unsustainable harvesting of plant species is leading to their depletion and thereby availability of the herbal drugs. For instance, the African cherry (Pygeum or Prunus africanum) widely used for the treatment of benign prostate hyperplasia is facing severe ecological threat due to its indiscriminate harvesting in Africa. The bark of the tree used for medicinal preparation is entirely wild-collected. Since 1995, it has been included in Appendix II of Convention of International Trade in Endangered Species (CITES), as an endangered species [33]. Further, this was also included on the IUCN Red List of Threatened Species. However, initiatives have been taken by some of the companies to cultivate Pygeum and harvest it sustainably. Sandalwood (Santalum spp.) grown in Southern Asia, Indonesia, Australia and the South Pacific for timber and fragrant oil production, has been similarly listed. Santalum spp. has self-incompatibility within the genus. Self-incompatible populations pose a threat to the plant species as the lack of genetic variability within remnant populations may result in sexual reproductive failure. This can have important conservation consequences for this type of clonal plant species. Development of Santalum stands with a range of genotypes is proposed to provide self-sustaining populations, capable of sexual reproduction [34]. These reports on adulteration, contamination with heavy metals, pesticides and microbes in herbal drugs and their effects on health have necessitated the development of effective identification systems for herbal materials and their components. Methods that ensure the quality and safety of these products have to be developed in order to ensure the quality and purity of herbal drugs. 3. Standardization of herbal drugs 3.1. Complexity and characterization: marker based analysis of herbal drugs Herbal medicines have distinctive characteristics that make them different from synthetic drugs. They contain more than one active compound and the active principle is frequently unknown. For instance the Chinese medicinal plant Huang-qin (Scutellaria baicalensis) has over 2000 compounds [35].The chemical profiles of medicinal plants are affected by conditions of cultivation, manufacturing, marketing, and distribution. Physiological, genetic, and environmental variables (photoperiod, climate, soil conditions, nutrient availability and moisture) affect the biochemical profiles and secondary metabolite production in plants. Secondary metabolite content is also dependent on time of harvesting, storage, drying, extraction and processing for final packaging. The development of plant based medicines requires comprehensive understanding of plant systems including biological, chemical, genetic, and agronomic aspects. Chemical consistency at all stages of manufacturing processes such as extraction, stability, shelf-life and purity is of utmost importance to ensure medicinal efficacy and consumer safety. Substantive evidence is lacking with respect to the unique physiology of medicinal plants and their bioactive constituents. The different steps for development of herbal medicines starting from collection of raw materials to isolation of active ingredients are shown in Fig. 1. Several markers such as taxonomic, chemical, genomic, proteomic markers aid in identification of herbal drug components. Such methods encompass morphological 466 N. Sahoo et al. / Fitoterapia 81 (2010) 462–471 As the genetic composition is unique for each species and is not affected by age, physiological conditions and environmental factors DNA based markers are also used in identification of inter- and intra-species variation. Random amplified polymorphic DNA (RAPD) based molecular markers have been found to be useful in differentiating different accessions of Taxus wallichiana, Neem, Juniperus communis L., Codonopsis pilosula, Allium schoenoprasum L, A. paniculata collected from different geographical regions [36]. Marker based analysis has limitations as the markers are not single compounds and often a combination of methods become necessary for herbal component detection. The safety and efficacy of herbal drugs are established through their long historical use. Though randomized clinical trials are reported for herbal drugs, well-controlled double blind thorough clinical and toxicological studies are lacking. An assessment of the clinical trial information for Liv.52, an ayurvedic drug useful for chronic liver ailments reveals the need for well selected end points to be adopted during randomized controlled clinical trial [37]. 