Pharma Raw Materials & Excipients: Legal Regulation in Russia

May 13, 2023

BRACE Law Firm ©

Manufacturers of medicinal products must ensure their efficacy and safety. To this end, the state has developed a comprehensive list of requirements for the organization of production. However, guaranteeing the safety of a finished medicinal product is impossible without the use of high-quality pharmaceutical raw materials (the "Pharma Raw Materials" or "Medicinal Raw Materials") and auxiliary agents for the production of medicinal products (the "Excipients").

For a long time, neither the global community nor our country paid due attention to this issue, and Excipients were considered absolutely neutral and without influence on the quality of the finished product. However, the development of scientific knowledge and application experience forced a review of this perspective. For instance, in 1995–1996 in Haiti, 88 children died from acute renal failure after using an antipyretic syrup based on paracetamol. It was established that the local manufacturer used glycerin contaminated with approximately 20 percent diethylene glycol as an Excipient. This chemical compound is used in the production of antifreezes and brake fluids, and if ingested, causes kidney damage. The subsequent investigation revealed that the manufacturer did not analyze incoming raw materials, did not control product quality during production, and did not sufficiently test finished products. As a result of such actions, certain batches of the drug were produced using an insufficiently purified batch of glycerin. The Haitian tragedy demonstrated the need to take measures to regulate the use of raw materials and auxiliary agents and to implement GMP rules in pharmaceutical production.

In this article, we will consider the requirements imposed by current legislation on the use of raw materials and auxiliary agents in the production of medicinal products.

What Are Medicinal Raw Materials and Excipients for the Production of Medicinal Products?

A medicinal product is a finished product used for the treatment, prevention, or diagnosis of diseases. It consists of a pharmaceutical substance (Active Pharmaceutical Ingredient / API) and Excipients.

A pharmaceutical substance can be obtained from various sources, both of chemical and organic origin. Current legislation does not contain a definition of the concept "medicinal raw materials." In pharmaceutics, medicinal raw materials are understood as materials of mineral, animal, and plant origin serving as a source for obtaining pharmaceutical substances.

Thus, raw materials of plant origin include parts of medicinal plants in a dried or freshly collected state, as well as certain natural plant secretions. A large number of widely used drugs are obtained using medicinal raw materials: alkaloids (morphine, codeine, papaverine), cardiac glycosides (digitoxin, digoxin), the antimalarial agent quinine, etc. Separate organs and tissues of animals (endocrine glands, salivary glands, lungs, etc.) are used as medicinal raw materials of animal origin. Popular medicinal products such as pancreatin and insulin are obtained in this manner. Certain penicillin-series antibiotics and a number of antitumor drugs are obtained using fungi and microorganisms.

Federal Law No. 61-FZ dated April 12, 2010, On the Circulation of Medicinal Products (the "Law on Circulation of Medicinal Products"), unlike "pharmaceutical raw materials," contains a definition of "auxiliary agents." According to Article 4 of the Law, Excipients are substances of inorganic or organic origin used in the process of production and manufacturing of medicinal products to impart necessary physicochemical properties to them.

The list of Excipients is quite broad; according to some data, more than 500 auxiliary agents and even more mixtures are used in production globally, and their number is constantly growing [1]. They can be applied for various purposes. There are binders (cellulose, purified water, ethyl alcohol, etc.), disintegrants that improve tablet solubility (gelatin, starch, sugar, etc.), and lubricants and glidants that reduce friction between all components (fatty acids and their salts, talc, kaolin, etc.). Furthermore, Excipients can significantly influence the pharmacological activity of drugs, namely by enhancing the action of medicinal products or, conversely, reducing their activity, as well as altering the nature of the drug's action under the influence of various factors.

Speaking of Excipients, we should say a few words about the distinction between such concepts as "Excipients used in the production of drugs" and "food additives" or "technological aids" (processing aids). In practice, judicial disputes arise due to a lack of understanding of the difference in these products.

Technical Regulation of the Customs Union TR CU 029/2012 Safety Requirements for Food Additives, Flavorings and Technological Aids (the "TR CU 029/2012") [2] provides the following definitions of food additives and technological aids:

Food Additive – any substance (or mixture of substances), having or not having its own nutritional value, usually not consumed directly as food, intentionally used in the production of food products for a technological purpose (function) to ensure production (manufacturing), transportation, and storage processes, which results or may result in said substance or products of its transformation becoming components of the food products.

