Pharmacognosy with the Basics of Plant Biochemistry - Kovalyov V. M. 2004

General Section
Standardization of Medicinal Plant Raw Materials

Medicinal plant raw Materials are products of cross-sectoral purpose and wide application. In accordance with the Decree of the Cabinet of Ministers of Ukraine "On Standardization and Certification," they are subject to mandatory standardization and certification. A national system for guaranteeing the quality of medicines, which include medicinal plant raw materials, has been established and is developing in Ukraine.

Legal relations associated with the creation, registration, production, quality control, and commercialization of medicines, including medicinal plant raw materials and their processed products, are regulated by the Law of Ukraine "On Medicines," enacted by the Resolution of the Verkhovna Rada of Ukraine on April 4, 1996.

In accordance with the Law, management in the field of the creation, production, quality control, and distribution of medicines is carried out by the Ministry of Health of Ukraine (MoH of Ukraine). In 1998, several documents stipulated by the Law were adopted, namely: the "Procedure for State Registration (Reregistration) of Medicines and Fees for State Registration (Reregistration) of Medicines" (Resolution No. 569 dated April 27, 1998), the "Regulations on the State Inspection for Quality Control of Medicines of the Ministry of Health of Ukraine" (Resolution No. 179 dated February 16, 1998), the procedure for conducting preclinical trials (Order No. 259 dated August 16, 1996), etc. The procedure for the creation and Introduction of medicines into production was approved (Order No. 87 dated September 4, 1996).

The MoH of Ukraine and its departments are tasked with ensuring state control over compliance with legislation regarding the production, export, import, wholesale, and retail trade of, in particular, medicinal plant raw materials (MPRM), and implementing state policy in this area; carrying out certification of medicinal plant raw materials and preparations based on them, issuing licenses for the wholesale and retail trade of goods of this group; organizing and developing drafts of state programs for controlling the market of medicines, including medicinal raw materials, herbal preparations, dietary supplements, cosmetics, etc.

The special state control body for medicine quality is the State Inspection, to which the state inspections for medicine quality control in the Autonomous Republic of Crimea, regions, and the cities of Kyiv and Sevastopol are subordinated. They conduct regular inspections of medicinal products and medicinal plant raw materials sold in Ukraine, as well as preliminary control for compliance with standard requirements of the first five pilot-industrial batches of medicinal plant raw materials or phytopreparations whose production and Processing are being mastered by the manufacturing enterprise.

The authorized state bodies of the MoH of Ukraine that resolve issues related to the registration of new medicinal plant raw materials and phytopreparations are:

The State Scientific Expert Center for Medicines of the MoH of Ukraine — an Organization that conducts expert evaluation of materials from preclinical and clinical studies of preparations derived from medicinal plant raw materials;

The Pharmacopoeia Committee — a scientific and expert body that conducts expert evaluations and approves regulatory analytical documentation (temporary pharmacopoeial monographs and pharmacopoeial monographs) for medicinal plant raw materials, finished medicines, active pharmaceutical ingredients, and excipients. The Pharmacopoeia Committee approves and revises regulatory analytical documentation only if it complies with regulatory technological documentation (production technological regulations).

The Pharmacopoeia Committee issues Conclusions on the state registration of medicinal plant raw materials and herbal preparations; participates in the certification of production forms and quality control laboratories; develops the State Pharmacopoeia of Ukraine and sectoral regulatory documents governing quality requirements for medicines.

The MoH of Ukraine is gradually bringing legislative requirements regarding the quality control and safety of medicines into compliance with European Union legislation. Currently, Ukraine has observer status in the European Pharmacopoeia and will subsequently be able to apply for full membership status.

Thus, three tiers of the system for ensuring and guaranteeing the quality of medicinal plant raw materials have been established and are developing in Ukraine:

the registration and licensing system established at the national level by laws and bylaws;

the quality control system — before commercialization, medicinal plant raw materials undergo mandatory testing for compliance with the requirements of temporary pharmacopoeial monographs (TPM) and/or pharmacopoeial monographs (PM) in the technical control departments (TCD) of enterprises; in addition, quality control laboratories operate in Ukraine to conduct independent analyses of finished products;

the introduction of the principles and rules of Good Manufacturing Practice (GMP) at Ukraine's pharmaceutical industry enterprises.