3.2. Quality control of herbal drugs Fig. 1. Steps involved in phytomedicine development. identification (macroscopic identification), anatomical identification (microscopic identification), chemical analysis such as TLC, HPLC, capillary electrophoresis, LC/MS, HPLC/MS, protein analysis and the use of molecular markers. The EMEA defines chemical markers as chemically defined constituents or groups of constituents of an herbal medicinal product which are of interest for quality control purposes regardless whether they possess any therapeutic activity. Chemical markers are categorized into analytical markers and active markers. Analytical markers are the constituents or groups of constituents that serve solely for analytical purposes, whereas active markers are the constituents or groups of constituents that contribute to therapeutic activities. In cases, where no active constituent or marker can be defined for a herbal drug, the percentage extractable matter with a solvent may be used. A total of 282 chemical markers are listed in the Chinese Pharmacopoeia (2005 edition) for the quality control of Chinese herbal medicines. They are helpful for identification of the adulterants, differentiation of herbal medicines with different sources, stability testing of proprietary products. Toxic components may be used as chemical markers in screening methods [9]. At present, some herbs do not have markers for quality control. According to the Chinese Pharmacopoeia, only 281 out of 551 herbs have one or two chemical markers for quality control. Shortage of chemical markers, purity levels of available markers are major hindrances in assuring quality control of herbal drugs. Secondary metabolites as markers have been extensively used in quality control and standardization of botanical drugs. Quality control of herbal medicines has a direct impact on their safety and efficacy. Environmental and agricultural practices are important in collecting herbal materials. The WHO has developed a series of technical guidelines and documents relating to the safety and quality assurance of medicinal plants and herbal materials. WHO had published the ‘Quality Control Methods for Medicinal Plant Materials’, a collection of recommended test procedures for assessing the identity, purity, and content of medicinal plant materials to assist national laboratories engaged in drug quality control [38]. In 2003, WHO published the ‘Guidelines on good agricultural and collection practices (GACP) for medicinal plants’ and in 2007, a new guideline ‘WHO guidelines for assessing quality of herbal medicines with reference to contaminants and residues’ was formulated [39]. The European Union, China and Japan have developed regional and national guidelines for good agricultural and collection practices for medicinal plants which ensure that soil and irrigation water used for herbal material cultivation and propagation are within the limits or free from harmful heavy metals, pesticides, herbicides and toxicologically hazardous substances [31]. Quality assurance of botanicals and herbal preparations is the prerequisite of clinical trials. The certification for this is based on parameters such as identification, water content, chemical assay of active ingredients, inorganic impurities (toxic metals), microbial limits, mycotoxins, pesticides and others. For herbal preparations, in addition to these tests, disintegration, dissolution, hardness/friability and uniformity of dosage unit should also be presented [40]. The chemistry, manufacturing and control (CMC) documentation that should be provided for botanical drugs is often different from that for synthetic or highly purified drugs, whose active constituents can be more readily chemically identified and quantified. In the US, it is not essential for the manufacturer of a botanical drug to identify the active constituents at the investigational new drug (IND) stage. N. Sahoo et al. / Fitoterapia 81 (2010) 462–471 Due to the variations and inherent complexities of herbal drugs, conventional quality control, botanical techniques are insufficient as the sole means for identifying or authenticating properties, safety and/or efficacy. This is true for a marker alone approach. A multi-technique approach is necessary in order to authenticate the link between the components and the traditional use. The concept of ‘Phytoequivalence’ was developed in Germany in order to ensure consistency of herbal products, where a chemical profile, such as a chromatographic fingerprint for an herbal product is constructed and compared with the profile of a clinically proven reference product [41]. 