THE USE OF QUALITY CONTROL PARAMETERS IN THE EVALUATION OF CRUDE DRUGS

THE USE OF QUALITY CONTROL PARAMETERS IN THE EVALUATION OF CRUDE DRUGS

CHAPTER ONE

• INTRODUCTION

1.1         BACKGROUND OF THE RESEARCH

The use of herbs as medicine is the oldest form of healthcare known to humanity and has been in all cultures throughout the history (Barnes et al., 2007). Early human recognized their dependence on nature for a healthy life and since that time humanity has depended on the diversity of plant resources for food, clothing, shelter, and medicine to cure myriads of ailments. Led by instinct, taste and experience, primitive men and women treated illness by using plants and animal parts, and minerals that were not part of their usual diet. Primitive people learned by trial and error to distinguish useful plants with beneficial effects from those that were toxic or inactive and also which combinations or processing methods had to be used to gain consistent and optimal results. Even in ancient cultures, tribal people methodically collected information on herbs and developed well – defined herbal pharmacopeias. Physical evidence of the use of herbal remedies some sixty thousand years ago has been found in a burial site of a Neanderthal man uncovered in 1960.

The World Health Organization (WHO) estimated that 4 billion people (80%) of the world population presently use herbal medicine for one form of primary health care or another. Its history is inextricably intertwined with that of modern medicine, but pharmacologists, rather than use of whole plant identity, isolate, extract, and synthesize individual components, thus capturing the active properties as against the herbalist who considers that the power of a plant lies in the interaction of all its ingredients.

Herbal medicines are promising choice over modern synthetic drugs. They Show minimum or no side effects and are considered to be safe. Generally herbal formations involve the use of fresh or dried plant part. Correct knowledge of such crude is very important aspect in preparation, safety and efficacy of the herbal product. Pharmacognosy is a simple and reliable tool, by which complete information of the crude drug can be obtained.

1.2    HERBAL MEDICINE

          An herb is a plant or part of a plant valued for its medicinal, aromatic, or savory qualities. Herbs can be viewed as biosynthetic chemical laboratories, producing a number of chemical compounds. Herbal remedies or medicines consist of portions of plants or unpurified plant extracts consisting several constituents which often work together synergistically. Herbal medicine or herbalism is the use of herbs   or herbal products, for their therapeutic or medicinal value. They come from any part of the plant but are most commonly made from leaves, roots, bark, seeds and flowers. They are eaten, swallowed, drunk, inhaled, or applied topically to the skin.

During the past decade, there has been increasing public interest and acceptance of natural therapies in both developing and developed countries. Due to poverty and limited access to modern medicine, about 80% of the world population, especially in the developing countries uses herbal medicine as their source of primary health – care (Bodeker et al., 2005, Mukherjee, 2002; Bisset, 1994). In these communities, traditional medical practice is often viewed as an integral part of their culture. In the west, people attracted to herbal therapies for many reasons, the most important reason being that, like our ancestors it is believed they will help us live healthier lives. Herbal medicines are often viewed as a balanced and moderate approach to healing. Individual   who use them as home remedies and over- the – counter drug spend billions of dollars on herbal products. As such, they represent a substantial proportion of the global drug market (WHO 2005, 2002a, 1999a, and b, 1990; Blumenthal, 2000; Roberts and Tyler, 1997).

The variability of the constituents in herbs or herbal preparations due to genetic, cultural and environmental factors has made the use of herbal medicine s more challenging than it could necessarily have been. For instance the availability and quality of the raw materials are frequently problematic, the active principles are diverse and may be unknown, and quality of different batches of preparation may be difficult to control and ascertain. In most countries, herbal products are launched into the market, without proper scientific evaluation, and without any mandatory safety and toxicological studies. There is no effective machinery to regulate manufacturing practices and quality standards. Consumers can buy herbal products without  prescription and management not recognizes the potential hazards in the inferior production. A well – defined and contents composition of the drug is therefore, one of the most important prerequisites for the production of a quality drug. Given the nature of the production of plants of plant origin, which is not usually constant and are dependent on and influenced by many factors, ensuring consistent quality of productions is vital for the survival and success of the industry (Bauer, 1998).