Technological Aid (Processing Aid) – a substance or materials or their derivatives which, not being components of food products, are intentionally used in the processing of food (alimentary) raw materials and (or) in the production of food products to fulfill certain technological purposes and, after their achievement, are removed from such raw materials or such food products, or the residual quantities of which do not have a technological effect in the finished food products.

Thus, both food additives and technological aids are intended for use in the production of food products.

In one case, a pharmaceutical company filed an application with the arbitration court to declare illegal a resolution of the customs authority on bringing it to administrative responsibility. As established during the court proceedings, the company submitted a declaration to the customs authority for the imported good: agglomerated isomalt, which is used as a sweetener in the production of Dietary Supplements (BAA) and as an Excipient in the pharmaceutical industry. The customs authority unjustifiably decided that the imported good complied with the requirements of TR CU 029/2012 and, accordingly, should be accompanied by a declaration of conformity as a food product. Due to the failure to submit the document, the Company was held administratively liable under Art. 16.3 of the Code of Administrative Offenses of the Russian Federation ("Non-compliance with prohibitions and (or) restrictions on the importation of goods into the customs territory of the Eurasian Economic Union or into the Russian Federation"), and a fine of 50,000 rubles was imposed. The Company tried to prove in court that the imported good is an Excipient for the production of drugs and the technical regulation governing requirements for food products does not extend to it. Unfortunately, these arguments did not receive a proper legal assessment in the courts, and the application was denied [3].

In another case, a Company challenged a decision of the customs authority on the classification of a chemical compound imported by it into the territory of Russia. The customs declaration stated the classification code in accordance with the the Commodity Nomenclature of Foreign Economic Activity of the Eurasian Economic Union (TN VED EAEU) – 2933 69 800 0 ("Other compounds containing an unfused triazine ring (hydrogenated or non-hydrogenated) in the structure"). The customs authority reclassified the good under TN VED EAEU code 3808 94 900 0 – ("Insecticides, rodenticides, fungicides, herbicides, anti-sprouting products and plant-growth regulators, disinfectants and similar products, put up in forms or packings for retail sale or as preparations or articles"). The dispute was considered by several judicial instances, the case was returned for a new trial to the court of first instance, examinations were conducted, and specialist opinions were obtained. After a judicial dispute lasting more than 2 (two) years, the Company succeeded in having the customs authority's decision recognized as illegal [4].

The cited examples clearly testify to the necessity of adopting a nomenclature of Excipients used in the production of medicinal products.

Requirements for Raw Materials and Excipients in the Production of Medicinal Products

Requirements for the production of medicinal products are regulated by the Rules of Good Manufacturing Practice of the Eurasian Economic Union, approved by Decision of the Council of the Eurasian Economic Commission No. 77 dated November 3, 2016 (the "GMP Rules"). They also contain requirements for raw materials and Excipients.

Let us cite the main ones:

• The selection, qualification, approval, and maintenance of the status of suppliers must be documented. Written policies, procedures, protocols, reports, and records regarding actions concerning suppliers must be available. Wherever possible, starting materials should be purchased directly from their manufacturer.
• A traceable supply chain must be established. Records regarding it must be available and retained.
• The duties of the Quality Unit (QC/QA) include: approval or rejection of starting raw materials, ensuring testing of starting raw materials and materials, and documenting the results.
• Excipients and their suppliers must be controlled based on the results of quality risk assessments.

Annex No. 7 to the GMP Rules contains requirements for the production of herbal medicinal products, including the plant raw materials used. Let us consider them in more detail.

Since seed selection, cultivation conditions, and harvesting can influence the quality of the finished medicinal product, these activities must be performed in accordance with the Good Agricultural and Collection Practice for Starting Materials of Herbal Origin (the "GACP Rules") [5].

• The GMP Rules also establish requirements for premises, equipment, quality control, and documentation used in the processing of plant raw materials.
• Plant raw materials should be stored in separate areas. They must be protected from the entry of insects and animals. Measures must be taken to prevent the spread of any animals and microorganisms.
• The manufacturer must ensure that suppliers of plant raw materials operate in accordance with the GACP Rules. Comprehensive documentation regarding audits of suppliers of starting materials of plant origin should be available.
• Specifications are a mandatory document, which are submitted and justified by the manufacturer. The specification for plant raw materials must include information on the scientific name of the plant, detailed data on its origin, information on which part of the plant is used; a description of the plant raw materials, as well as data from their macro- and microscopic examinations; data on necessary tests and methods for conducting them.
• Manufacturing formulas and processing instructions must describe the operations carried out with plant raw materials (for example, cleaning, drying, grinding, and sifting), methods for removing foreign materials, and appropriate cleaning (selection) procedures for material of plant origin before its storage.
• Personnel conducting sampling and quality control must have special training and experience working with plant raw materials, intermediate products, or herbal medicinal products.
• The identity and quality of plant raw materials, intermediate products, and herbal medicinal products should be determined in accordance with normative documentation.
• Each batch should be identified by the documentation for that batch. Reference samples of plant raw materials must be retained.