4. Regulatory norms development for herbal drugs The first international recognition of the role of traditional medicine and use in primary health care was in The Declaration of Alma-Ata. It states, inter alia, that “…Primary health care relies, at local and referral levels, on health workers, including physicians, nurses, midwives, auxiliaries and community workers as applicable, as well as traditional practitioners as needed…” [42]. The safety problems emerging with herbal medicinal products are due to a largely unregulated growing market where there is a lack of effective quality control. Lack of strict guidelines on the assessment of safety and efficacy, quality control, safety monitoring and knowledge on traditional medicine/complementary and alternative medicine (TM/CAM) are the main aspects which are found in different regulatory systems. Under some regulatory systems plant may be defined as a food, a functional food, a dietary supplement or a herbal medicine. As per WHO, herbal medicines include herbs, herbal materials, herbal preparations and finished herbal products that contain as active ingredients parts of plants, or other plant materials, or combinations. Similarly in the EU, the EMEA defines herbal drugs as the whole, fragmented or cut, plants, parts of plants, algae, fungi, lichen in an unprocessed state usually in dried form or afresh. Unprocessed exudates are also considered as herbal drugs. When herbal drugs are subjected to treatments such as extraction, distillation, expression, fractionation, purification, concentration or fermentation, they are known as herbal drug preparations. This includes powdered herbal drugs, tinctures, extracts, essential oils, expressed juice or process exudates. Virtually all herbal products sold in the US are treated as dietary supplements and therefore as foods. A botanical product which is derived from one or more plants, algae, or macroscopic fungi and prepared from botanical raw materials by one or more of the processes such as pulverization, decoction, expression, aqueous extraction, ethanolic extraction, or other similar process, intended for use as a drug is known as Botanical Drug Product (Section 201(g)(1)(B), Federal Food, Drug, and Cosmetic Act). The safety of herbal medicines is a global concern and national health authorities have developed mandates to ensure the safe use of herbal medicines. In 2001, WHO initiated a global survey in 191 member states on national policies on TM/CAM and regulation of herbal medicines. Research data, appropriate control mechanisms, education of providers and expertise are identified to be most important for the field of regulation of herbal medicine [43]. The survey 467 revealed that till 2003, 37% of member states had laws and regulations for herbal medicine, out of this 42% member states had separate laws and regulation. Further it was found that nearly 68% of member countries sell herbal medicines as Over the Counter (OTC) drugs and about 35% of member states treat herbal medicines as prescription medicines. Medical claims, health claims and nutrients content claims are the most common types of claims with which herbal medicine may legally be sold. Only 24% of responding countries indicated that national pharmacopoeia for herbal drug existed and in use and 18% countries indicated that such a document was in preparation. Fifty one percent countries indicated that the same GMP rules as for conventional pharmaceuticals are also applicable to manufacturing of herbal drugs. Out of the total 142 responded member states only 15% members have herbal medicines included in their essential medicine list. China reported highest 1242 herbal medicines in the essential medicine list [44]. Some of the parameters that help in understanding the development of herbal drug regulation in a given nation are general policy structure, drug registration system, development of pharmacopoeia, national monographs, inclusion in essential medicine list and drug type (OTC or prescription). Using these parameters we have compared the herbal drug regulation in South East Asian and some Western Pacific countries (Table 2). Of the eighteen countries studied, except Bhutan, Sri Lanka and Maldives, all countries have herbal drug regulation and registration system. Nine countries (Korea, Indonesia, India, Myanmar, Sri Lanka, Thailand, China, Malaysia, and