HERBAL PRODUCT REALIZATION IN ACCORDANCE WITH WHO AND ISO GUIDELINES

HERBAL PRODUCT REALIZATION IN ACCORDANCE WITH WHO AND ISO GUIDELINES

1. J. Ameh*, F. Tarfa, S. Ayuba, K. S. Gamaniel

Department of Medicinal Chemistry and Quality Control (MCQC) ¹, National Institute for Pharmaceutical Research and Development (NIPRD), Idu Industrial Area, PMB 21 (Garki), Abuja, Nigeria

ABSTRACT

Background: Following the Alma-Ata Declaration of 1978, the World Health Organization (WHO) began the issuance of guidelines for developing standardized herbal preparations from Traditional Medicine (TM). Similarly in 1987, the International Organization for Standardization (ISO) launched the most anticipated industrial standard (ISO 9001) in world history. The seventh (7^th) clause of ISO 9001’s eight clauses is devoted to “Product Realization”- a quality management system (QMS) procedure that includes: planning of product realization; appreciation of customer-related processes; design and development processes; purchasing; production and service provision; and control of measuring and monitoring equipment.

Purpose: The article takes a hard look at the QMS processes involved in product realization and the critical stages of the WHO model of herbal drug development from TM, with a view to devising a framework that can be used to promote the production of quality herbal products, commencing from the stage of ethnobotanical survey, through the laboratory, to the clinic.

Methodology: Both the WHO model of herbal drug development and the 7^th clause of ISO 9001:2008 were critically reviewed and combined to yield a framework that is discussed within the context of guiding herbal drug development from TM.

Results and Discussion: The resulting WHO-ISO framework of herbal product realization is discussed in terms of its relevance to practical problems of GMP-production using herbal starting materials, given their innate variability in composition, potency and appearance.

Conclusion: The provisions of ISO 9001’s seventh clause can, to a large extent, be applied to the production of quality herbal products developed in accordance with WHO.

Measuring and monitoring (M&M)

INTRODUCTION: Medicinal herb or “herbal substance” is also called herbal drug among other synonyms by WHO ¹, European Pharmacopoeia ² and others ³. Typically, it is a plant preparation derived from one or more parts, such as the leaves, flowering parts, stem or root bark or whole stem or root, based on established herbal tradition. WHO¹ defined “herbal substance” as: “material derived from plant by extraction, mechanical manipulation, or some other process”. The term specifically applies to whole preparations not isolated or purified components thereof. In herbological terminology each “herbal substance” from a given plant is in its entirety regarded as the active substance, even though the preparation may contain several chemically defined entities ⁴. This is because it is conceived that the entities act cooperatively to achieve the pharmacological attribute of the plant. The practice of preparing herbal cocktails is termed “chemistry-manufacturing-control” (C-M-C) by WHO ¹, because it involves an understanding of physicochemical processes and how to control them.

The C-M-C of a given “herbal product”, defined by WHO¹ as an “herbal material administered to clinical subjects”, focuses on the fact that herbal substances are prone to contaminations by herbicides, pesticides, mycotoxins and others ⁵ and are subject to profound variations in physicochemical characteristics ^{6, 7}, such as moisture content, ash values, extractability and others ⁸. The cultivation, harvest, contaminations, process history and the physicochemical characteristic of an herbal substance are critical to its C-M-C evaluation, if good manufacturing practice (GMP) is to be applied in producing an herbal product ^{8, 9}.

The methodology section of this article examined WHO guidelines on herbal drug research and development (R&D); and the parameters for “product realization” according to ISO 9001:2008, with a view to developing a conceptual framework that can be used to guide research, development and quality production of herbal products.

