WHO Guidelines for Quality Control & Standardization of Herbal Drugs By: Sandeep Kumar Singh Pre Ph.D. Course work Enrol No. Ph.D./PHR/12/033 Guru Ghasidas Vishwavidyalaya, Bilaspur (C.G.).

Contents −Definitions of relevant terms −Need of quality control −Safety in quality management −Ishikawa diagram −Constraints in quality control of herbal drugs −Three pillars of ideal herbal drug and their rational use −World health organization −Guidelines provided by WHO for herbals −Standardization of herbal drugs crude plant Parts/plant material −Processed plant materials/non-plant materials −Flow diagram standardization −Analytical procedures −References 2

Herbal medicines are the oldest form of healthcare known to humanity and has been used in all cultures throughout history 3

4 The definitions of terms that will be encountered in the discussion are given:  Quality : status of a drug that is determined by identity, purity, content, and other chemical, physical or biological properties  Safety : to assure the drug didn’t have any hazardous effect  Purity: not contaminated with potentially harmful substances  Potency: is the content of active constituents within the defined limits?  Identity: is the herb the one it should be?  Quality control : it refers to processes involved in maintaining the quality and validity of a manufactured product Definitions of relevant terms

5 Definition continued…  Herbal preparations are preparations obtained by scientific treatments such as extraction, distillation, fractionation, purification, or fermentation. These include comminuted or powdered herbal substances, tinctures, extracts, essential oils and processed exudates  Herbal substances are precisely defined by the plant part used (leaves, stems, rhizomes, roots and bark) Certain exudates that have not been subjected to a specific treatment are also considered to be herbal substances  Markers are chemically defined constituents or groups of constituents of a herbal substance, which are of interest for control purposes, independent of whether they have any therapeutic activity

Need of quality control – Quality control and standardization – Reduce adulterations with substandard drugs – Improper authentication – Scientific validation of the therapeutic claims – Identity, purity, efficacy and safety – Customer satisfaction and confidence 6

Adulteration with other medicines Mistaken use of wrong species Incorrect dosing Poor quality products Toxicity Interactions with other medicinesProblemsProblems Misconception that all herbs are safe Misuse of herbal drugs Safety in quality management

Ishikawa cause and effect diagram for content variation of herbal drugs 8 *Shinde M.V., Dhalwal K., Potdar K., Mahadik K. Application of quality control principles to herbal drugs. International Journal of Phytomedicine 1(2009); p. 4-8.

Regulatory Aspects Adulteration/ Substitution No Certification of Raw Materials Pharmacovigilence Data Not Collected Herbal Pharmacopoeia? Lack of Public Test Houses Lack of Safety Evaluation Facility Poor Investment In R&D Of HMP Constraints in Quality Control of Herbal Drug Products Main Dependence on Wild Sources Lack of Trained Man Power Constraints in quality control of herbal drugs

Three pillars of ideal herbal drug and their rational use QUALITY EFFICACYSAFETY GUIDELINES – RATIONAL USE AVAILABILITY ACCESSABILITY QUALITY SAFETY EFFICACY Appropriate use of herbal drug 10

World Health Organization −The World Health Organization (WHO) is a specialized agency of the United Nations (UN) that is concerned with international public health −It was established on 7 April 1948, with its headquarters in Geneva, Switzerland −WHO is a member of the United Nations Development Group (UNDP) −World Health Organization, provides guidelines for prevention, control, safety, efficacy as well as evaluation and standardisation of herbal materials (e.g. WHO, 2005, 2002a,b, 1999a,b, 1998a,b, 1996a,b, 1990, 1981, 1979) 11

What WHO has done?

Guidelines provided by WHO for herbals A set of guideline for the assessment of herbal remedies has been published by WHO. These guidelines specify criteria to be used in evaluating commercial crude drugs intended for use (WHO Traditional Medicine Strategy ). WHO guidelines on safety monitoring of herbal medicines in pharmacovigilance systems (2004).

Quality control methods for medicinal plant materials (1998). WHO Guidelines on good manufacturing Practices (GMP) for Herbal Medicines (2005). Guidelines continued…

WHO Monographs on Selected Medicinal Plants: Vol. 1 (1999) Vol. 2 (2004) Vol. 3 (2007) Vol. 4 (2009) Guidelines continued…

WHO Guidelines For Assessing Quality of Herbal Medicine With Reference to Contaminants and Residues (2007). Basic tests for drugs – Pharmaceutical substances, Medicinal plants materials and dosage forms (1998). Guidelines continued…

General Guidelines for Methodologies on Research and Evaluation of Traditional Medicine (2000). WHO Guidelines on GACP for Medicinal Plants (2003). Guidelines continued…

Research Guidelines for Evaluating the Safety and Efficacy of Herbal Medicines (1993). Regulatory Situation of Herbal Medicines - A Worldwide Review (1998). Guidelines continued…

Standardization of herbal drugs crude plant parts/plant material Definition: − name of plant − part of plant − Nature/condition of material: whole, powdered, fresh, dried, etc Authentication/confirmation of: − Correct geographical origin − Correct stage of growth Absence of foreign matter: − other plant parts or materials − soil, stones, dust − insects and other animal matter (as determined by microscopy, macroscopy, chromatography) Microscopic characteristics confirming identity: − qualitative features − quantitative features, (e.g. stomatal number) Radioactive contamination limits: arising from environmental pollution or microbial decontamination procedures Assay: for materials containing constituents of known therapeutic activity, or known unique (marker) compounds. Non-specific assay methods for groups of compounds may be used where specific assay methods are not available for single compounds 19

