unit ...5 REGULATORY REQUIREMENTS FOR HERBAL MEDICINES Objectives: Upon completion of this Chapter, the student should be able to understand: + Regulatory requirements for quality, safety and efficacy of herbal medicines. * WHO Guidelines on safety monitoring of herbal medicines. * Comparison of various Herbal Pharmacopoeios. * Chromatographic fingerprinting, Marker compounds and the role which chemical and biological markers play in the standardization of herbal produets. 5.1 INTRODUCTION Recently, herbal medicinal products (HMP) have gained importance and are extensively used in the prevention and treatment of various diseases. A commercial herbal medicinal product should comply with the regulatory requirements of quality, safety and efficacy. Currently, the standards and regulations of herbal medicinal products vary from country to. country, which poses a challenge to the manufacturing companies to place a standardized herbal product in the international market. Regulations for Herbal Medicines: In India, Department of Ayurveda, Yoga and Naturopathy, Unani, Siddha and Homoeopathy (AYUSH) is the regulatory authority which controls product licensing, composition, formulation and ensures manufacturing of products, labeling, packing, quality as per Schedule “T" for good manufacturing practice (GMP) and monitors export of Ayurveda, Siddha and Unani products. Herbal products are licensed under Ayurveda, Siddha and Unani drugs, as patent or proprietary medicines. BtRegulatory Requirements for Herbal Medicines Quality Control and Standardization of Herbals Development of Herbal Medicinal Product: ‘Aoeoie/ ‘Ayyesjuonewojut leajydesBouqia ‘Aewwns ‘Moy woudojenap jonpod jeuro}pow jeqoH{ :}°5 “Bis [apionseaiseoueisqns| motnsono (6D ae pprcecisenusisars| Teuune mowono uan/ou a oudH su 12O1o-UON s8000Ke uoneoyeds aaa aqord Kundu jeu aw ot uoneaunsne fe soppris BOUND WaNos fenpIsom s8000 uoneoypeds SarenueTO me anna svodere : ‘SOIpNYs |EdIUIIB4d enneweno SS8001d wueyducs gro | | ssverduos woueyduee 5 pode en ‘pemepuswon eoueyu0 09 woishs yonpoid jeu quauidojenep ovo Keaye || 30488 || ainsop || ‘nuonesedoud ss0001d woos ][saer ]| cue a hiojes_| | 262018 |] ourewoo] | Teaion suumaeynuew | | Amaers || antoy || Yrs t t ft ft t t ft kg t yonpodd [EUIOIPOW 1eGseH 52Quality Control and Standardization of Herbals Regulatory Requirements for Herbal Medicines 1. Good Agricultural and Collection Practice (GACP): GACP applies the guidance to the cultivation and collection procedures, right from selection of herbs, botanical identity, soil, seed, cultivation techniques, environment and surroundings, climate, irrigation, maintenance, harvesting and drying. The collection procedures should be carried out by trained personnel with adequate knowledge about cultivation techniques including; the use of pesticides, etc Well-organized quality assurance should be maintained with active principle content, morphological and microscopical features, limit values for microbial contamination, chemical residues, heavy metals, etc. Documentation of process and procedures, funigants, labeling, agreements, audit results should be maintained. Post harvesting procedures are to be inspected. The processing of the collected herbs is to be carried out in specified facilities and stored appropriately. Testing details, solvents used purification stages, standardizations, etc. details of impurities like; pesticides, fumigants, microbial contamination and its control should be documented, 2. Good Manufacturing Practice (GMP): Implementation of GMP ensures product uniformity batch to batch and assists to comply with the quality standards to meet the requirements. The quality assurance system and documentation are crucial for GMP. Research and development laboratory in accordance with the GLP is mandatory, along with compliance to GACP. This set up will qualify for standardized manufacturing of herbal medicines, Standardization should be followed right from seed to shelf with well-planned analytical method development and analytical method validation. A detailed product development report for herbal preparation and herbal product with a well-defined process flow accompanied by process controls will ensure that quality is built into the product. Manufacturing flow chart with process control specification and standard testing procedures are must for processing of herb, herbal preparation and herbal medicines. The active herb specification should include; physical and chemical parameters, impurities, microbial contaminants and adulteration. As the extraction and processing of herbal preparation involve the use of solvents, the parameter on residual solvents should be a part of the specification. The Medicinal Plants Division of ICMR as per WHO guidelines and with the involvement of approved laboratories has addressed the data generation for monographs. Each monograph is titled with botanical nomenclature, macroscopic and microscopic characteristics and phytochemical constituents, identification criteria using fingerprinting techniques (TLC/GLC/HPLC), quantitative estimation and marker principles. It also includes; information on pharmacological, clinical, toxicological aspects, dose, adulterants/substitutes, etc. 3. Good Laboratory Practice (GLP): Well planned analytical method development and analytical method validation in approved laboratories as per GLP, will help in setting up of a quality management system to ensure uniformity, consistency, reliability, reproducibility of the testing parameters. It ensures 53Quality Control and