METHODOLOGY

1. WHO Model of Herbal Drug Development: The WHO approach to herbal drug development is spelt out in the following documents:
2. Research guidelines for evaluating the safety and efficacy of herbal medicines ⁷;
3. The manual on quality control methods for medicinal plant materials ⁶;

• General guidelines on methodologies for research and evaluation of tm ⁵; and

1. The 16-page document on information needed to support herbal clinical trials ¹.
2. WHO manual on Quality Control Methods for Medicinal Plant Materials: The manual contains a long list of tests/ procedures that includes the comparison of medicinal plant materials or products with suitable standards to determine whether they should be accepted, rejected or reworked. The term “standards” implies that certain procedures need to be established for such tests, measurements and comparisons. The International Pharmacopoeia by WHO is copiously referenced by the manual. Some of the WHO procedures most commonly utilized in NIPRD includes: macroscopic and microscopic examinations; physicochemical tests like loss on drying, ash values and water extractability, bitterness, foaming index and so on; some basic tests for primary and secondary metabolites; and chromatography, especially TLC, but HPLC, GC-MS and other more advanced chromatographic techniques are also practised. Tests involving spectroscopy, such as light and atomic absorption, as described in the manual or in the WHO pharmacopeia are also applied in NIPRD. Some specific key features/ prescriptions of the manual are as follows:
3. Calculation of Results and Statistical Analysis:
   12. Rounding up or down: Results of tests, assays or standardizations of Volumetric Standards (VS) are calculated to one decimal place more than indicated in the requirement and then rounded up or down. Examples: 12.45 to 12.49 become 12.5. 1.340 to 1.344 becomes 1.34.
   13. Calculation of values such as loss on drying, total ash extractable matter, etc. etc. These must be calculated with reference to the air-dried sample, usually as %w/w, unless otherwise stated.

• Statistical analysis: Student’s “t” distribution may be used as a test of the null hypothesis. The levels of significance may be set at 0.05, 0.01 and 0.001 corresponding to 95%, 99% and 99.9% confidence limits.

1. Conditions of Storage: These are specified in accordance with the following:
   1. Containers and enclosures: These must not interact with the material. The following types were specified.

• Well-closed container: protects the content from extraneous matter or from loss of material under, normal conditions of handling, shipment or storage.
• Tightly-closed container: protects the content from extraneous matter, from loss of material, and from efflorescence, evaporation, or deliquescence, under normal conditions of handling, shipment or storage.
  1. Protection from light: This is achieved either by using an opaque container, or by shielding the container with light-resistant coverings, or by storage in a dark place.

1. Size of Cut: Cut materials, where necessary, are graded according to the aperture size of mesh through which the materials pass, as follows:

Description                              Aperture Size [mm]

Coarse cut                                           4.00

Medium cut                                        2.80

Fine cut                                               2.00

1. Sampling: Sampling is so critical in medicinal plants research that elaborate procedures are required, especially because medicinal plant materials generally lack homogeneity (table 1). The questions that may arise are: What special handling procedures are required? Which parts of the plant are to be included in the sample? These are addressed as follows:

2. Sampling of Materials in Bulk: First, each container is inspected to ascertain conformity with prescribed packaging and labelling. Checks are made for damaged or poorly labelled containers, and where necessary these are sampled individually and separately. Second, if the rest of the batch is uniform, containers are selected for sampling as shown in Table 2.

TABLE 1: SAMPLING OF MATERIALS IN BULK AS PER WHO (1998)

Third, the selected containers are opened, and the contents are examined, looking out for the characteristics stated in Table 2.

TABLE 2: CHARACTERISTIC TO LOOK FOR IN SAMPLES SUPPLIED IN BULK

Fourth, the following points/actions are taken note/ carried out in the actual act of sampling:

• Three (3) original samples from each container – from: top, middle and bottom are taken.
• The 3 original samples are combined into a pooled sample and mixed carefully.
• The average sample is obtained by “quartering” the pooled sample. b. Quartering

1. Quartering consists of the following steps:
2. A pooled sample from original samples is mixed carefully and thoroughly, and constituted it into a square-shaped heap.
3. The heap is divided diagonally into 4 equal parts, and any 2 diagonally opposite parts are selected and mixed carefully.
4. The process is repeated as necessary until the required quantity of sample is obtained.
5. Any remaining material is returned to the batch.