Medicinal plants are of great importance to the health of individuals and communities. The medicinal values of these plants lie in some chemical substances that produce a definite physiological action on the human body. Many of these indigenous medicinal plants are   used as spices and chemical factory as it contain a multitude of chemical compounds like saponin, alkaloids, glycosides, resins, oleoresins, sesquiterpene, locations, and oils  (essential and fixed).

The purpose of standardized extraction procedures for crude drugs (medicinal plant parts). Is to attain the therapeutically desired portion and to eliminate unwanted materials by treatment with a selective solvent known as menstruum. The extract thus obtained, agent as such in the form of tinctures or fluid extracts or further processed to be incorporated in any dosage form as tablet and capsules.

1.3              QUALITY CONTROL AND STANDARDIZATION OF HERBAL MEDICINE – CONCEPT AND SCOPE

Generally, all medicines, whether they are synthetic or of plant origin, should fulfill basic requirements  being safe and effective (EMEA,  2005; WHO, 2002 C  1998 c, 1996, 1991 a,  b, 1990, 1988). The term” herbal drugs” denotes plants or parts that have been converted into phytopharmaceuticals by means of simple processes involving harvesting, drying and storage (EMEA, 1998). Hence they are capable of variations. This variability is also caused by differences in growth, geographical location, and time of harvest.

Standardization of herbal medicines is the process of prescribing a set of standards or inherent characteristics, constant parameters, definitive qualitative and quantitative values that carry an assurance quality, developing and agreeing upon technical standards. Specific standards are worked out by experimentation and observations, which would lead to the process of prescribing a set of characteristics exhibited by the particular herbal medicine (Kindle, et al., 2012). Hence standardization is a tool in the quality control process.

Several problems not applicable to synthetic drugs often influence the quality of herbal drugs. For instance:

• Herbal drugs are usually mixtures of many constituent.
• The active principle(s) is (are), in most cases unknown.
• Selective analytical methods or reference compounds may not be available commercially.
• Plants materials are chemically and naturally variable.
• Chemo – varieties and chemo cultivars exist.
• The sources and quality of the raw materials are variable (kunle et al., 2012).

The methods of harvesting, drying, storage, transportation, and processing (for example, mode of extraction and polarity of the extracting solvent, instability of constituents, etc) also affect herbal quality.

At present no official standards are available for herbal preparations. Those manufacturers, who are current doing some testing for their formulations, have their own parameters, many of which are very preliminary in nature. Presently it is very difficult to identify the presences of all the ingredients as claimed in a formulation. Hence the first task is to evolve such parameters by which the presence of the entire ingredient can be identified. Various chromatographic and spectrophotometric methods and evaluation of physiochemical properties can be tried to evolve pattern for identifying the presence of different ingredients, whatever possible these methods can be applied to quantitative estimation of bioactive group of compounds like alkaloids, phenol flavonoids, polyphenolic components or estimation of particular compound (Wani, 2007)

1.4    THE NEED FOR STANDARDIZATION – PRODUCER AND CONSUMER^’S PERSPECTIVE

In the global perspective, there is a shift towards the use of medicine of herbal origin, as the dangers and the shortcoming of modern medicine are getting more apparent. It is the cardinal responsibility of the regulatory authorities to ensure that consumers get the medication, which guarantees purity, safety, potency and efficacy. The regulatory authorities rigidly follow various standards of quality prescribed for raw material and   finished   products in pharmacopeias,  formularies and manufacturing operation through statutory imposed good manufacturing practices. These procedures logically would apply to all types of medicine or one of the traditional systems (Barnes, 2007).

The quality of herbal medicine that is, the profile of the constituents in the final product has implications in efficacy and safety. However, due to the complex nature  and inherent variability of the constituents of plant- based drugs, it is difficult to establish quality control parameter though modern analytical technique are expected to help in circumventing this problem. This is further complicated by the use of combination of herbal ingredients as being used in traditional practice. It is common to have as many as five different herbal ingredients in one product. Thus batch to batch variation starts from the collection of raw material itself in the absence of any reference standard for identification. Hence for herbal drugs and products, standardization should encompass the entire field of study from cultivation of medicinal plants to its clinical application (Barnes, 2007).

