Topic 1 Common approaches for quality control of drugs. Harmonization of pharmacopoeias

Learning Objectives

• compare and analyze the equal pharmacopoeial monographs (Ph. Eur., USP, JP) and select optimal methods of quality control for different active substances and excipients.

Every medicine is characterized by special requirements of efficiency and safety, which determine its quality. High-grade medicines and their active substances always comply with all regulatory requirements. Medicine quality control is carried out during the whole manufacturing process (at every stage), also when releasing the drug on the market and during its circulation there.

The process of standardization and quality control is implemented in three main areas: identification of medicines, purity assessment (absence of impurities) and assay. Drugs quality indicators together with the methods of their analysis are stated in special regulatory documents (RD). The main one is Pharmacopoeia.

Pharmacopoeia, or pharmacopoea, in its modern technical sense, is a book containing directions for the identification of samples and the preparation of compound medicines. It is published by the authority of a government or a medical or pharmaceutical society. Descriptions of preparations are called monographs.

Pharmacopoeia is a collection of official documents (standards and regulations) that sets quality standards for pharmaceutical substances (active pharmaceutical ingredients – API), excipients, diagnostic and medicinal products in different pharmaceutical forms. The provisions of Pharmacopoeia are based on the achievements of pharmaceutical chemistry and pharmaceutical analysis, its criteria, methods and techniques. This document includes instructions for the manufacturing and quality control of pharmaceutical substances, excipients, diagnostic substances and pharmaceutical forms; determines the doses; establishes requirements for medicinal plant materials.

Implementation of Pharmacopoeia standards and requirements combined with the requirements of GMP standards will ensure the quality of pharmaceutical substances and preparations.

Pharmacopeia has two main sections: general chapters and specific monographs. Specific monographs are devoted to individual substances or finished dosage forms of medicines (USP, JP). Pharmacopoeia monograph is the standard of quality for specific (individual) drug. The general chapters contain information about the methods of analysis, reagents, etc. For example, there are a lot of general chapters in Ph.Eur: Methods of Analysis (Apparatus. Physical and physicochemical methods. Identification. Limit tests. Assays. Biological tests. Biological assays) – Methods in pharmacognosy – Pharmaceutical technical procedures – Materials for Containers –Allergen products – Dosage Forms – Essential oils – Extract – Herbal drugs – Homoeopathic preparations – Immunosera for human use – Products of fermentation – Radiopharmaceutical preparations – Recombinant DNA technology – Substances for pharmaceutical use – Vaccines for human – Vaccines for veterinary use – Vegetable fatty oils. The State Pharmacopeia is the official document, which is under state supervision. State Pharmacopeia is a document of national legislative power, and its requirements are mandatory for all institutions in the state, engaged in the manufacture, storage and use of medicines, including herbal (medicinal plant materials).

In the world pharmaceutical practice, the recognized leaders among the pharmacopoeias are the Pharmacopoeia of Europe, the United States pharmacopoeia and Japan pharmacopoeia.

The Convention developed and the circle of members Pharmacopoeia expanded. Today its membership includes 36 countries and 22 observers. Russia has observer status.

Members of the European Pharmacopoeia Commission are: Austria, Belgium, Bosnia and Herzegovina, Bulgaria, Croatia, Cyprus, Czech Republic, Denmark, Estonia, Finland, France, Germany, Greece, Hungary, Iceland, Ireland, Italy, Latvia, Lithuania, Luxembourg, Malta, Montenegro, Netherlands, Norway, Poland, Portugal, Romania, Serbia, Slovak Republic, Slovenia, Spain, Sweden, Switzerland, the former Yugoslav Republic of Macedonia, Turkey, United Kingdom and the European Union. The observers to the European Pharmacopoeia Commission are: Albania, Algeria, Australia, Belarus, Brazil, Canada, China, Georgia, Israel, Madagascar, Malaysia, Morocco, Republic of Kazakhstan, Russian Federation, Senegal, Syria, Tunisia, Ukraine, United States of America and WHO (World Health Organization).

Since 1975 if the country wishes to register its products in the European Union it has to use the European Pharmacopoeia. The network of analytical laboratories, controlled by the European Pharmacopoeia Directorate, was organized in 1994. In the same year the attestation procedure for pharmaceutical substances conformity to the demands of European Pharmacopoeia monographs has been introduced.

Since 1975 if the country wishes to register its products in the European Union it has to use the European Pharmacopoeia. The network of analytical laboratories, controlled by the European Pharmacopoeia Directorate, was organized in 1994. In the same year the attestation procedure for pharmaceutical substances conformity to the demands of European Pharmacopoeia monographs has been introduced.

Standards of European Pharmacopoeia were widely used in Russian Federation until recently, when they found a reflection in the Russian Pharmacopoeia XIII. European Pharmacopoeia is also being used as a national standard in some countries of the former Soviet Union.

The European Pharmacopoeia is published by the Directorate for the Quality of Medicines & HealthCare of the Council of Europe (EDQM). Commission of European Pharmacopoeia, which includes all members and observers, also regulates workon Ph. Eur. Commission meets three times a year. During the rest year, its work is led by elected Bureau. Its functions include the work program adoption, definition of expert groups as well as pharmacopoeia texts approval.

After each monograph has been approved, special group of experts regulates it. The group works according to prescribed control procedures, technology development and revision of pharmacopoeia monographs.

The proposals from national delegations, expert groups, and pharmaceutical industry representatives replenish Ph. Eur. The decision on new monograph inclusion depends on the therapeutic effect of drug, widespread of it use, on the number of countries that have ratified it and on its proven quality.