Ukraine adheres to GMP rules that comply with the requirements of the WHO and EU countries. The first step towards ensuring a European level of quality for all products of pharmaceutical enterprises was the approval of Methodological Guidelines MG 64U-1-97 "Production of Medicines. Good Practices and Quality Control." Since January 1, 2002, GMP rules have become mandatory in Ukraine. The Structure/175.html">Implementation of GMP principles will increase manufacturers' responsibility for the quality of their products, driven by self-discipline rather than solely by state supervisory inspections.

By Cabinet of Ministers of Ukraine Resolution No. 244 dated March 19, 1997, an action plan was approved for the phased implementation of European Union directive requirements, sanitary, environmental, veterinary, and phytosanitary norms, as well as international and European standards in Ukraine. During 1998–2000, sectoral programs are being implemented in Ukraine to introduce standards for competitive products harmonized with international and European standards. The responsible executors of these programs in the pharmaceutical industry are the MoH of Ukraine and the State Committee for Standardization, Metrology, and Certification of Ukraine.

Analytical Regulatory Documentation

According to DSTU 1.0–93 "State Standardization System of Ukraine," a regulatory document for medicinal plant raw materials is a document establishing rules, General Principles, or characteristics related to various activities or their results. A standard is a regulatory document that establishes rules, requirements, general principles, or characteristics for general and repeated use in order to achieve an optimal degree of order in a given field.

The analytical regulatory documents regulating the quality of MPRM at pharmaceutical enterprises are temporary pharmacopoeial monographs or pharmacopoeial monographs. At enterprises of other profiles (food, perfumery and cosmetics industries, etc.) that use medicinal plant raw materials, the regulatory documents will be state standards of Ukraine or technical specifications of Ukraine.

A Pharmacopoeial Monograph of Ukraine (PM U) is an analytical regulatory document that establishes requirements for medicines, including medicinal plant raw materials, their packaging, storage conditions and shelf life, and quality control Methods.

A Temporary Pharmacopoeial Monograph of Ukraine (TPM U) is a pharmacopoeial monograph with a validity period limited to 1–3 years. It is approved for the initial industrial batches of new types of MPRM and phytopreparations recommended for medical use or utilization in the pharmaceutical industry.

State Standards of Ukraine (DSTU) are registered by the State Standard Committee for high-volume products and plant raw materials used in many sectors of the national economy.

Technical Specifications of Ukraine (TU U) are regulatory documents that establish requirements for specific products (in this case, MPRM) and regulate relations between the supplier (manufacturer) and the consumer of the products.

Sectoral Standards of Ukraine (SSTU) are standards that set forth additional technical specifications for the manufacture and supply of, in this case, a medicine or medicinal plant raw material (scientific and technical terms, designations, general technical documentation, technological norms, etc.), for example, SSTU 64-195 "Medicinal Plant Raw Materials. Procedure for Establishing Shelf Life."

Depending on which standardization organization (international, regional, or national) adopts the standards, they are accordingly classified as international, regional, or national. In addition, there are interstate standards (GOST) adopted by states that have joined the Regulation on Conducting a Coordinated Policy in the Field of Standardization, Metrology, and Certification. These GOST standards are applied directly by these states.

A State Standard of Ukraine is considered a national standard for any other party (any country in the world).

Following Ukraine’s declaration of independence, the need arose to build a national system of drug standardization. A vital task of the Pharmacopoeia Committee (PC) of the Ministry of Health of Ukraine—operating on The basis of the State Scientific Center for Medicines (SSCM) since March 19, 1992—is The Development of the State Pharmacopoeia (SP). Within the PC, the State Pharmacopoeia of Ukraine department was established to harmonize the requirements of the National Pharmacopoeia of Ukraine with the European and American Pharmacopoeias, as well as with the pharmacopoeias of the CIS countries, primarily Russia.

The developing SP of Ukraine will comprise Two Types of monographs: general and individual. General monographs include those that:

regulate General provisions and define terminology, Abbreviations, etc.;

address GENERAL ISSUES OF pharmacopoeial analysis, such as “Chemical Reference Standards”, “Validation of Analytical Procedures”, “Statistics”, etc.;

describe and establish General Requirements for dosage forms and substances, for example, “Infusions and Decoctions”, “Herbal Teas”, “Roots”, “Leaves”, etc.;

describe and regulate certain methodological and metrological requirements for quality control methods of medicines (“Chromatography”, “Spectrophotometry”, “Toxicity”, “Dosage Uniformity”, etc.). General monographs are strictly normative in nature and should therefore be regarded as a mandatory guide for developing and evaluating any quality control methods for medicinal raw materials.