1.5    CURRENT REGULATIONS FOR STANDARDIZATION OF CRUDE DRUGS

Internationally several pharmacopoeias have provided monographs stating parameters and standard of many herbs and some product made out of these herbs. Several pharmacopoeias like:

.  Pharmacopoeia committee

.  Chinese Herbal Pharmacopoeia

.   United States Herbal Pharmacopoeia

.  British Herbal Pharmacopoeia

.  British Herbal Compendium

.  Japanese Standards for Herbal Medicine

.  The Ayurvedic Pharmacopoeia of India

Lay down monograph for herbs and herbal products to maintain their quality in their respective nations ( Agarwal,2005). Government of India too has brought out Ayurvedic Pharmacopoeia India, which recommends basic quality parameters for eighty common Ayurvedic herbal drugs.

1.6    STANDARDIZATION AND QUALITY CONTROL PARAMETERS FOR EVALUATION OF HERBAL CRUDE DRUGS

According to WHO (1996a and b, 1992), standardization and quality control of herbal crude drugs is the process involving the physicochemical evaluation of crude drugs covering the aspects as, selection and handling of crude drug materials, safety, and efficacy and stability assessment of finished products, documentation of safety and risk based on experience provision of product information to consumer and product promotion. The quality and purity required in a drug are achieved by standards given in the official work of reference. To establish identity and quality required of the drug, several methods may be considered ( Pulok, 2002, Hylands, 2002). These are enumerated below:

• Macroscopic Examination: In case of whole drugs, the macroscopic and secondary characters are sufficient for identification of right variety and search of adulterants.
• Microscopic Examination: These are valuable both for powders and ungrounded drugs for identification of right variety and search of adulterants.
• Solubility: The solubility, especially exceptional behavior toward solvent, is useful in examination of many oils and olio – resins.
• Physical Constituents: Physical constituents such as specific gravity, optical rotation, viscosity and refractive index are especially valuable for the evaluation of facts, oleo – resins, balsams and similar substances.
• Foreign Organic Matter: Remove off matter other than source plant to get the drug in pure form.
• Swelling Index: It measures the swelling property of the medical plant.
• Ash Values: It is criteria to judge the identity and purity of crude drug – total ash, sulfated ash, water soluble ash and acid insoluble ash etc.
• Extractive Values: These are indicating the approximate measure of chemical constituents of crude drug.
• Moisture Content: To check moisture content helps prevent degradation of product.
• Crude Fiber: To determine excessive woody material. Criteria for judging purity.
• Chromatographic examination: Include identification of crude drug based on use of major chemical constituent as marker.
• Qualitative Chemical Evaluation: Covers criteria for identification and characterization of crude drug with respect to phytochemical contents.
• Quantitative Chemical Evaluation: Covers criteria to estimate the amount of active constituents.
• Volatile Oils: It covers the measurement of the volatile content of the plant.
• Bitterness Value: The bitter properties of plant material are determined by comparing the threshold bitter concentration of an extract of the materials with that of a dilute soluble of guanine hydrochloride R.
• Hemolytic Activity: The hemolytic activity of plant materials, or a preparation containing saponins, is determined by comparison with that of a reference material, saponin R.
• Foaming Index: The foaming ability of an aqueous decoction of plant materials and their extracts is measured in terms of a foaming index.
• Pesticide Residues: It measures the pesticide residues in the plant.
• Arsenic and heavy metals: Contamination of medicinal plant materials with arsenic and heavy metals can be attributed to many causes including environmental pollution and traces of pesticides.
• Microorganisms: Current practices of harvesting, handling and production may cause addition contamination and microbial growth.
• Aflatoxins: Minute presence in crude drug can be toxic and hence their presence is being tested.
• DNA Fingerprinting: Technique is useful for identification of phytochemically indistinguishable genuine drug from substituted or adulterated drug.
• Chemical Fingerprinting: To allow the detection of all the components in extracts.
• Biological Profiling: It identifies the biological active plants allowing highly sophisticated standardization and quality control.
• Radioactive Contamination: A certain amount of exposure to ionizing radiation cannot be avoided since they are many sources, including radio nuclides occurring naturally in the ground and the atmosphere.
• Toxicological Studies: To help determine pesticide residue, potentially toxic elements, safety studies in animals like LD50 and microbial count approach to ascertain their presence or absence.