Vietnam) have their National Monographs for herbal drugs. In Bhutan, Nepal and Philippines the development of monographs are in progress. Pharmacopoeias for the herbal medicines are developed in fifteen countries (except for Maldives, Malaysia and Singapore). In seven countries, Bhutan, India, Thailand, China, Philippines, Republic of Korea and Vietnam, the essential medicine list includes herbal drugs. Philippines has the highest number included in the list with 2000 herbal drugs followed by China with 1242 herbal drugs. India has separate essential medicine lists for the traditional herbal drugs such as Ayurveda and Unani. Except Bhutan in all other countries, the herbal drugs are available as OTC drugs. In Bhutan, where no separate regulation for herbal drugs is available, these are sold as prescription medicines only. There are varied requirements for registration and marketing authorization of herbal drugs in the EU, US and India (Table 3). The Committee on Herbal Medicinal Products (HMPC) established within the European Medicines Agency (EMEA), has introduced a simplified registration procedure for traditional herbal medicinal products in EU member states. The simplified procedure allows the registration of herbal medicinal products without requiring particulars and documents on tests and trials on safety and efficacy, provided that there is sufficient evidence of the medicinal use of the product throughout a period of at least 30 years, including at least 15 years in the Community (Article 16c (1) (c) of Directive 2001/83/EC). EMEA has several guidelines related to quality, clinical safety and efficacy and nonclinical aspects of herbal drugs [45]. In the US, herbal medicines have been regulated under the Dietary Supplement Health and Education Act of 1994. A 468 N. Sahoo et al. / Fitoterapia 81 (2010) 462–471 Table 2 Herbal drug regulation in selected countries. Country Regulation on Herbal drug National monograph registration herbal drug system (year) Pharmacopoeia Inclusion in essential medicine list Drug type Bangladesh 1992 Yes No Not available Prescription and OTC Bhutan No Democratic People's 1999 Republic of Korea No Yes In development Korean herbal medicine monographs (1986) 103(till 1998) Not available Prescription Prescription and OTC India 1940 Yes Yes Indonesia 1993 Yes Maldives Myanmar No 1996 No Yes No In development No In development OTC OTC Nepal 1978 Yes Materia medika Indonesia (246 monographs) No Monograph of Myanmar medicinal plants(2000) In development Bangladesh national formularies on unani and ayurvedic medicine In development Pharmacopoeia of the Democratic People's Republic of Korea (1996) Ayurvedic pharmacopoeia of India and the Unani pharmacopoeia of India Farmakope Indonesia In development Not available Sri Lanka No No Thailand 1967 Yes Prescription and OTC Prescription and OTC Prescription and OTC Australia 1989 Yes China 1963 Yes Japan 1960 Malaysia 1984 Approval system Yes Philippines Republic of Korea Singapore Vietnam 1984 1986 1998 1989 Yes Yes No Yes Compendium of medicinal plants Ayurveda pharmacopoeia ( 100 monographs) (1979) Yes, 21 monographs Thai herbal pharmacopoeia, traditional formularies of herbal medicines (5 volumes) No British pharmacopoeia is used Yes, 92 monographs Chinese pharmacopoeia (1963) No Japanese pharmacopoeia Malaysian herbal monograph (1999) In development No No Vietnam medicinal plants Ayurveda (2001)–315, Prescription and OTC Unani (2000)–244, Siddha (2001)–98 No OTC No 16 herbal preparation No OTC 1242 Prescription and OTC Prescription and OTC OTC Not available No No In development Korea pharmacopoeia (1959) No Vietnam pharmacopoeia 2000 515 No 267 OTC OTC OTC Prescription and OTC Source: 1st WHO global Survey on National Policy and regulation of TM/CAM, 2005. botanical drug product may be marketed in the United States as an OTC drug monograph or as an approved NDA or ANDA (21 CFR parts 331–358). The manufacturer would need to submit a petition in accordance with 21 CFR 10.30 to amend the monograph to add the botanical substance as a new active ingredient [46].In India, Department of Ayurveda, Yoga & Naturopathy, Unani, Siddha and Homoeopathy (AYUSH) established in 1995 under the Ministry of Health & Family Welfare is responsible for the regulation of herbal medicines. The Drugs & Cosmetics Act of 1940 lays down the various rules for production and marketing of Ayurveda, Siddha and Unani (ASU) drugs. Schedule T of Drugs & Cosmetics Act, 1940, specifically deals with the GMP for ASU drugs. Most