• Final samples: Final samples are obtained from an average sample by quartering, as described above. This means that an average sample gives rise to 4 final samples. Each final sample is divided into 2 portions. One portion is retained as reference material, while the other is tested.
  1. Establishment of limits: Where possible or necessary analytical results from 20 successive batches are pooled together, and the grand mean and “three sigma limits” (± 3 Standard Deviations) are calculated, to represent established limits.
  2. Harvesting/ collection and drying of aerial parts: Aerial parts are harvested in the mornings by cutting the plant at least 1 cm above ground level with the aid of sharp scissors. The parts are routinely shaken to remove dust, dead parts and unwanted debris and foreign matters. The parts may be treated with running potable water to remove unwanted items. Subsequently, the parts are dried in a shade by placing them on stainless steel mesh or by any other suitable means. The materials are considered sufficiently dry once they are brittle to touch and amenable to grinding with an electrically powered grinding machine.
  3. Harvesting/ collection and drying of underground parts: Underground parts are harvested in the mornings by digging out the system underground and cutting off portions thereof with a sharp cutlass or axe. The parts are routinely treated with running potable water to remove unwanted soil particles. Subsequently, the parts are cut into manageable bits and dried in a shade by placing them on stainless steel mesh or by any other suitable means. The materials are considered sufficiently dry once they become brittle and amenable to grinding with an electrically powered grinding machine.
  4. Examination of fresh or air-dried materials: Examinations of materials for purposes of authentication are based on visual inspection, including microscopy, to establish shape, size, colour, texture, and appearance of cut surfaces. Odour and taste, called organoleptic characteristics, are also used in identification. Items usually required include devices for measurements including: ruler, graph paper, caliper, micrometer screw-gauge, razor blade or scalpel, and hand lens or microscope may be used to determine shape and size.
  5. Tests for primary and secondary metabolites: The manual provide detailed chemical microscopy especially for primary metabolites. Tests for secondary metabolites (phytochemicals) may be performed according to standard procedures as described elsewhere. Such tests, as described and applied elsewhere ^10-15 in related studies, include: Dragendorff’s test for alkaloids; Borntrager’s test for anthraquinones; Keller-Killani’s test for cardiac glycosides; Foaming test for saponins; Aqueous FeCl₃ test for tannins; and Salkowaski’s test or Libermann-Burchad test for terpenoids/ steroids.

2. WHO guidelines on safety and efficacy of herbal drugs and research on TM: The 1993 WHO document ⁷ containing the guidelines for conducting scientific research on the safety and efficacy of herbal medicines (HMs) reflect the consensus reached by 17 experts in pharmacology, biochemistry, and TM. The guidelines respond to the need to assure the safety of widely used HMs while also facilitating the search for new pharmaceutical products. Specific research criteria are covered together with general principles of investigation, including ethical concerns. The document has three parts.

The first discusses the special properties of herbal medicines that need to be considered when designing research protocols.

The second part provides detailed guidance on the objectives of research, the contents of a research protocol, and the methods of investigation for non-clinical studies and for Phase I to Phase IV clinical trials.

The third part, which forms the core of the book, presents three sets of research guidelines: for quality specifications of plant materials and preparations, for pharmacodynamic and general pharmacological studies of HMs, and for toxicity investigation of HMs.

Topics covered range from the information required to establish the identity and quality of plant materials or preparations, through the selection of appropriate test systems for pharmacodynamic studies, to detailed advice on the many different tests, examinations, observations, and experimental procedures required, in experimental animals and controls, to establish the safety of herbal medicines. The guidelines are intended to facilitate the work of research scientists and clinicians while also furnishing some reference points for the governmental, industrial, and non-profit organizations providing financial support. The 2000 WHO document ⁵ on research methodologies on TM is mostly an update of 1993 document on essentially the same subject ⁷, but incorporating aspects of non-herbal TM. Key conclusions on aspects of documentation of safety of use of herbal drugs based on TM experience are shown in Table 3.

TABLE 3:  DOCUMENTATION OF SAFETY OF USE OF HERBAL DRUGS BASED ON TM EXPERIENCE

The above was prepared based on guidelines provided by WHO⁷ regarding the documentation of the safety of use of an herbal drug based on traditional experience, as elaborated upon elsewhere^16-19.