1.7      PURITY DETERMINATION

Each monograph includes standards of purity and other qualitative assessments which include when appropriate:  foreign matter, ash, acid – insoluble ash, moisture content, loss of moisture on drying, and extractives.

High performance thin layer chromatography (HPTLC) is valuable quality assessment tool for the evaluation of botanical materials. It allows for the analysis of a broad number of compounds both efficiently and cost effectively. Additionally, numerous samples can be run in a single analysis thereby dramatically reducing analytical time. With HPTLC, the same analysis can be viewed using different wavelengths of light thereby providing a more complete profile of the plant than is typically observes with more specific types of analyses (Chakravarth. B.K., 1993).

 1.8   W.H.O   GUIDELINES FOR QUALITY STANDARDIZED HERBAL FORMULATIONS

Standardization and quality control parameter for herbal formulations are based on the following fundamental parameters:

1. Quality control of crude drugs material, plant preparations and finished products.
2. Stability assessment and shelf life.
3. Safety assessment; documentation of safety based on experience or toxicological studies.
4. Assessment of efficacy by ethnomedical information and biological activity evaluation.

  1.9    QUALITY CONTROL OF CRUDE MATERIAL

According to pharmaceutical manufacturers association of U.S. “quality is the sum of the factors which contribute directly or indirectly to the safely, effectiveness and acceptability of the product” (Valpoote, 2003). Standardization describes all measures taken during manufacturing process and quality control leads to reproducible quality of particular product. Growing need for standardization and quality control of herbal medicine is recognized by WHO. In policies and checklist on Traditional  Medicine (TM) WHO has given emphasis on development of national standards and technical guidelines and methodology  for evaluating safety, efficacy and quality of TM. WHO as gives stress on development of national pharmacopoeia and monographs of medicinal plants, cultivation and conservation of medicinal plants to ensure their sustainable use are also of prime importance as botanicals are considered (WHO, 2002). Standardization of botanicals offers many obstacles because synthetic drugs have well defined structure and other analytical parameters as well as reference standard for comparison also established assays and pharmacopoeias. Therefore, quality control is not problematic for synthetic drugs (Bhutani, 2003). There are several challenges as standardization of herbal product is considered like controversial identity of  various plants, deliberated adulteration of plant material, problem in storage and transport, which should be considered (IJNP, 2003).

One of the impediments in the acceptance of the herbal products worldwide is the lack of standard quality control profiles. Most of the herbal formulations, especially the classical formulations of traditional medicine, are poly herbal. Each formulation contains 10 – 20 or more ingredients; a few have even 50 – 75 ingredients. Many preparations are either liquid or semi – liquid.  For such formulations, it is very difficult to established parameters for quality control. Even official standards are not available. The unique processing methods followed for the manufacture of these drugs turn the single drugs into very complex mixture, from which separation identification and analysis of the component is very difficult (Hyland, 2002).

In Germany, Physicians are required to have some training in herbal medicine. Considerable research on herbal medicine including double – blind, placebo – controlled trails are ongoing. Physicians recommend and patient use herbal medicines extensively. Manufacturers are required to meet standards of purity and pharmaceutical activity. Commission E, which has had oversight of herbal medicine and has determined their safety and efficacy has published 387 monographs (recently translated into English by the   America Botanical Council). Several other European countries also have policies and procedure that allow rational oversight of herbal medicines (Gram, 1997).

In the United States, herbs are use either as dietary supplements, with minimal standards of safety and efficacy or as drugs, which require expensive and cumbersome testing procedures. Middle – of –the – road approach that acknowledge the long history of the use of many herbal medicine, examine data from many sources including other countries, insists on strict production standards, requires absolute safety and classification of efficacy that vary from “unproved”  for some conditions to “ demonstrated” for others. The use of translated commission E monographs would be very helpful for the physicians.