Standardization of Herbals Regulatory Requirements for Herbal Medicines reliable and quality-oriented data and contributes towards a quality product. Stability studies of herbal substances, herbal preparations and herbal medicines should be carried out. The container closure system also plays a major role. 4. Good Clinical Practice (GCP): Herbal medicines under the Herbal Anatomical Therapeutic Chemical (HATC) are classified based on nomenclature and therapeutic activity to aid the study of safety and clinical data. Department of AYUSH implemented pharmacovigilance program keeping in mind the growing demand of acceptance of Ayurveda and thus, to ensure its safety and efficacy and reporting of adverse reactions and to investigate the same. The Health Authority and Ethical committee give clearance for conducting a clinical trial. For health conditions, well-established usage in the country of origin would serve the requirement with the supporting ancient texts, pharmacopoeia and monographs stating the sarne, whereas, in case of acute and chronic disease conditions, a clinical trial is to be carried out. The trial when conducted requires a detailed protocol, a principle investigator and evidence of safety and efficacy of the herbal medicine. 5.2 WHO GUIDELINES ON SAFETY MONITORING OF HERBAL MEDICINES IN PHARMACOVIGILANCE SYSTEMS WHO guidelines provide practical technical guidance for monitoring the safety of herbal medicines within pharmacovigilance systems. The global consumption of herbal medi enormous, so that, in terms of population exposure alone, it is essential to identify the risks associated with their use. The safety of herbal medicines is an important public health issue. Herbal medicines are frequently used in conjunction with other medicines and it is essential to understand the consequences of such combined use and monitor whether any adverse effects are arising. This can be achieved most readily within existing pharmacovigilance systems. Problems: Among consumers, there is a widespread misconception that “natural” always means “safe” and a common belief that remedies from the natural origin are harmless and carry no risk. However, some medicinal plants are inherently toxic. Adverse effects may arise from the mistaken use of the wrong species of medicinal plants, incorrect dosing and errors in the use of herbal medicines both by healthcare providers and consumers. Interactions with other medicines and use of products contaminated with hazardous substances such as; toxic metals, pathogenic micro-organisms and agrochemical residues can also cause adverse effects, The objectives of these guidelines are: 1. To support Member States, in the context of the WHO International Drug Monitoring Programme. 2. To provide practical technical guidance for monitoring the safety of herbal medicines within pharmacovigilance systems. 54Quality Control and Standardization of Herbals Regulatory Requirements for Herbal Medicines 3. To include herbal medicines in National drug safety monitoring systems. 4, To provide standard definitions of terms relating to pharmacovigilance and safety monitoring of herbal medicines. 5. To promote the safe and proper use of herbal medicines. The WHO guidelines were developed with the view that, within current pharmacovigilance systems, monitoring of the safety of medicines should be enhanced and broadened in ways that will allow the successful monitoring of herbal medicines. It is not the intention to suggest that different systems should be instituted for this purpose. However, because of the unique characteristics of the provision and use of herbal medicines, several technical issues need to be addressed if adequate and effective monitoring is to be introduced. The guidelines, therefore, identify the particular challenges posed in monitoring the safety of herbal medicines effectively and propose approaches for overcoming them. Special attention is also given to the reporting system for adverse reactions to herbal medicines and to the analysis of the causes of the reported adverse reactions. Currently, the majority of adverse events related to the use of herbal products and herbal medicines that are reported are caused by poor product quality or improper use of herbal products. Member States are, therefore, encouraged to strengthen national regulation, registration and quality assurance and control of herbal medicines. Also, national health authorities should give greater attention to consumer education and to qualified practice in the provision of herbal medicines. 5.3 COMPARISON OF VARIOUS HERBAL PHARMACOPOEIAS Herbal Pharmacopoeia is a reference book for the preparation of quality medicines published by the authority of a Government and represents qualitative and therapeutic monographs on botanicals. Herbal Pharmacopoeia is a compiled document which: (@) Defines a botanical drug (b) Provides information for its proper identi (©) Contains the basic description including; nomenclature, plant parts used, active constituents, range of application, contraindications and side effects, incompatibilities with other medications, dosage, use and action of the herb. It is an important reference for all individuals and organizations working within pharmaceutical research and development, manufacture and testing around the globe. The modem-day pharmacopoeias are strictly for standards of medicines and every developed country has a pharmacopoeia for their medicaments of synthetic as well as natural origin. Some popular herbal pharmacopoeias of the world are: 1. American Herbal Pharmacopoeia (AHP) 2. African Herbal Pharmacopoeia (AfrHP) ation. 