3. Information needed to support herbal clinical trials: We earlier (Ameh et al., 2011) emphasized that drug development from a traditional herb can take the route of standardization of the herb or its extract for immediate use without further chemical manipulations. Standardization in this sense implies there is sufficient chemical data for identifying the herb, for processing the herb, and for controlling the processes. In other words there is sufficient C-M-C data ¹ to produce the “herbal product” – namely: an “herbal material administered to clinical subjects” (WHO, 2005b). In the 2008 Annual Lecture of the Nigerian Academy of Science, Professor Wambebe ²⁰ (formerly Dean, Faculty of Pharmaceutical Sciences, ABU, Zaria and the first Director General of NIPRD) had made the following pertinent comment on “Drug Development Chain”:

“A simplified drug development chain encompasses discovery phase…Traditional medicine belongs to the discovery phase in that chain. If a proper ethnomedical survey is conducted accompanied by clinical observational study following WHO guidelines, it is possible to save substantial funds and drastically reduce the time needed to obtain credible data….” Wambebe ²⁰. The logic of the position follows directly from the reasoning provided in the aforesaid references ^{1, 5, 7}.

4. Synopsis on ISO 9001:
   1. ISO 9001 as an industrial standard: ISO 9001 as an industrial standard or QMS is a document of about 30 pages with 8 clauses, published by ISO and obtainable from its headquarters in Basle, Switzerland, or from any of its national affiliates. The standard is designed to be met by any organization that:
      1. needs to demonstrate its ability to consistently provide product or service that meets both customer and applicable legal requirements;
      2. aims to enhance customer satisfaction by effectively and continually improving its QMS; and

• plans to provide continual assurance of conformity to customer and applicable legal requirements.

These aims or approaches (often called “QMS requirements” or “quality procedures”) are generic and are intended to be applicable to every organization irrespective of type, size and product it provides. Wherever any requirement cannot be applied due to the nature of an organization and its product, such can be considered for exclusion.

But wherever exclusions are made, claims of conformity to the standard are not acceptable unless such exclusions are limited to requirements within the 7th clause of the standard, and such exclusions do not affect the organization's ability, or responsibility, to provide product that meets customer and applicable legal requirements. ISO 9001 defines the minimum requirements for a well-managed organization.

In other words, noncompliance to an ISO 9001 requirement puts at risk an organization's ability to consistently and efficiently satisfy the expectations of its customers/ stakeholders.

4. The six QMS requirements or “The Six Quality Procedures”: These procedures or requirements, as one may choose to call them, actually refer to sub-clause 4.1 (General requirements) under clause 4 (Quality Management System) of ISO 9001.

The sub-clause prescribes that organizations shall establish, document, implement, and maintain a QMS, and continually improve its effectiveness. To do so means that the organization shall operate its QMS with a view to carrying out (or meeting) the following six procedures (or requirements):

1. Determine the processes needed for the QMS, and their application throughout the organization;
2. Determine the sequence of the processes and their interactions;

• Determine the criteria and methods for operating and controlling the processes;

1. Determine and ensure the availability needed resources and supporting information;
2. Check, measure and analyze the processes, where applicable; and
3. Implement actions to achieve planned results and continual improvement of the processes. The processes needed for the QMS invariably include the processes for management activities (clause 5), provision of resources (clause 6), product realization (clause 7), and measurement, analysis, and improvement (clause 8).

Philosophically, ISO 9001 is formulated on the basis of management by objectives (MBOs) and draws upon eight quality management principles. Ideally therefore, quality assurance (QA) or total quality management (TQM) covers activities in research, development, production and documentation.

It embraces the rule: "do it right the first time". It involves regulating the quality of raw materials, the state of production line and works-in-progress, the product and related management processes.

One of the most widely used paradigms for TQM or quality assurance management (QAM) is the “Shewhart cycle”, also called “PDCA approach”, meaning, “Plan-Do-Check-Act” ^{21, 22}. The foregoing is illustrated in Figure 1 using NIPRD QMS processes as an example.