of the herbal products do not have to demonstrate their safety and efficacy by clinical trials. Among the Latin American countries Brazil, Argentina and Mexico are the major players in herbal market. Herbal drug regulation exists in Brazil since 1967. Herbal medicines are sold as both prescription based and OTC drug. Legal requirements for phytopharmaceutical drug registration in Brazil are described in Directive 6, issued in 1995 by the Brazilian Drug Division (DIMED) which enforces drug regulation. The fourth version of regulation RDC/48/2004 was published in 2004. As per the directive complete documentation of efficacy, safety and constant defined quality are required as a condition for the registration of phytopharmaceutical products. Efficacy and safety test results in humans, in conformity with the guidelines of Directive 116 published by Federal Health Agency are also required for registration. Scientific documentation from the literature may be submitted, instead of controlled clinical trials or animal tests, if they already exist for the proposed preparation. The national pharmacopoeia and monographs are legally binding for the manufacturers [47]. In Mexico a large proportion of the population relies heavily on traditional practitioners and medicinal plants to meet primary health care needs. Herbal medicines are available as both prescription and OTC drugs. In Argentina laws and regulations on TM/CAM, specifically on phytotherapeutic medicines and vegetable drugs were established in 1998 in the Resolution 144/98. They are regulated as prescription medicines, over the counter medicines and dietary supplements. The relevant regulatory requirements for manufacturing include adherence to information in pharmacopoeias and monographs and special GMP rules. In both Mexico and Argentina safety assessment requirements include traditional use without demonstrated 469 N. Sahoo et al. / Fitoterapia 81 (2010) 462–471 Table 3 Herbal medicine regulation in EU, US and India. Country Regulatory authority Description Regulation/Act EU European Medicines Agency (EMEA): The Committee on Herbal Medicinal Products (HMPC) Directive 2004/24/EC (Traditional Herbal Medicinal Products Directive) and Regulation (EC) No 726/2004. Articles 16a to 16i of Directive 2001/83/EC US USFDA: Center for Drug Evaluation and Research (CDER) Establishment of HMPC and regulation of herbal medicine Registration Procedure for traditional herbal medicinal products Botanical drug definition Regulation of herbal product India Procedure for marketing of Botanical drug as OTC drug Center for Biologics Evaluation and Research Regulation of Allergenic extracts and (CBER) vaccines that contain botanical ingredients Department of Ayurveda, Yoga & Naturopathy, Production and marketing of ASU drugs Unani, Siddha and Homoeopathy (AYUSH) GMP for ASU drugs harmful effects, reference to documented scientific research on similar products, toxicological studies when traditional use cannot be demonstrated and submission of a full toxicological and pharmacological dossier. Compliance with these requirements is ensured by regular inspections [44]. Herbal medicines are the most commonly used type of traditional medicine in the Eastern Mediterranean Region. In Iran, herbal medicines are produced locally and a large population depends on them for primary health care. In other countries, such as the United Arab Emirates, the majority of herbal products are obtained from the United States, Europe or Asia. In this region herbal medicines are generally categorized as ‘traditional herbal medicines’ that have been widely used, supported by well-established safety and efficacy data, or have been used within the local community for a minimum period of fifteen years. ‘New herbal medicines’ are those used for only a short period of time and to a very small extent (few uses in a small number of patients), or used in a new combination of herbal substances never combined before. Only few countries in the region have regulations for ensuring quality. A recent survey in this region also showed that there is a necessity for proper handling and licensing of herbal medicines [48] Important data related to safety, efficacy and quality control are often either insufficient or not available. In most countries, either no safety monitoring system exists or the existing system excludes herbal medicines. The Eastern Mediterranean Drug Regulatory Authorities Conferences in 1999 and 2001 provided a general guidance to drug regulatory authorities in