55Quality Control and Standardization of Herbals Regulatory Requirements for Herbal Medicines British Herbal Pharmacopoeia (BHP) Korean Herbal Pharmacopoeia (KHP) Pharmacopoeia of the People's Republic of China (ChP) The Turkish Pharmacopoeia (TP) Farmacopea Argentina Brazilian Pharmacopoeia Indian Herbal Pharmacopoeia 1. American Herbal Pharmacopoeia (AHP): The AHP develops qualitative and therapeutic monographs on botanicals including; many of the Ayurvedic, Chinese and Western herbs most frequently used in the United States. These monographs represent the most comprehensive and critically reviewed body of information on herbal medicines in the English language and serve as a primary reference for academicians, health care providers, manufacturers and regulators 2. African Herbal Pharmacopoeia (AfrHP): The AfrHP provides comprehensive, up to date botanical, commercial and phytochemical information on over 50 of the most important African medicinal plants. The technical data were made on plant samples sourced from across the continent. These monographs were prepared by leading African scientists and have been reviewed by international experts. ‘Additional data includes; micro-morphology of the plant material, distribution maps and TLC chromatograms. These data are crucial for producers, collectors and traders in medicinal plants and extracts as well as researchers, manufacturers and practitioners. The scope, quality and standard of these herbal monographs are comparable to those prepared in Europe, North America and Asia. 3. British Herbal Pharmacopoeia (BHP): The BHP provides quality standards for 169 herbal raw materials. European Pharmacopoeia Commission (Council of Europe) has led to the introduction of many more herbal monographs in the European Pharmacopoeia. The BHP monograph includes a brief description of the form of the material, its main geographical sources, macroscopical and microscopical descriptions of the herbal material, prepared by eminent pharmacognosists, together with odour and taste descriptions. It also includes; comparative identification and qualitative phytochemical analysis. However, the BHP remains a very useful aid to quality assurance, particularly for herbs not featured in official pharmacopoeias. 4, Korean Herbal Pharmacopoeia (KHP): The recent KHP contains total of 2,462 official monographs (Part I and Part Il). Part I includes; frequently used drugs and their primary preparations and Part Il includes; crude drugs, biological drugs, radioactive drugs, combined preparations, additives for preparations and quasi-drugs. The Pharmacopoeia comprises the following items, in the order, general notices, general requirements for preparations, monographs, general tests, processes and apparatus and general information followed by the index. ~Pernauaw 56Quality Control and Standardization of Herbals Regulatory Requirements for Herbal Medicines 5. Pharmacopoeia of the People’s Republic of China (ChP): The Ministry of health published the Republic of China's first pharmacopoeia as Chinese Pharmacopoeia in 1953. Under the umbrella of the China Food and Drug Administration (CFDA), the Chinese Pharmacopoeia Commission (ChPC) and its stakeholders (drug control institutions, research institutions, universities and drug manufacturers) prepared the Chinese Pharmacopoeia in line with the basic principles, goals and requirements of the era. The Chinese Pharmacopoeia includes; monographs of vegetables, oil, fats and extracts, medicinal materials and the prepared slices of Chinese crude drugs, single item preparations, chemical drugs, antibiotics, biochemical and radioactive drugs, pharmaceutical excipients and biologicals. General chapters include; general requirements of preparations, testing methods, standard substances, reagents and the guidelines. 6. The Turkish Pharmacopoeia (TP): Turkish Pharmacopoeia includes; European Pharmacopoeia monographs as well as national monographs. It has a section containing herbal, biological or biotechnological products and finished products. They are first published in the Turkish Pharmacopoeia Journal and then in the Turkish Pharmacopoeia and become official. In the latest version, the number of national monographs has reached 32 and most of them are monographs of medicinal and aromatic herbal ingredients. 7. Farmacopea Argentina: Farmacopea Argentina is published by The National Administration of Medicines Food and Medical Technology and it is in Spanish language. Farmacopea Argentina provides specification for biological, herbal products, medical products, blood products, radiopharmaceutical products, for vaccines and includes general monographs and supplementary texts. 8. Brazilian Pharmacopoeia: Brazilian Pharmacopoeia is published by Pharmacopoeia Coordination Brazilian Health Surveillance Agency in three different languages; Portuguese, English and Spanish. Apart from Brazilian Pharmacopoeia, Herbal Medicines National Formulary (Portuguese/ Spanish) and Herbal Medicines Memento (Portuguese) are also used in Brazil, Brazilian Pharmacopoeia provides specification via monographs for APIs and excipients, for dosage forms, for biological, for herbal products and includes monographs for medical devices. 