FIGURE 1: MANAGEMENT RESPONSIBILITY CORRESPONDS TO CLAUSE 5 OF ISO 9001; WHILE RESOURCE MANAGEMENT, PRODUCT REALIZATION AND MEASUREMENT/ ANALYSIS/ IMPROVEMENT CORRESPOND TO CLAUSES 6, 7 AND 8 RESPECTIVELY

Footnote to Figure 1: Management responsibility corresponds to clause 5 of ISO 9001; while Resource management, Product realization and Measurement/ analysis/ improvement correspond to clauses 6, 7 and 8 respectively.

Management responsibility: NIPRD’s CEO is accountable to the customer/ stakeholder. The CEO must engage qualified staff and systems to enable the QMS function to satisfy customer/ stakeholder

Resource management: Administration and Finance are critical to the CEO’s resource management functions, since they are respectively responsible for personnel administration and material management

Product realization: R&D units are critical to the CEO’s functions in product realization/ service provision, since they are responsible for delivering on the Institute’s Mandate

Measurement/ analysis/ improvement: All units have measureable objectives and functions. Thus, the CEO must manage staff and systems to ensure customer/ stakeholder satisfaction QMS improvement

3. The eight quality management principles that underlie ISO 9001: All ISO standards including ISO 9004 - Managing for Sustained Success and ISO 9001are formulated on the bases of 8 quality management principles that are aligned with the philosophy and objectives of most quality award programmes in the world’s most industrialized nations. The 8 principles are associated with the following themes:

1. Customer focus.
2. Leadership.
3. Involvement of people.
4. Process approach to management.
5. System approach to management.
6. Continual improvement.
7. Factual approach to decision making.
8. Mutually beneficial supplier relationships.

4. Key terminologies of ISO 9001:2008

1. Traceability: Traceability is concerned with and refers to the fact that typically, recorded data are meant to show how and where raw materials and products were processed, in order to allow products and problems to be traced to their sources.
2. Product realization: Product realization refers to the scenario in which, when developing a new product, an organization plans the stages of development, with appropriate testing at each stage. The organization tests and documents whether the product meets design requirements, legal requirements, and user or customer needs. Product realization is the subject of 7^th clause of ISO 9001 and the main issue in this article as will be seen in the Results and Discussion.
3. Quality plan: Quality plan refers to a document specifying the QMS processes (including the product realization processes), and the resources to be applied to a specific product or project.
4. Monitoring and measurement: Monitoring and measurement refer to the scenario in which an organization must regularly review its performance through meetings and internal audits, and determine whether the QMS is working and what improvements can be made. The organization must have a documented procedure for internal audits and a procedure for dealing with past problems and potential problems. It must keep records of these activities and the resulting decisions, and monitor their effectiveness. It must have documented procedures for dealing with actual and potential non-conformances (problems involving suppliers, customers, or internal problems).
5. Continual Improvement: Continual Improvement refers to the scenario in which an organization 1) makes sure no customer uses a bad product, 2) determines what to do with a bad product, 3) deals with the root cause of problems, and 4) keeps records to use as a tool to improve the QMS.
6. Customer requirements: Customer requirements refer to the attributes that the buyer of a product (or user of a service) wants. The core business of an organization is to determine customer requirements and to meet them – basis for “Customer focus”.

RESULTS AND DISCUSSION: Once the CEO (or the officer concerned in the herbal drug organization) is convinced of the merit of developing an herbal product from a named part of a named plant, a formal ethnobotanical survey is conducted, if necessary, to ascertain/ conduct the following scenarios/ attendant actions:

1. Where no toxicological data exist, evidence is sought to confirm that the use of the drug for least 20-30 years were without untoward effects.
2. Where some toxicological data exist, evidence is sought to confirm that the period during which the drug had been in use is at least 20 years; that the health disorder treated with the drug justified the attendant risks; and that the number of patients so treated was of sufficient statistical power.

• Where there is a well-defined toxicity, attempts are made to establish its dose-dependency and to explain any possible consequence thereto.