the development and implementation of preliminary regulatory systems for herbal medicines. In 2006 WHO developed the Guidelines on minimum requirements for the registration of herbal medicinal in the Eastern Mediterranean Region Products [49]. This guideline gives an overview of general requirements for safety and efficacy for traditional as well as new herbal medicinal products, quality control aspects, pharmacovigilance and control of advertisements for herbal medicines. Standards for medicinal plants are being developed worldwide but as yet there is no consensus as to how these should be adopted. Several publications, United States Pharmacopoeia, British Herbal Compendium, British Herbal 201(g)(1)(B), Federal Food, Drug, and Cosmetic Act Dietary Supplement Health and Education Act of 1994 (DSHEA) 21 CFR 10.20, 10.30, 312, 314, 321, 324, 330, 331–358 Section 351 of the Public Health Service Act (42 U.S.C. 262). Drugs & Cosmetics Act, 1940 Drugs & Cosmetics Rules, 1945 Schedule T, Drugs & Cosmetics Act, 1940 Pharmacopoeia, Chinese Pharmacopoeia, and Physician's Desk Reference (PDR) for herbal medicines, Ayurvedic Pharmacopoeia of India have monographs for herbal raw materials to which respective countries adhere, but there is no interlinking of these monographs. For a given plant the monograph may vary in different publications. Different country standards with respect to a single formulation create difficulties for manufacturers in herbal drug trade. 5. International harmonization Harmonizing efforts have been initiated on pharmacopoeial specifications, standardization and classification of herbal drugs to ensure uniformity of quality, safety and efficacy of the same herbal medicines across countries. The pharmacopoeias of Korea, Japan and China list similar herbal medicines, but their specifications are somewhat different. The same crude plant material may be described but the family or species of the original plant may be different. Further, the same crude plant material may be specified but the name expressed by the Chinese letter or Latin binomial pharmacopoeia name or the part used for the herbal medicine is different [50]. The Western Pacific Regional Forum for the Harmonization of Herbal Medicine (FHH) tried to harmonize the crude drug monographs in the pharmacopoeias of six Asian countries (Japan, China, Korea, Singapore, Vietnam, and Hong Kong) in order to help in promoting commercialization of safe and effective herbal drugs across countries. Among the American countries harmonization of process requirements and herbal product registration was initiated in the year 2000. The working group on Medicinal Plant of the Pan American Network of Drug Regulatory Harmonization (PANDRH) is working to promote a common understanding on the types of herbal products, definition of terms used, identification of procedures and the minimum requirements for registration of herbal products [51]. The ‘WHO International Standard Terminologies on Traditional Medicine in the Western Pacific Region’ has been prepared with international standard terminology that will help in defining a common scientific basis across different traditional medicine systems [52]. This compilation 470 N. Sahoo et al. / Fitoterapia 81 (2010) 462–471 has about 4000 traditional medicine terms. It is suggested that this would help in developing evidence-based clinical practice guidelines on traditional medicine. A system for Anatomical Therapeutic Chemical (ATC) classification of herbal remedies which is fully compatible with the general medicines has been proposed. With a few modifications this system has now been adopted and published in the Guidelines for Herbal ATC Classification and Herbal ATC Index [10]. India has nearly eight thousand herbal drug companies, of which about five thousand have GMP compliant manufacturing units and majority of them are of small and medium size. Seventy percent of the Indian exports from the herbal sector consist largely of raw materials and thirty percent consist of finished products including herbal extracts [53]. There are fifty five major herbal drug exporting companies in India. We have carried out a preliminary study based on twenty five point questionnaire to identify the challenges these companies face with respect to manufacturing and exporting of herbal drugs. Compliance to different national regulatory standards is identified as one of the major hindrances for commercialization. Thirty-three percent of the industries surveyed stated achieving regulatory compliance to different country standards is very difficult and time consuming and sixty-six percent of them feel the need for development/adoption of a Common Technical Document (CTD) for marketing authorization application in different countries. 