9. Indian Herbal Pharmacopoeia (IP): The Indian Herbal Pharmacopoeia has 40 monographs published by the Indian Drugs Manufacturers Association (IDMA) in collaboration with Regional Research Laboratory (RRL), Jammu, Index of pharmacopoeias published by World Health Association, Geneva has a comprehensive list of pharmacopoeias of different countries. Ayurvedic Pharmacopoeia of India (API) has monographs of 600 plants/animals/minerals and derived drugs (Part I, Volume 1 to 8). Monographs of 152 compound Ayurvedic formulations are published in Ayurvedic Pharmacopoeia of India (Part I, Volume 1 to 3). a7Quality Control and Standardization of Herbals Regulatory Requirements for Herbal Medicines Other than API, Siddha Pharmacopoeia of India (Volume 1 and 2), Homeopathic Pharmacopoeia of India (Volume 1 to 6) and Unani Pharmacopoeia of India (Volume 1 to 6) are the standard books available for Indian herbs. The innovative work, Quality standards of Indian Medicinal plants by Indian Council of Medical Research (ICMR) are a non-pharmacopoeial masterpiece for reference on standards of Indian herbs. Monographs on 449 plants (Volume 1 to 13) included in the book would help in improving monographs in API and other Pharmacopoeias of Indian origin. The Pharmacopoeia Commission for Indian Medicine (PCIM) under ministry of AYUSH is fully functional to improve the Pharmacopoeias for Indian Herbs. * The first official Pharmacopoeia of India published in 1868. In 1946, Government of India issued one list known as “The Indian Pharmacopoeial list”. The committee under the chairmanship of Sir R. N. Chopra along with other nine members prepared "The Indian Pharmacopoeial list’. It was prepared by the Department of Health, Govt. of India, Delhi in 1946.In 1948, Government of India appointed an Indian Pharmacopoeia committee for preparing “Pharmacopoeia of India’. Tenure of this committee was 5 years. Indian Pharmacopoeia committee under the chairmanship of Dr. B. N. Ghosh published first edition of IP in 1955. Supplement to this edition was published in 1960, * The Second edition of IP was published in 1966 under the chairmanship of Dr. 8. Mukherjee. Official titles of monographs were given in English. Formulations of the drugs were given immediately after the monograph of drugs. 274 monographs from IP 1955 and their supplements were deleted. Supplement to this edition was published in 1975. In this, 126 new monographs were included and 250 monographs were amended. * The Third edition of IP was published in 1985 with two volumes and nine appendices. 261 new monographs were added, Addendum I to IP was published in 1989 where, 46 new monographs were added and 126 amended. Addendum II was published in 1991 where, 62 new monographs were added and 110 amended. * The Fourth edition of IP was published in 1996 under the chairmanship of Dr. Nityanand, It covered 1149 monographs and 123 appendices. It included 294 new monographs and 110 monographs were deleted. Addendum I was made effective from 31* December 2000 where, 42 new monographs were added. Addendum II was made effective from 30" June 2003 where, 19 new monographs were included + The Fifth edition of IP was published in 2007 and an addendum to this edition was published in 2008. IP 2007 was presented in three Volumes. Volume I contains general notices and general chapters. Volume Il and III contain general monographs on drug substances, dosage forms and pharmaceutical aids, 58Quality Control and Standardization of Herbals Regulatory Requirements for Herbal Medicines * The Sixth edition of IP was published in 2010 by the Indian Pharmacopoeia Commission (IPC). The Indian Pharmacopoeia 2010 was presented in three volumes. Volume I contains the notices, preface, the structure of the IPC, acknowledgments, introduction and the general chapters. Volume Il contains the general notice, general monographs on dosage forms and monographs on drug substances and pharmaceutical aids (A to M). Volume III contains monographs on drug substances, dosage forms and pharmaceutical aids (N to Z). It also includes monographs on vaccines and immunosera for human use, herbs and herbal products, blood and blood related products, biotechnology products and veterinary products. The number of monographs of excipients, anticancer drugs, herbal products and antiretroviral drugs has been increased in this edition. A chapter on Nuclear magnetic resonance spectroscopy (NMR) was also incorporated in Appendices. + The Seventh Edition of the Indian Pharmacopoeia (IP 2014) was published by the Indian Pharmacopoeia Commission (IPC) on behalf of the Government of India, Ministry of Health and Family Welfare. The Indian Pharmacopoeia 2014 was presented in four volumes. The scope of the Pharmacopoeia has been extended to include; additional anticancer drugs and antiretroviral drugs and formulations, products of biotechnology, indigenous herbs, herbal products and veterinary vaccines. The IP 2014 included 2550 monographs of drugs out of which 577 are new monographs consisting of APIs, excipients, dosage forms and herbal products, etc. * The Eighth edition of the Indian Pharmacopoeia (IP 2018) was published by the Indian Pharmacopoeia Commission (IPC) on behalf of the Ministry of Health and Family Welfare, Government of India, IP 2018 was brought out in four volumes incorporating 220 new monographs including; chemical monographs (170), herbal monographs (15), blood and blood related products (10), vaccines and immunosera for human use monographs (02), radiopharmaceutical monographs (03), biotechnology derived therapeutic products (06), veterinary monographs (14), 366 revised monographs and 7 monographs have been deleted 5.4 ROLE OF CHEMICAL AND BIOLOGICAL MARKERS IN STANDARDIZATION OF HERBAL PRODUCTS Importance of Standardization: Standardization of crude drug means confirmation of its identity and determination of its quality, purity and detection of nature of adulterant by various parameters (pharmacognostic parameters, physicochemical parameters, phytochemical parameters, microbiological assay and chromatographic analysis). Standardization of crude drug is important, to assess the quality of the raw materials, estimate the amount of active principle present in it and to achieve batch-to-batch consistency of the finished products. 