Individual monographs include those describing requirements for specific types of medicinal plant materials (MPM) and medicinal products. Due to the inherent Variability of The chemical composition of MPM, individual monographs are informational and normative in nature.

All categories of regulatory and analytical documentation (RAD) for medicinal plant materials (FS, TFS, DSt U, TU U) are standardized—meaning they share an identical structure, content, and presentation in accordance with GOST 42U-1-92, “Procedure for the Development, Coordination, and Approval of Regulatory and Technical Documentation for Medicines and Medicinal Plant Materials”.

Individual pharmacopoeial monographs (FS) and temporary pharmacopoeial monographs (TFS) for herbal teas and medicinal plant materials include the following sections:

composition (for herbal teas), Latin, Ukrainian, and Russian names of the medicinal plant(s) and family;

external characteristics; Cell/15.html">Microscopy; identification tests;

disintegration (for briquetted and cut-pressed products);

mass deviation (for briquetted and cut-pressed products);

numerical values: content of pharmacologically active components or biological activity;

moisture content; total ash; ash insoluble in a 10% Hydrochloric acid solution;

degree of comminution; PARTS OF THE raw material that have changed color;

other plant parts not subject to harvesting; organic impurities; mineral impurities;

packaging; labeling; transportation; storage; shelf life; principal pharmacological action.

The content of BIOLOGICALLY ACTIVE SUBSTANCES (BAS) indicates the lower permissible limits (in percentages), whereas for all other parameters, the standard establishes upper limits.

The document number consists of the RAD category, the Ministry of Health of Ukraine code, the serial number of the monograph, the code of the organization that developed the document, and the year of approval. For example,

The Pharmacopoeia Committee maintains sequential numbering of approved FS or TFS. Once approved, FS and TFS are registered in the State Register of Medicines of Ukraine and assigned a registration number.

Procedure for the development, coordination, and approval of RAD for medicinal plant materials

To introduce new types of medicinal plant materials or drugs into production, a series of consecutive steps must be taken regarding the creation of analytical regulatory documentation, the material and technical base for production, and the control over manufacturing processes and quality.

The Mechanism of interaction between the developer and the manufacturer in The process of creating and introducing a medicinal product is shown in the diagram.

Class="center">Interaction between the developer and the manufacturer in the process of creating and introducing medicinal products

The developer of the new product provides the manufacturer with materials that substantiate the Prospects of introducing the medicinal product (results of scientific studies on its specific activity, draft temporary pharmacopeial monograph). The manufacturer decides on the feasibility of creating and launching the medicinal product into production under its own trademark. Based on the draft temporary pharmacopeial monograph, it manufactures and tests pilot batches of the medicinal product, and submits them for experimental and clinical trials at certified facilities of the State Scientific and Expert Center for Medicinal Products of the Ministry of Health of Ukraine. These studies are conducted on a contractual basis between the manufacturer and the testing facilities.

In accordance with the approved pilot-industrial, start-up, or industrial regulations, the manufacturer produces and tests pilot batches of the medicinal product (at least five batches) in order to verify their quality, the developed technology, and to substantiate the indicators and norms introduced into the draft analytical documentation. The State Scientific and Expert Center for Medicinal Products of the Ministry of Health of Ukraine reviews the submitted materials and authorizes clinical trials. Based on the results obtained, it approves the instructions for use of the medicinal product and recommends the drug for implementation. The Pharmacopeial Committee approves the temporary pharmacopeial monograph and notifies the State Inspection for Quality Control of Medicinal Products accordingly.

Upon approval of the analytical normative documentation, the manufacturer produces five commercial batches of the medicinal product and submits them for preliminary inspection to the State Inspection for Quality Control of Medicinal Products of the Ministry of Health of Ukraine. Based on the test results, the State Inspection issues a Conclusion regarding the compliance of the medicinal product quality with the requirements of the analytical documentation.

The permit for industrial production and medical use of the medicinal product is issued by the Ministry of Health of Ukraine. Registration of the new medicinal product is carried out by the Registration Bureau of the Ministry of Health of Ukraine for a period of three years, and the product is entered into the relevant section of the State Register of Medicinal Products of Ukraine (State Register).

The sale of medicinal plant raw materials and preparations derived from them is carried out only if There is a quality certificate (analysis protocol) issued to the manufacturers, which guarantees the consumer high product quality.