1. Where there is a potential for abuse, an appropriate approach to dealing with it must be articulated.
2. Where the period of use is less than 20 years, attempts are made to conduct a formal toxicity studies.

The scenarios/action above are as per WHO⁷ as summarized in Table 3. In the meantime quality control studies designed as per WHO ⁶ are undertaken to confirm or verify the following, as described below:

Since, the regulatory requirements for an herbal product need not be less stringent than those for regular pharmaceuticals; its production should conform to good manufacturing practice (GMP) and relevant industrial standards, where such exist. Such conformities must take into cognizance the inherent variability of biological materials.

Accordingly, the following quality control actions described earlier ^{8, 9} should be considered:

1. Limits must be set for the starting materials.
2. The manufacturing process must be chosen, such that mechanical efficiency and biochemical compatibility are simultaneously attained.

• The manufacturing process must be observable and reproducible.

1. The finished product must pass relevant tests, including, where possible, one directly related to the disease condition of interest.

To attend to these steps methodically ^{8, 9}, as set out and described in detail in Tables 4-11, is to develop a system for assuring the quality of herbal products that are in compliance with both WHO and ISO 9001 requirements. The contents of the Tables are briefly described as follows:

1. Tables 4 and 5 deal with functions concerned with planning of product realization and customer-related processes.
2. Tables 6 and 7 deal with design and development processes.

• Table 8 deals with purchasing processes.

1. Tables 9 and 10 deal with production and service provision.
2. Table 11 deals with control of measuring and monitoring equipment.

While the successful application of the WHO model by NIPRD ^21-23, had led to the development of Niprisan^® - an antisickling phytomedicine, the application of ISO 9001 is widely applauded as the most successful industrial standard in world economic history ^24-26.

TABLE 4: DEPARTMENTAL ROLES IN PLANNING OF PRODUCT REALIZATION AS PER ISO 9001:2008

Footnote to Table 4: A document specifying the processes of the QMS (including the product realization processes), and the resources to be applied to a specific product, project or contract, can be referred to as a quality plan. The requirements in sub-clause 7.3 (Design and Development) can also be applied to the development of product realization processes.

TABLE 5: DEPARTMENTAL ROLES IN CUSTOMER-RELATED PROCESSES AS PER ISO 9001: 2008

Footnote to Table 5: Post-delivery activities include actions such as the need to institute a pharmacovigilance programme and the need to respond to reports of adverse effects. In situations where a formal review is not practical for each order, relevant product information such as catalogues or advertising material may be used as a basis for a review.

 TABLE 6: DEPARTMENTAL ROLES IN DESIGN AND DEVELOPMENT PROCESSES AS PER ISO 9001: 2008

Footnote to Table 6: Design and development review, verification, and validation have distinct purposes. They can be conducted and recorded separately or in any combination. Information for production and service can include details for product preservation.

 TABLE 7: DEPARTMENTAL ROLES IN DESIGN AND DEVELOPMENT PROCESSES AS PER ISO 9001: 2008

Footnote to Table 7: Information for production and service can include details for product preservation.

 TABLE 8: DEPARTMENTAL ROLES IN PURCHASING PROCESSES AS PER ISO 9001: 2008

Footnote to Table 8: In view of the technical nature of some purchases it is necessary that the Purchasing Officer be familiar (or be specially assisted) with the technicalities involved and reasons behind a given purchase decision.

 TABLE 9: DEPARTMENTAL ROLES IN PRODUCTION AND SERVICE PROVISION AS PER ISO 9001: 2008

Footnote to Table 9: Some pharmacopoeial or compendial tests such disintegration and dissolution tests for tablets and capsules may be applied to herbal preparations.

 TABLE 10: DEPARTMENTAL ROLES IN PRODUCTION AND SERVICE PROVISION AS PER ISO 9001: 2008

Footnote to Table 10: Chromatographic fingerprints and the use of marker substance and the availability of reference crude extracts are essential as a means by which identification and traceability can be maintained in herbal drug production. Customer property can include the personal data and traditional knowledge revealed by an herbalist.