59Quality Control and Standardization of Herbals Regulatory Requirements for Herbal Medicines Chromatographic Fingerprinting: Chromatographic fingerprinting is a chromatogram representing the characteristic of the herbs. It is one of the most important methods for the evaluation of herbal crude drugs. Chromatographic fingerprinting plays an important role in the standardization of herbal crude drugs. They are used for confirming the presence of different herbs in polyherbal formulation as well as in quantification of marker compounds. Marker Compounds: Marker compounds are the pure and single isolated chemical constituents within a crude drug that confirms the exact botanical identity of that starting material or the crude drug. Marker compounds are of interest for quality control purposes and they may or may not contribute to the therapeutic activity. Role of markers in the standardization of herbal products: As per WHO, there are three kinds of herbal medicinal products: raw plant materials, processed plant materials and medicinal herbal drugs. Herbal drugs are finished labeled products that contain active ingredients such as; aerial or underground parts of plants or other plant materials or a combination thereof, whether in the crude state or as plant preparations. The use of herbal medicines has increased with the global trend of people returning to natural therapies. Herbal medicinal products and dietary supplements that people take to improve their health are sold as tablets, powders, capsules, teas, extracts and fresh or dried plants. Correct identification and quality assurance of the starting materials is therefore, an essential requirement to ensure reproducible quality of herbal medicine which contributes to its safety and efficacy. Marker compounds may serve to calculate the amount of active components of herbal drug in the preparation or in the finished product. Markers are used at various stages of the development and manufacturing of an herbal medicine like; authentication and differentiation of species, collecting and harvesting, quality evaluation and stability assessment, diagnosis of intoxication and detection of lead compounds. Types of Marker compounds: 1. Chemical Markers 2. Biochemical Markers 3. Molecular or DNA Markers 1. Chemical Markers: Chemical markers are a unique component that contributes to the therapeutic effects of herbal medicine. The study of chemical markers is applicable to many research areas including; the authentication of genuine species, search for new resources or substitutes of raw materials, optimization of extraction and purification methods, structure elucidation and purity determination. 5.10Quality Control and Standardization of Herbals Regulatory Requirements for Herbal Medicines Types of Chemical markers include: Table 5.1: Different Types of Chemical Markers Sr. | Types of Chemical Definition with examples No. (Markers 1. | Active principles | Well defined chemicals with known clinical activity. e.g. Withanolides in Withania somnifera. 2. | Active markers | They are the constituents or group of constituents with a known pharmacological activity that contribute to efficacy. They may or may not have proven clinical efficacy. eg. Allin in Allium sativum. 3. | Analytical markers | They are the constituents or group of constituents that serve solely for analytical purpose and have no clinical or pharmacological activities. They help in the identification of raw materials and extracts or used to achieve standardization. eg: Different alkyl amides found in the roots of Echinacea purpurea and Echinacea angustifolia but totally absent in Echinacea pallida. 4, | Negative markers | Negative markers demonstrate allergenic or toxic properties. eg. Ginkgolic acidin Ginkgo, showed signs of apoptosis as well as of necrosis. Applications of chemical markers: (2) Identification of adulterants. (b) Differentiation of herbal medicines with multiple sources. (©) Determination of the best harvesting time, (4) Confirmation of collection sites. (e) Assessment of processing methods. (f) Identification and quantitative determination of proprietary products. (g) To evaluate the stability of proprietary product quality over time and determine the recommended shelf life. (h) Diagnosis of herbal intoxication in which, toxic components may be used as chemical markers in screening methods. eg. Rapid diagnosis of acute hidden aconite poisoning in urine samples by HPLC-MS and other techniques. () Detection of lead compounds for new drug discovery. E.g. Gambogic acid is a potential lead compound for new anti-cancer drugs. aanQuality Control and Standardization of Herbals Regulatory Requirements for Herbal Medicines 2. Biochemical Markers: Biochemical markers are either proteins or isozymes. Isozymes, also known as Allozymes, are enzymes that are functionally similar but differ from each other in the location, structure, net charge, electrophoretic mobility, types of activators and inhibitors and heat stability. The isozymes pattern has been used in many population genetic studies including measurement of outcrossing rates, sub-population structure and population divergence. These are particularly valuable to distinguish closely related species and therefore, useful to study diversity and identification of crops. Eg: The Isozymes pattern of glucose 6 phosphate dehydrogenase has been used for the identification of Eclipta prostrate (False daisy) The peroxidase isozymes pattern is used to distinguish the three Gastrodia elata variants. 