The proposals from national delegations, expert groups, and pharmaceutical industry representatives replenish Ph. Eur. The decision on new monograph inclusion depends on the therapeutic effect of drug, widespread of it use, on the number of countries that have ratified it and on its proven quality.

US Pharmacopeia Convention is one of the most influential pharmacopoeia organizations in the world. Its quality standards are not only introduced in the US and Canada, but are also put into service in a number of countries actively producing drugs (India, China, etc). USA Pharmacopeia Convention is a nonprofit organization, but its financial resources and influence are very high over the world. Convention publishes a number of periodicals devoted to drug quality standards, develops and sells worldwide a rich collection of pharmacopoeia chemical reference materials, which quality is recognized all over the world.

Japanese Pharmacopoeia (JP) is another leading international pharmacopoeia. The new edition is published every five years. Current edition (JP 17) came in 2016. JP is published not only in Japanese but also in English.

British Pharmacopoeia (BP) has been published since 1864, the current edition – BP 2019. BP operates in the United Kingdom simultaneously with the European Pharmacopoeia. BP monographs for substances are practically the same as the corresponding Ph. Eur. monographs. BP also contains monographs for finished dosage forms of medicines.

In addition, the World Health Organization since 1950 publishes the International Pharmacopoeia. Today it is represented by the 8th edition, published in 2018. The main objective of the International Pharmacopoeia is to maintain the medicines quality in developing countries. In the absence of state resources to develop their own pharmacopoeia, these countries can take the International Pharmacopoeia as a national one.

The XIV edition of Russian Federation (Ph.RF) State Pharmacopoeia was published in 2018. Monographs describe physical and chemical characteristics of different dosage forms, analysis methods, demands for drug quality indicators. Monographs defines the quality requirements of medicines, active pharmaceutical substances and excipients.

Harmonization of pharmacopoeias. Increased facilities for travel have brought into greater prominence the importance of an approach to uniformity in the formulae of the more powerful remedies, in order to avoid danger to patients when a prescription is dispensed in a different country from that in which it was written. The first attempts were made by international pharmaceutical and medical conferences to settle a basis on which an international pharmacopoeia could be prepared, but due to national jealousies and the attempt to include too many preparations nothing has yet been achieved.

Globalization processes indicated the need for harmonization of medicines quality requirements. Harmonisation of various countries pharmacopoeia requirements is determined by ICH (www.ich.org) – the International Conference on Harmonization of Medicines Quality and the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. The World Health Organization and three leading Pharmacopeias (Ph. Eur, USP, JP) are directly involved in ICH activity. The purpose of ICH is to develop common requirements for standardization, quality control, efficiency, safety, production and registration of medicines. Representatives from three leading Pharmacopoeias meet twice a year since 1990 in the Pharmacopoeial Discussion Group to try to work towards «compendial harmonisation»’. Specific monographs are proposed, and if accepted, proceed through the stages of review and consultation. Adoption of a common monograph provides a common set of tests and specifications for a specific material. Not surprisingly, this is a slow process.

Though formerly printed there has been a transition to a situation where pharmaceutical information is available as printed volumes and on the internet. The rapid increase in knowledge renders necessary frequent new editions, to furnish definite formulae for preparations that have already come into extensive use in medical practice, so as to ensure uniformity of strength, and to give the characters and tests by which their purity and potency may be determined. However each new edition requires several years to carry out numerous experiments for devising suitable formulae, so that current pharmacopoeia is never quite up to date.

General monographs of Ph. Eur. «Pharmacopoeial harmonization» states: «It provides information on the degree of harmonization and consequently interchangeability of various general chapters and monographs of the European Pharmacopoeia and those of the Japanese Pharmacopoeia and United States Pharmacopoeia».

The European Pharmacopoeia Commission recognizes the utility of working with other pharmacopoeial bodies to develop harmonized monographs and general chapters. Such harmonization is fully compatible with the declared aims of the Commission and has benefits of different kinds, notably the simplification and rationalization of quality control methods and license in procedures. Such harmonization also enhances the benefits of the work of the International Conference on Harmonization (ICH) and the Veterinary International Cooperation on Harmonization (VICH) since some of the guidelines developed depend on pharmacopoeial general chapters for their application.

Harmonization is carried out in the Pharmacopoeial Discussion Group (PDG), in which the European Pharmacopoeia, the Japanese Pharmacopoeia and the United States Pharmacopoeia are associated. Where harmonization of monographs is carried out, the aim is to arrive at identical requirements for all attributes of a product. For some products, it can be extremely difficult to achieve complete harmonization, for example because of differences in legal status and interpretation.

Anniversary of the Pharmacopoeia Convention and marks the occupation of the new purpose – designed headquarters building of the EDQM, the European Directorate for the Quality of Medicines & He-alth Care, in Strasbourg.

The monographs of the Pharmacopoeia, both specific and general, together with other texts made mandatory by virtue of reference in monographs, are applicable throughout the 37 Member States including the European Union itself, which is also a signatory to the European Pharmacopoeia Convention. This means that the European Pharmacopoeia holds a special place in the regulatory processes within the European Union, its text being made mandatory or given ‘mandatory’ applicability by virtue of reference in European Council Directives. In addition to the 37 signatories to the European Pharmacopoeia Convention, there are also a large number (20) of observer countries. Consequently, the quality standards developed through the Pharmacopoeia have an impact on the quality of medicinal products and substances used across a large part of the globe.

The cooperation between the experts from industry, academia, regulatory authorities and official government laboratory scientists represents the pinnacle of scientific cooperation to produce a high standard of technical monographs and chapters.