In our opinion, the need for greater regulation of requirements for the raw materials and Excipients used is evident.

Requirements for Raw Materials and Excipients during Registration of Medicinal Products and Determination of Their Interchangeability

Raw materials and Excipients used in the production of medicinal products are not subject to state registration. However, in accordance with the Rules for Registration and Expertise of Medicinal Products for Medical Use, approved by Decision of the Council of the Eurasian Economic Commission No. 78 dated November 3, 2016, the registration dossier for a medicinal product must contain detailed information on the starting materials and raw materials used in the production of the Active Pharmaceutical Ingredient and Excipients included in the composition of the medicinal product.

If an Excipient and starting material are described in a monograph of the European Pharmacopoeia, the applicant may submit a certificate of compliance with the monograph of the European Pharmacopoeia. If starting materials and raw materials or Excipients are not described in the Pharmacopoeia of the Eurasian Economic Union or pharmacopoeias of EAEU member states, a reference to a monograph of a pharmacopoeia of another state may be applicable. Within the framework of quality control of Excipients, it is necessary to submit a list of all starting materials used for the production of Excipients, indicating at which stage of the process each is applied.

The composition of Excipients in an original and generic medicinal product may differ. Exceptions are provided by Part 11 of Article 18 of the Law on Circulation of Medicinal Products. The composition of generic medicinal products:

• intended for parenteral (subcutaneous, intramuscular, intravenous, intraocular, intracavitary, intra-articular, intracoronary) administration in the form of an aqueous solution;
• solutions for oral administration;
• powders or lyophilizates for the preparation of solutions;
• ear or eye medicinal products produced in the form of aqueous solutions;
• medicinal products intended for topical application and prepared in the form of aqueous solutions;
• aqueous solutions for use in the form of inhalations using a nebulizer or as nasal sprays used via similar devices;
• must contain the same Excipients in the same quantities as the reference medicinal product. If the compositions of Excipients differ, the person who filed the application for registration of the medicinal product shall submit evidence that the Excipients used do not affect the safety and (or) efficacy of the medicinal product. In the event the applicant cannot submit such evidence, they must conduct appropriate studies to prove the absence of influence of different Excipients or auxiliary devices on the safety and (or) efficacy of the medicinal product for medical use.

We should also say a few words about the role of Excipients in determining the interchangeability of medicinal products. The interchangeability of medicinal products is determined in accordance with Article 27.1 of the Law on Circulation of Medicinal Products, including based on the criterion of equivalence or comparability of the composition of Excipients of the medicinal product.

If the compositions of Excipients differ, interchangeability may be recognized if a bioequivalence study or therapeutic equivalence study of the medicinal product is conducted, during which the absence of clinically significant differences in pharmacokinetics and (or) efficacy and safety of the medicinal product is proven. In the presence of clinically significant differences in pharmacokinetics and (or) efficacy and safety of the medicinal product, interchangeability is determined with an indication regarding the exclusion of separate groups of patients.

Summarizing, we note that the assortment of raw materials and Excipients used in production is constantly expanding; at the same time, the regulatory and legal framework for their circulation is obviously lagging. In this regard, the approval of a nomenclature of Excipients used in the production of medicinal products, and more detailed regulation of requirements for quality and control over the circulation of raw materials and Excipients in the pharmaceutical market, is an urgent problem.

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References

[1] G.N. Aleeva, M.V. Zhuravleva, R.Kh. Khafizyanova. The Role of Excipients in Ensuring Pharmaceutical and Therapeutic Properties of Medicinal Products // Chemical-Pharmaceutical Journal, 2009, Vol. 43, No. 4.

[2] Approved by Decision of the Council of the Eurasian Economic Commission No. 58 dated July 20, 2012.

[3] Resolution of the Ninth Arbitration Appellate Court dated October 10, 2022, No. 09AP-60075/2022 in Case No. A40-110991/2022.

[4] Resolution of the Thirteenth Arbitration Appellate Court dated February 20, 2023, No. 13AP-34406/2022 in Case No. A56-62306/2021.

[5] Approved by Decision of the Council of the Eurasian Economic Commission No. 15 dated January 26, 2018.