3. Molecular or Genetic markers or DNA markers: DNA markers are the most widely used type of marker mainly due to their abundance. DNA markers are unlimited in number and are not affected by environmental factors, age and physiological conditions of the plant. DNA can be extracted from fresh or dried plant tissue hence, the physical form of the sample for assessment does not restrict detection. Application of DNA markers: (d In Herbal drug technology: DNA - based molecular markers have proved their utility in the fields like; taxonomy, physiology, embryology and genetics. (ii) Genetic variation/genotyping: Random Amplified Polymorphic DNA (RAPD) based molecular markers have been found to be useful in differentiating different accessions of Andrographis paniculata, Azadirachta indica, Allium schoenoprasum collected from different geographical locations. Interspecies variation has been studied using Restriction Fragment Length Polymorphism (RFLP) in different genera such as; Glycyrrhiza, Curcuma and Echinacea. Authentication of Medicinal plants: Rare and expensive medicinal plant species are often adulterated or substituted by morphologically similar, easily available or less expensive species. Sequence Characterized Amplified Region (SCAR), PCR, RAPD and RFLP are used for differentiation of the plants and to detect substitution or adulteration by other closely related species. Eg: Swertia chirata is frequently adulterated or substituted by Andrographis paniculata. (iv) Medicinal plant breeding: Molecular markers have been used as a tool to verify sexual and apomictic offspring of intraspecific (means within the same species) cross in Hypericum perforatum (St. John's wort), a well-known diuretic and anthelmintic drug. (v) Food and Nutraceuticals: Capsicum, maize and soybean have been successively categorized from Non-GMO products. (vi) As a new pharmacognostic tool: DNA markers have shown utility in quality control of commercially important botanicals like; Ginseng, Andrographis paniculata and 5.A2Quality Control and Standardization of Herbals Regulatory Requirements for Herbal Medicines Echinacea. Although DNA analysis is currently considered to be innovative technology. It has certain limitations due to which, its use has been limited to academia. Another important issue is that DNA fingerprint will remain the same irrespective of the plant parts used, while the phytochemical content will vary with the physiology, plant parts used and environment. EXERCISE Long Essays: 1. What are the different regulatory requirements for herbal medicines? 2. Give a detailed comparison of various herbal pharmacopoeias. 3. Write a note on Indian Herbal Pharmacopoeia. 4, What are Marker compounds? Explain role of markers in standardization of herbal products. 5. What is Chromatographic fingerprinting? Explain the role of biological markers in standardization of herbal products. Short Essays: Explain WHO guidelines on safety monitoring of herbal medicines. Explain the role of chemical markers in standardization of herbal products. Write a note on ChP. Write a short note on AfrHP and AHP. Explain the role of biological markers in standardization of herbal products. iple Choice Questions (MCQs): 1. The group of constituents that serve solely for analytical purpose and have no clinical or pharmacological activities is known as ... (@) Active markers (b) Analytical markers (©. Negative markers (@) None of these 2. RAPD stands for (@) Random Amplified Polymorphic DNA (b) Restriction Amplified Polymorphic DNA (©) Random Amplified Polymorphism DNA (d) Rapid Amplified Polymorphic DNA 3, The Fourth edition of IP was published in? Bupwne Mul (a) 1996 (b) 1997 (9 1998 (d) 1999 4. Markers are (a) Pure herbal extracts (b) Pure and mixture of constituents (©) Pure and single constituents (d) All the options 5.13Quality Control and Standardization of Herbals Regulatory Requirements for Herbal Medicines 5. AYUSH stands for (@) Allopathy, Yoga and Naturopathy, Unani, Siddha and Homoeopathy (b) Ayurveda, Yoga and Naturopathy, Unani, Siddha and Homoeopathy (0) Ayurveda, Yoga, Unani, Siddha and Homoeopathy (d) None of these 6. Biochemical markers are (a) Enzymes (b) Proteins (©) Isozymes (@) All the options 7. Herbal Pharmacopoeia is a ...... (a) Pharmacognosy Book (b) Monographs on botanicals (©) Books on herbs (d) None of these 8. IDMA stands for ..... (@) Indian Drugs Manufacturers Association (b) Indian Drugs Manufacturing Association (©) Indian Drugs Manufacturers Associate (d) None of these 9, The Third edition of IP was published in 1985 with ...... volumes. (@ Two (b) Three (© Four (d) Five 10. The Eighth edition of the Indian Pharmacopoeia was published in? (@) 2015 (b) 2016 (2017 (d) 2018 11, Fingerprinting techniques includes ...... (@ Tic (b) HPTLC (0. HPLC (@) All the choices 12, The first official Pharmacopoeia of India was published in ..... (a) 1867 (b) 1868 (© 1869 (d) 1870 Answers 1 2 @ 3 @ 40 5._(b) 6 @) 7.) & 2 @) 10. (d) 11 (d) 12. (b) Ahh 514Definitions Active ingredients: The herbal material(s) or the herbal preparation(s) will be considered to be