6. Conclusions Advances in detection and quantitation of herbal drug components have increased the understanding of the relation between the specific component(s) and effects. There is a widespread concern on the unintended/harmful effects of herbal drugs with greater number of studies carried out on herbal drug reactions in the developed countries. This is challenging the notion that long traditional use is an indication for safety of herbal medicines. Manufacturers, particularly in South East Asia, face the challenge of proving the authenticity and purity of herbal drug preparations during commercialization. Marker based standards are becoming popular for the identification/authentication of herbal drug components. However, as herbal drugs are plant extracts based the need for adoption of multi-marker system and effect of storage conditions are important points to be considered. A general comparison of the pharmacopoeial standards reveals that there is a wide variation in plant specific parameters, quality standards such as permissible limits for heavy metal, pesticide and microbial contamination in different countries. Country specific standards as well as regional guidelines have been evolved some of which only have been adopted. The development of a CTD is an important lead with respect to unification but so far there is no consensus on use of a single unified approach either system wise or drug wise. With respect to South East Asia India is among the leading countries with respect to development of pharmacopoeial standards as well as modification of existing regulatory guidelines. Evidence-based submissions for regulatory approval and interlinking of various pharmacopoeial and/monographs would help herbal manufacturers gain greater access to regulated markets across the world. Conflict of interest statement We have no conflicts of interest that are directly relevant to the content of this review. References [1] Rates SMK. Toxicon 2001;39:603. [2] World Health Organization. Traditional medicine; 2008. http://www. who.int/mediacentre/factsheets/fs134/en/, Last accessed on 3rd September 2009. [3] Mukherjee PK, Wahile AJ. Ethnopharmacology 2006;103:25. [4] Karnataka Medicinal Plants Authority. Authenticity, purity of herbal drugs critical for sustained growth in global markets: KMPA chief; 2009. www. Pharmabiz.com, Last accessed on 3rd September 2009. [5] Iwu MM, Duncan AR, Okunji CO. New antimicrobials of plant origin. In: Janick J, editor. Perspectives on new crops and new uses. Alexandria: ASHS Press; 1999. p. 457. [6] World Health Organization. Guidelines for the Regulation of Herbal Medicines in the South-East Asia Region: Developed at the Regional Workshop on the Regulation of Herbal Medicines, Bangkok, 24–26 June 2003. New Delhi: Regional office for South East Asia, World Health Organization; 2003. [7] Cuzzolin L, Zaffani S, Benoni G. Eur J Clin Pharmacol 2006;62:37. [8] Elvin-Lewis M. J Ethnopharmacol 2001;75:141. [9] Li S, Han Q, Qiao C, Song J, Cheng CL, Xu H. Chin Med 2008;3:7. [10] Uppsala Monitoring Centre. Herbal drug side reactions; 2009. http:// www.who-umc.org/DynPage.aspx?id=13120&mn=1510, Last accessed on 3rd September 2009. [11] European Medicines Agency. Committee for proprietary Medicinal Products. Herbal drugs with serious risks. Doc. Ref. EMEA/ HMPC/246736/2005; (http://www.emea.europa.eu/pdfs/human/hmpc/ CPMP%20List%20of%20herbs%20with%20serious%20risks.pdf.) Last accessed on 3rd September 2009. [12] Medicines and Healthcare products Regulatory Agency. Safety of herbal medicinal products; July 2002. http://www.mhra.gov.uk/home/groups/ es-herbal/documents/websiteresources/con009293.pdf. [13] Mainardi T, Kapoor S, Bielory L. J Allergy Clin Immunol 2009;123(2): 283. [14] Zou L, Harkey MR, Henderson GL. Life Sci 2002;71:1579. [15] Lam Y, Poon W, Lai C, Chan AY, Mak TW. J Pharm Biomed Anal 2008;46: 804. [16] Yee S, Chu S, Xu Y, Choo P. Health Policy 2005;71:133. [17] Chan K. Chemosphere 2003;52:1361. [18] Mitra SK, Kannan R. Ethnobot Leafl 2007;11:11. [19] Yap KY, Chan SY, Lim CS. Food Chem 2008;107:570. [20] Ramawat K.G., S. Goyal. The Indian herbal drugs scenario in global perspectives. In: Ramawat K.G., Mérillon J.M. (editors). Bioactive Molecules and Medicinal Plants. New York: Springer Berlin Heidelberg; 