   TABLE 11: DEPARTMENTAL ROLES IN CONTROL OF M&M EQUIPMENT AS PER ISO 9001: 2008

Footnote to Table 11: Some calibrations are done daily, some whenever the equipment is to be used, some seasonally and some yearly. The frequency of calibration is normally stated in the relevant SOPs or compendia or equipment SOP or manual.

CONCLUSION: Both ISO 9001’s provisions for product realization and WHO guidelines for quality control and development of herbal drugs from Traditional Medicine can be applied to the research, development and actual production quality herbal medicines. We affirm that a widespread application of these guidelines will revolutionize herbalism worldwide and contribute immensely to the economy of countries that have a rich biodiversity and herbal tradition.

ACKNOWLEDGMENT: We are indebted to the Standards Organization of Nigeria (SON) - affiliate of ISO, for a copy of ISO 9001:2008 provided during a 2-week SON workshop on quality management sponsored by NIPRD for a select staff of the Institute. We particularly and gratefully acknowledge the personal enlightenment offered by Engineer Timothy N. Abner, Dr. Justin B. Nickaf and Engineer Shehu I. Maik all of SON during the workshop held at Bolton White Apartments, Abuja, in November-December 2011.

REFERENCES:

1. WHO: Information needed to support Clinical Trials of herbal products. TDR/GEN/Guidance/05.1Operational Guidance: Special Programme for Research and Training in Tropical Diseases, 2005.
2. European Pharmacopoeia: European Pharmacopoeia (Supplement 2000). Technical Secretariat of the European Pharmacopoeia Commission, 2000.
3. Gaedcke FW, Steinhoff SK and Blasius HR: Herbal Medicinal Products: Scientific and Regulatory Basis for Development, Quality Assurance and Marketing Authorization. Stuttgart: Medpharm Scientific Publishers, First Edition 2003.
4. Bandaranayake WM: Quality Control, Screening, Toxicity, and Regulation of Herbal Drugs. In: Modern Phytomedicine - Turning Medicinal Plants into Drugs. Edited by Iqbal Ahmad, Farrukh Aqil, and Mohammad Owais 2006 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim, Germany, 2003: 25-57.
5. WHO: General guidelines for methodologies on research and evaluation of traditional medicine (Document WHO/EDM/ TRM/2000.1). World Health Organization, 2000.
6. WHO: Quality control methods for medicinal plant materials. World Health Organization, 1998.
7. WHO: Research Guidelines for Evaluating the Safety and Efficacy of Herbal Medicines, World Health Organization, 1993.
8. Ameh SJ, Obodozie OO, Afolabi EK, Oyedele EO, Ache TA, Onanuga CE, Ibe MC and Inyang US: Some basic requirements for preparing an antisickling herbal medicine-NIPRISAN®. African Journal of Pharmacy and Pharmacology 2009; 3 (5): 259-264.
9. Ameh SJ, Tarfa FD, Abdulkareem TM, Ibe MC, Onanuga C and Obodozie OO: Physicochemical Analysis of the Aqueous Extracts of Six Nigerian Medicinal Plants. Tropical Journal of Pharmaceutical Research 2009; 9 (2): 119-125.
10. Ameh SJ, Obodozie OO, Inyang US, Abubakar MS and Garba M: Quality Control Tests on Andrographis paniculata Nees (Family: Acanthaceae) – an Indian ‘Wonder’ Plant Grown in Nigeria. Tropical Journal of Pharmaceutical Research 2010; 9 (4): 387-394.
11. Ameh SJ, Tarfa FD, Abdulkareem TM, Ibe MC, Onanuga C and Obodozie OO: Physicochemical Analysis of the Aqueous Extracts of Six Nigerian Medicinal Plants. Tropical Journal of Pharmaceutical Research, 2010; 9 (2): 119-125.
12. Ameh SJ, Obodozie OO, Inyang US, Abubakar MS and Garba M: On the production of CONAVIR® immune-booster by good manufacturing practice: Development of specifications for the herbal component. African Journal of Pharmacy and Pharmacology 2010; 4(6): 395-401.
13. Ameh SJ, Obodozie OO, Inyang US, Abubakar MS and Garba M: A Normative Study of Nigerian Grown “Maha-Tita” (King of Bitters) - Andrographis paniculata International Journal of Drug Development & Research 2010; 2(2): 291-299
14. Ameh SJ, Obodozie OO, Gamaniel SK, Abubakar MS and Garba M: Physicochemical variables and real time stability of the herbal substance of Niprd-AM1®- an antimalarial developed from the root of Nauclea latifolia M. (Rubiaceae). International Journal of Phytomedicine 2010; 2: 332-340.
15. Ameh S, Obodozie O, Gamaniel K, Abubakar M and Garba M: Herbal Drug Regulation Illustrated with Niprifan^® Antifungal Phytomedicine. In: Eldin, A. B., (Ed) Modern Approaches to Quality Control, ISBN 978-953-307-329-3. INTECH Open Publisher, University Campus, STeP Ri Slavka Krautzeka 83/A, 51000 Rajeka, Croatia, 2011: 367-382.