active ingredient(s) of a herbal medicine(s). However, if constituents with known therapeutic activities are known, the active ingredients should be standardized to contain a defined amount of these constituents. Adverse event/experience: Any untoward medical occurrence that may present during treatment with a pharmaceutical product but that does not necessarily have a causal relationship with the treatment. Adverse reaction: A response to a drug that is noxious and unintended, and that occurs at doses normally used in humans for the prophylaxis, diagnosis or therapy of disease, or for the modification of physiological function. Constituents with known therapeutic activity: They are chemically defined substances or groups of substances which are generally accepted to contribute substantially to the therapeutic activity of a herbal substance, a herbal preparation or a herbal medicinal product. Declaration: A statement of the content of the active substance(s) expressed qualitatively and quantitatively per dosage unit, per unit of volume or weight according to the dosage form. Drug extract ratio (DER): It means the ratio between the quantity of herbal substance used in the manufacture of a herbal preparation and the quantity of herbal preparation obtained. The number (given as the actual range) written before the colon is the relative quantity of the herbal substance; the number written after the colon is the relative quantity of the herbal preparation obtained. Excipients: Excipients may be defined as constituents of the medicinal product other than the active substance(s). However, in the context of this guideline only two categories of excipients are addressed: Excipients for adjustment are used for standardization of herbal substances/preparations. Other excipients are technological excipients (e.g. carrier substances) which may be part of herbal preparations. Extraction solvents: They are solvents which are used for the extraction process. fed herbal products: They consist of herbal preparations made from one or more herbs. if more than one herb is used, the term “mixture herbal product” can also be used ished herbal products and mixture herbal products may contain excipients in addition to the active ingredients. However, finished products or mixture of herbal products to which chemically defined active substances have been added, including synthetic compounds and/or isolated constituents from herbal materials, are not considered to be herbal DaQuality Control & Standardization of Herbals Definitions * Genuine (Native) herbal preparation: It refers to the preparation without excipients, even if for technological reasons the genuine herbal preparation is not available. However, for soft and liquid herbal preparations, the genuine herbal preparation may contain variable amounts of (extraction) solvent. * Ratio of herbal substance to genuine herbal preparation (DER genuine): It is the ratio of the quantity of the herbal substance to the quantity of the resulting genuine herbal preparation. The number (given as the actual range) written before the colon is the relative quantity of the herbal substance; the number written after the colon is the relative quantity of the genuine herbal preparation obtained. * Herbs; It includes crude plant material, such as; leaves, flowers, fruit, seeds, stems, wood, bark, roots, rhizomes or other plant parts, which may be entire, fragmented or powdered, * Herbal medicines: They include; herbs, herbal materials, herbal preparations and finished herbal products. In some countries herbal medicines may contain, by tradition, natural organic or inorganic active ingredients that are not of plant origin (e.g. animal and mineral materials). * Herbal medicinal products: Any medicinal product, exclusively containing an active substance one or more herbal substances or one or more herbal preparations, or one or more such herbal substances in combination with one or more such herbal preparations. * Herbal preparations: They are obtained by subjecting herbal substances to treatments such as; extraction, distillation, expression, fractionation, purification, concentration or fermentation. These include; comminuted or powdered herbal substances, tinctures, extracts, essential oils, expressed juices and processed exudates. + Herbal substances: All mainly whole, fragmented or cut plants, plant parts, algae, fungi, lichen in an unprocessed, usually dried form but sometimes fresh. Certain exudates that have not been subjected to a specific treatment are also considered to be herbal substances, Herbal substances are precisely defined by the plant part used and the botanical name according to the binomial system (genus, species, variety and author) ‘+ Markers: They are chemically defined constituents or groups of constituents of a herbal substance, a herbal preparation or a herbal medicinal product which are of interest for control purposes independent of whether they have any therapeutic activity. Markers serve to calculate the quantity of herbal substance(s) or herbal preparation(s) in the herbal medicinal product if the marker has been quantitatively determined in the herbal substance or herbal preparation. * National pharmacovigilance center: A single, governmentally recognized center (or part of an integrated system) within a country with the clinical and scientific expertise to collect, collate, analyses and give advice on all information related to drug safety. D.2Quality Control & Standardization of Herbals Definitions ‘+ Pharmacovigilance: It is the science and