2008.p.325. [21] Mazzanti G, Battinelli L, Daniele C, Costantini S, Ciaralli L, Evandri MG. Food Chem Toxicol 2008;46:3043. [22] Dargan PI, Gawarammana IB, Archer JRH, House IM, Shaw D, Wood DM. Int J Environ Health 2008;2(3/4):463. [23] Ernst E. Trends Pharmacol Sci 2002;23(3):136. [24] Rai V, Kakkar P, Khatoon S, Rawat AKS, Mehrotra S. Pharm Biol 2001;39 (5):384. [25] Saper RB, Kales SN, Paquin J, Burns MJ, Eisenberg DM, Davis RB, et al. JAMA 2004;292(23):2867. [26] Saper RB, Phillips RS, Sehgal A, Khouri N, Davis RB, Paquin J, et al. JAMA 2008;300(8):915. [27] Ang HH. Food Chem Toxicol 2008;46:1969. [28] Xue J, Hao L, Peng F. Chemosphere 2008;71:1051. [29] Jian X, Dongjing L, Shilin C, Yonghong L, Zhongmei Z. Mode Tradit Chin Med Mater Med 2008;10(1):91. [30] Rai V, Kakkar P, Singh J, Misra C, Kumar S, Mehrotra S. Environ Monit Assess 2008;143:273. [31] World Health Organization. WHO guidelines for assessing quality of herbal medicines with reference to contaminants and residues; 2007. http://apps.who.int/medicinedocs/index/assoc/s14878e/s14878e.pdf, Last accessed on 30th January 2010. [32] Bugno A, Almodovar AAB, Pereira TC, Pinto TJA, Sabino M. Braz J Microbiol 2006;37:47. [33] Stewart KM. Ethnopharmacology 2003;89:3. [34] Warburton CL, James EA, Fripp YJ, Trueman SJ, Wallace HM, et al. Biol Conserv 2000;96:45. N. Sahoo et al. / Fitoterapia 81 (2010) 462–471 [35] Saxena PK, Cole IB, Murch SJ. Approaches to quality plant based medicine: significance of chemical profiling. In: Verpoorte R, et al, editor. Applications of Plant Metabolic Engineering. Netherlands: Springer; 2007. p. 311. [36] Joshi K, Chavan P, Warude D, Patwardhan B. Curr Sci 2004;87(2):159. [37] Stickel F, Schuppan D. Dig Liver Dis 2007;39:293. [38] World Health Organization. Quality control methods for medicinal plant materials; 1998. http://whqlibdoc.who.int/publications/1998/ 9241545100.pdf, Last accessed on 3rd September 2009. [39] World Health Organization. Guidelines on good agricultural and collection practices (GACP) for medicinal plants; 2003. http://whqlibdoc.who.int/ publications/2003/9241546271.pdf, Last accessed on 3rd September 2009. [40] Ong ES. J Chromatogr B 2004;812:23. [41] Liang Y, Xie P, Chan K. J Chromatogr B 2004;812:53. [42] World Health Organization. The Declaration of Alma-Ata; 1978. http:// www.who.int/hpr/NPH/docs/declaration_almaata.pdf, Last accessed on 3rd September 2009. [43] World Health Organization. Essential medicines Biennial Report 2006– 2007, WHO/PSM/TCM/2008; 2008. http://www.who.int/medicines/ areas/access/EssentialMedsBiennialReport06_07.pdf, Last accessed on 3rd September 2009. [44] World Health Organization. National policy on traditional medicine and regulation of herbal medicines. Report of a WHO global survey; May 2005. [45] European Medicines Agency. Herbal medicinal products, guidelines; 2009. http://www.emea.europa.eu/htms/human/hmpc/hmpcguide. htm, Last accessed on 3rd September 2009. 471 [46] US Food and Drug Administration. Guidance for industry: botanical drug products (the botanical guidance); 2004. http://www.fda.gov/ downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm070491.pdf, Last accessed on 3rd September 2009. [47] Petroick PR, Marques LC, De Paula IC. J Ethnopharmacol 1999;66(1):51. [48] Azaizeh H, Saad B, Khalil K, Said O. eCAM 2006;3(2):229. [49] World Health Organization. Guidelines on minimum requirements for the registration of herbal medicinal products in the Eastern Mediterranean Region. World Health Organization, Regional Office for the Eastern Mediterranean Cairo, 2006. (http://www.emro.who.int/dsaf/ dsa545.pdf). Last accessed on 30th January 2010. [50] Choi DW, Kim JH, Cho SY, Kim DH, Chang SY. Toxicology 2002;181–182: 581. [51] Regional meeting on regulatory aspects of herbal products, Final report, November 2000, Division of Health Systems and Services Development, Pan American Health Organization, World Health Organization. (http:// www.paho.org/english/ad/ths/ev/PM-Registration_herbal-medic.pdf). Last accessed on 30th January 2010. [52] World Health Organization. WHO International Standard Terminologies on Traditional Medicine in the Western Pacific Region; 2007. http:// www.wpro.who.int/publications/PUB_9789290612487.htm, Last accessed on 3rd September 2009. [53] Working Group on “Access to Health Systems including AYUSH”, Eleventh Five Year Plan (2007–2012) Government of India Planning Commission. Available at URL http://planningcommission.nic.in/plans/ planrel/11thf.htm. Last accessed on 3rd September 2009.