Processed plant materials/non-plant materials (extracts, tinctures, comminutions etc.) Definition: liquid, solid, etc Organoleptic characteristics: − Macroscopy − Smell − Taste − Texture − Colour Chromatographic profile using more than one method: − to confirm presence of unique compounds (markers) − to confirm characteristic TLC chromatogram − to confirm characteristic HPTLC chromatogram (TLC + densitometry = HPTLC) Water content (for hygroscopic materials): Ash values: indicate extent of contamination with inorganic material. Determined by incineration. Values include acid insoluble and sulphated ash Volatile matter: for plants containing volatile oils: − Determined by steam − Distillation Powdered material: test method and acceptable limits for particle size, distribution 20

continued... If the product is a mix of plant materials, the supplier must provide evidence that each component plant has been individually tested. Heavy metal limits: from environmental pollution and pesticides Microbial contamination limits: microbial contamination arises from cultivation, harvesting, processing and storage: −confirmation of absence of E. coli, S. aureus, P. aeruginosa and −Salmonella −limits for aflatoxins (fungal toxins) Residual solvents from processing Pesticide residue limits: arising from cultivation (FAO and WHO limits) Extractive values: extraction by different solvents indicates proportion of polar and non-polar components Assay: for materials containing constituents of known therapeutic activity, or known unique (marker) compounds; −Non-specific assay methods for groups of compounds may be used where specific assay methods are not available for single compounds 21

QUALITY EVALUATION OF HERBAL DRUGS CHEMICAL BIOLOGICAL ORGANOLEPTIC BOTANICAL PHYSICAL Moist. Cont. Extract. Values Ash Values Fluores. Analy. Macroscopic Microscopic Qualitative Quantitative SEM Studies Powder Studies Shape External Marking Colour Odour Taste Texture Fracture Antagonistic Microbial Contamination Toxicological Pharmacological Other specific activities Bacterial Fungal Qualitative Quantitative Chromatography Heavy metal Pesticide residue Mycotoxin HPTLC GLC HPLC HPTLC Finger printing Sec. Metabolites DNA Finger printing Standardization & quality evaluation of herbal drugs 22

Analytical procedures Botanical parameters: – Sensory evaluation: including visual macroscopy/ touch/odour/taste – Foreign matter: including foreign plants, foreign animals, foreign minerals, etc. – Microscopy: including histological observation and measurements 23 *Aggrawal, S.S., Herbal Drug Technology. Universities Press, ** Rangari, V.D., Text book of Pharmacognosy and Phytochemistry Vol. I, Carrier Pub., 2006.

continued… Physico-chemical methods: −Ash values: Total, acid insoluble, water soluble −Extractive values: in hot water, cold water and ethanol, −Volatile matter: Loss on drying, −Volatile oils: by steam distillation. −Determination of crude fibers, −Determination of moisture content. 24

continued… Biological parameters: −Bitterness value: unit equivalent bitterness of standard solution of Quinine HCI −Hemolytic property: on ox blood by comparison with standard reference solution of saponin −Astringent property: tannins that bind to standard Frieberg Hide powder −Swelling index: in water −Foaming index: foam height produced by 1g material under specified conditions 25

continued… Toxicological parameters: These include the various identification procedures: −Arsenic: stain produced on HgBr 2 paper in comparison to standard stain −Pesticide residues: including total organic chloride and total organic phosphorus −Heavy metals: like cadmium, mercury and lead −Microbial contaminations: total viable aerobic count of pathogens; viz. Enterobacteriaceae, E. Coli, Salmonella, P. aeruginosa, S. aureous, (e.g. Mellilotus officinalis)* −Aflatoxins: by TLC using standard aflatoxins (B 1, B 2, G 1 and G 2 ) −Radioactive contaminations 26 *Warude D., Patwardhan B. Quality and Regulatory Issues. Journal of Scientific and Industrial Research. Vol. 64, Feb 2005; p

References −Aggrawal, S.S., Herbal Drug Technology. Universities Press, −EMEA. Guidelines on Quality of Herbal Medicinal Products/Traditional Medicinal Products, EMEA/CVMP/814OO Review. European Agency for the Evaluation of Medicinal Products (EMEA), London, −Mukherjee, P.W. Quality Control of Herbal Drugs: An Approach to Evaluation of Botanicals. Business Horizons Publishers, New Delhi, India, −Rangari, V.D., Text book of Pharmacognosy and Phytochemistry Vol. I, Carrier Pub., −Shinde M.V., Dhalwal K., Potdar K., Mahadik K. Application of quality control principles to herbal drugs. International Journal of Phytomedicine 1(2009); p −WHO. Quality Control Methods for Medicinal Plant Materials, World Health Organization, Geneva, WHO. Guidelines for the Appropriate Use of Herbal Medicines. WHO Regional Publications, Western Pacific Series No 3, WHO Regional office for the Western Pacific, Manila,

continued… −WHO. The International Pharmacopeia, Vol. 2: Quality Specifications, 3rd edn. World Health Organization, Geneva, −WHO. Quality Control Methods for Medicinal Plant Materials. World Health Organization, Geneva, −WHO. WHO Global Atlas of Traditional, Complementary and Alternative Medicine. 2 vol. set. Vol. 1 contains text and Vol. 2, maps. World Health Organization, Geneva, −WHO. Guidelines on Good Agricultural and Collection Practices (GACP) for Medicinal Plants. World Health Organization, Geneva, −Warude D., Patwardhan B. Batanicals: Quality and Regulatory Issues. Journal of Scientific and Industrial Research. Vol. 64, Feb 2005; p

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