activities relating to the detection, assessment, understanding and prevention of adverse effects or any other possible drug-related problems. * Quantification: It means adjusting the herbal substance or herbal preparation to a defined range of constituents (active markers) exclusively achieved by blending different batches of herbal substances and/or herbal preparations (e.g. quantified extract). * Side effect: Any unintended effect of a pharmaceutical product occurring at doses normally used in humans that is related to the pharmacological properties of the drug ‘© Specification: A list of tests, references to analytical procedures, and appropriate acceptance criteria which are numerical limits, ranges, or other criteria for the tests described. It establishes the set of criteria to which a herbal substance/preparation or herbal medicinal product should conform to be considered acceptable for its intended use. “Conformance to specifications" means that the herbal substance/preparation and/or herbal medicinal product, when tested according to the listed analytical procedures, will meet the listed acceptance criteria. Specifications are binding quality standards that are agreed to between the appropriate governmental regulatory agency and the applicant. * Standardization: It means adjusting the herbal substance/preparation to a defined content of a constituent or a group of constituents with known therapeutic activity respectively either by adding excipients or by blending batches of the herbal substance and/or herbal preparation (e.g. standardized extracts). ‘+ Strength: The content of the active substance(s) expressed quantitatively per dosage unit, per unit of volume or weight according to the dosage form. ‘+ Therapeutic activity: It refers to the successful prevention, diagnosis and treatment of physical and mental illnesses. Treatment includes beneficial alteration or regulation of the physical and mental status of the body and development of a sense of general well-being as well as improvement of symptoms. ‘+ Traditional use of herbal medicines: It refers to the long historical use of these medicines. Their use is well established and widely acknowledged to be safe and effective, and may be accepted by national authorities. ‘* In Process Control (IPC): It controls performed during manufacture of the medicinal product (finished product) in order to monitor and if necessary to adjust the process to ensure that the medicinal product conforms to its specifications. The control of the environment or equipment may also be regarded as a part of an in process control. Akt D3ABBREVIATIONS ADI ‘AESGP AGES ALARA ASU AYUSH BAH BfArM BAR BMDio BMDLin Bw cDSCO co cyP DCGI EFSA ESTRI FDA GAcP Gc GMO HATC HDPE HMP HMPC HPLC HPTLC Average daily intake Association of the European Self-Medication Industry Austrian Medicines Agency As Low As Reasonably Achievable : Ayurveda, Siddha, or Unani ‘Ayurveda, Yoga and Naturopathy, Unani, Siddha and Homoeopathy Bundesverband des Arzneimittel - Hersteller e. V. (German Medicines Manufacturers Association) The Federal Institute for Drugs and Medical Devices (BundesinstitutfarArzneimittel und Medizinprodukte), Germany The Federal Institute of Risk Assessment / Bundesinstitut fur Risikobewertung, Germany Bench Mark Dose (giving 10% response) Bench Mark Dose Lower Confidence Limit Body weight Central Drugs Standard Control Organization : Common Technical Document Cytochrome P450 Drug Controller General of India The European Food Safety Authority Electronic Standards for the Transfer of Regulatory Information Food and Drug Administration Good Agricultural and Collection Practices Gas chromatography Genetically Modified Organism Herbal Anatomical Therapeutic Chemical High Density Polyethylene Herbal Medicinal Products Committee on Herbal Medicinal Products High Performance Liquid Chromatography High Performance Thin Layer Chromatography AAQuality Control & Standardization of Herbals Abbreviations HsOs IAEA IARC ICH ICMR IND LC-MS/MS LoD MedDRA MDI MHRA MOE Ms MS/MS. M3 MS NDA NFL NUT NMR NTP PA PANO PCIM PCR PDCA Ph. Eur. PIDM RAPD Ref RFLP SCAR : Hepatic Sinusoidal Obstruction Syndrome The International Atomic Energy Agency : International Agency for Research on Cancer International Council for Harmonization : Indian Council of Medical Research : Investigational new Drug Applications Liquid chromatography ~ mass spectrometry 2 Loss on Drying 1 Medical Dictionary for Regulatory Activities : Mean daily intake of drugs : Medicines and Healthcare products Regulatory Agency 1 Margin of exposure 2 Mass Spectrometry : Tandem mass spectrometry : Non-clinical safety studies : Data elements and standards for drug dictionaries : New Drug Application National Formulary of India : Not Less Than : Nuclear Magnetic Resonance National Toxicology Program (USA) : Pyrrolizidine alkaloid PA-N-oxide : Pharmacopoeia Commission for Indian Medicine 2 Polymerase Chain Reaction Plan-Do-Check-Act : European Pharmacopoeia : Programme for International Drug Monitoring Random Amplified Polymorphic DNA 2 Reference : Restriction Fragment Length Polymorphism Sequence Characterized Amplified Region A2Quality Control & Standardization of Herbals Abbreviations SHR SPE-LC- MS/MS. soP sts Std Tic Ts uv vs WHO Spontaneously hypertensive rat Solid Phase Extraction (SPE) in combination with Liquid Chromatography tandem Mass Spectrometry Standard Operating Procedure Soft Tissue Sarcomas : Standard Thin Layer Chromatography Test Solutions : Ultraviolet : Volatile Solid : World Health Organization Atte