• Ameh SJ, Obodozie OO, Inyang US, Abubakar MS and Garba M: Current phytotherapy - a perspective on the science and regulation of herbal medicine. Journal of Medicinal Plants Research 2010; 4(2): 072-081.

17. Ameh SJ, Obodozie OO, Inyang US, Abubakar MS and Garba M: Current phytotherapy – an inter-regional perspective on policy, research and development of herbal medicine. Journal of Medicinal Plant Research 2010; 4(15): 1508-1516.
18. Ameh SJ, Obodozie OO, Babalola PC and Gamaniel KS: Medical Herbalism and Herbal Clinical Research: A Global Perspective. British Journal of Pharmaceutical Research 2011; 1(4): 99-123.
19. Ameh SJ, Obodozie OO, Chindo BA, Babalola PC and Gamaniel KS: Herbal Clinical Trials-historical Development and Application in the 21st Century. Pharmacologia 2012;3: 121-131 DOI: 10.5567/pharmacologia.2012.121.131
20. Wambebe C: From plants to medicines: challenges and prospects. The Nigerian Academy of Sciences. Public Lecture. Reiz Continental Hotel, Abuja. May 22, 2008: 1-17.
21. Wambebe C, Khamofu H, Momoh JA, Ekpeyong M, Audu BS, Njoku SO, Nasipuri NR, Kunle OO, Okogun JI, Enwerem NM, Gamaniel SK, Obodozie OO, Samuel B, Fojule G, Ogunyale PO: Double-blind, placebo-controlled, randomized cross-over clinical trial of NIPRISAN in patients with sickle cell disorder. Phytomedicine 2001; 8(4):252-261.
22. Obodozie OO, Ameh SJ, Afolabi EK, Oyedele EO, Ache TA, Onanuga CE, Ibe MC and Inyang US: A Normative Study of the Components of Niprisan – an herbal medicine for sickle cell anemia. Journal of Dietary Supplements 2010; 7: 21-30.
23. Ameh SJ, Obodozie OO, Inyang US, Abubakar MS, Garba M: Climbing black pepper (Piper guineense) seeds as an antisickling remedy. In V. R. Preedy, R. R. Watson, V. B. Patel (Editors), Nuts & Seeds in Health and Disease Prevention (1^st), Academic Press (Elsevier), 2011: 333-343.
24. Naveh E and Marcus A: Financial performance, ISO 9000 standard and safe driving practices effects on accident rate in the U.S. motor carrier industry. Accident Analysis & Prevention 2007; 39 (4): 731–742.
25. Sharma DS: The association between ISO 9000 certification and financial performance. The international Journal of Accounting 2005; 40: 151–172.
26. Chow-chua C, Goh M and Wan TB: Does ISO 9000 certification improves business performance? The International Journal of Quality & Reliability Management 2002; 20 (8): 936–953.
    

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    How to cite this article:

    Ameh SJ, Tarfa F, Ayuba S, Gamaniel KS: Herbal Product Realization in accordance with WHO and ISO Guidelines. Int J Pharm Sci Res. 3(10); 4019-4035.

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