Active Pharmaceutical Ingredients (APIs) in Russia: Legal Regulations

February 28, 2023

BRACE Law Firm ©

 

Provision of citizens with medicinal products is one of the most important tasks of any state and a matter of national security. Recent years have clearly demonstrated the dependence of the Russian pharmaceutical market on import supplies, not only of medicinal products themselves but also of their direct components and auxiliary materials, such as packaging and packaging materials.

The basis of any medicinal product is an active pharmaceutical ingredient; the efficacy of the medicine largely depends on it. Therefore, in the current situation, it is extremely important to establish the production of APIs in Russia, as well as to exercise control over their circulation.

In this article, we will analyze what active pharmaceutical ingredients are, and the requirements established by legislation for the production of APIs for medical use and their circulation on the market.

Concept of Active Pharmaceutical Ingredient

Before analyzing the topic, let us clarify the relationship between the concepts of "medicinal agent," "medicinal product," and "active pharmaceutical ingredient."

The fundamental regulatory act governing the circulation of medicinal agents in Russia is Federal Law No. 61-FZ dated April 12, 2010, On the Circulation of Medicinal Products (the "Law on Circulation of Medicinal Products"), Article 4 of which provides the main conceptual apparatus.

Thus, medicinal agents include active pharmaceutical ingredients and medicinal products. Under "medicinal products", the law understands medicinal agents in the form of dosage forms used for prevention, diagnosis, treatment of disease, rehabilitation, and for preservation, prevention, or termination of pregnancy.

Thus, a medicinal product represents a finished product used for the treatment, prevention, or diagnosis of diseases. The composition of every medicinal product includes active pharmaceutical ingredients aimed at eliminating pathological symptoms, as well as excipients used to give medicinal products the necessary physicochemical properties.

In turn, an active pharmaceutical ingredient (pharmaceutical substance) is a medicinal agent in the form of one or several active substances possessing pharmacological activity, regardless of the nature of origin, intended for the production, manufacturing of medicinal products and determining their efficacy.

Thus, based on the definition given by the legislator, the following features of an API can be distinguished. It:

• represents a substance or a combination of substances that may have different origins:
  • plant or animal, if extracted from living organisms;
  • mineral, if extracted from objects of inorganic nature;
  • biotechnological, if obtained by processing biological raw materials;
  • chemical, if synthesized and does not occur in nature.
• possesses pharmacological activity, i.e., a set of effects caused by the administration of this substance into the body and used in the treatment or prevention of diseases;
• is intended for the manufacturing or production of medicinal products.

Inclusion of Active Pharmaceutical Ingredients in the State Register of Medicinal Products

Another important difference between APIs and medicinal products is that they are not subject to registration and, accordingly, do not have a Registration Certificate (Clause 5, Part 5, Article 13 of the Law on Circulation of Medicinal Products).

At the same time, by virtue of Article 34 of the Law on Circulation of Medicinal Products, information on them must be entered into the State Register of Medicinal Products (the "SRMP"), with the exception of those produced for clinical studies and export. Two methods are provided for including active pharmaceutical ingredients in the SRMP:

1. Within the framework of state registration of a medicinal product, if the substance included in the composition of the medicinal product is used only for the production of this medicinal product. In this case, information is entered into Clause 11 of the registry entry for the medicinal product in the SRMP: the name of the substance, the name and address of its manufacturer, shelf life and storage conditions, the number of the pharmacopoeial monograph or other normative documentation based on which production is carried out, and presence in the list of narcotic drugs, psychotropic substances, and their precursors. Examination of the quality of such an API during the registration of the medicinal product is not conducted.

2. Within the framework of a separate state service "Inclusion in the State Register of Medicinal Products of a pharmaceutical substance produced for sale," if the active pharmaceutical ingredient is produced for independent sale.

Information on such a substance is entered into the SRMP in a separate tab "Pharmsubstances" indicating the name of the API (INN or grouping (chemical) and trade name), the name and address of the manufacturer, information on the registration of the substance manufacturer as a taxpayer in the country of registration (also regarding medicinal agents for medical use), shelf life and storage conditions, the number of the pharmacopoeial monograph or other normative documentation based on which production is carried out, and presence in the list of narcotic drugs, psychotropic substances, and their precursors.

Prior to inclusion in the SRMP, an examination of the quality of the active pharmaceutical ingredient is performed. To conduct it, the applicant (developer, manufacturer, or authorized person) submits the following package of documents to the Ministry of Health of Russia (for APIs produced for medical use):

• application for inclusion in the SRMP;
• information on the license for the production of medicinal agents, and for foreign manufacturers – on the production permit issued by the authorized body of the manufacturer's country, and a conclusion on compliance with GMP rules;
• technical document for the substance (description of its structure and properties, production technology and control methods at all stages of production, confirmation (validation) of production processes and analytical methods used in quality control, stability data, etc.);
• information on the registration of the manufacturer company in the country of registration;
• application for the issuance of a permit to import into the Russian Federation a specific batch of an unregistered medicinal agent intended for conducting the said examination.

For the review of documents on the inclusion of an active pharmaceutical ingredient in the SRMP, a state duty in the amount of 253,000 rubles is paid (Clause 17, Part 1, Art. 333.32.1 of the Tax Code of the RF).

Within 10 business days from the date of acceptance of the application, the Ministry of Health of Russia verifies the documents for completeness and reliability and sends an assignment to conduct a quality examination to an expert institution (FSBI "SCEMP") or notifies the applicant of refusal with reasons.

Additionally, the applicant provides the expert institution with samples of the API in the quantity necessary to reproduce the quality control methods. The quality examination and the drafting of a conclusion based on its results are carried out by the expert organization within 60 business days.

Based on the results of the received conclusion, within 5 business days, the Ministry of Health of Russia makes a decision to include the substance in the SRMP or to refuse such inclusion. The basis for refusal to include an active pharmaceutical ingredient in the SRMP is the conclusion that the quality of the API is not confirmed by the data obtained. It is not permitted to include one active pharmaceutical ingredient produced for sale and manufactured by the same manufacturer in the SRMP in the form of two or more registry entries.

In case of changes to the documents for an API, amendments are made to the SRMP. At the same time, the circulation of produced active pharmaceutical ingredients is allowed within 180 days before and after the decision to amend the SRMP (Part 12 of Article 34 of the Law on Circulation of Medicinal Products).

Exclusion from the SRMP is carried out in the following cases:

• upon the application of the developer or manufacturer;
• absence of the API in circulation in the Russian Federation for 3 (three) or more years;
• submission of a conclusion on the risk or threat to the life or health of a human or animal when using the medicinal agent.

Refusal to conduct examinations and (or) issue permit documents may be appealed in court. The challenge is carried out according to the rules of Chapter 24 of the APC RF "Challenging non-normative legal acts, decisions, and actions (inaction) of state authorities." In court, it will be necessary to prove the following circumstances in aggregate:

• non-compliance of the challenged decision, action (inaction) with the law or other legal act;
• violation of the rights and legitimate interests of the applicant in the sphere of entrepreneurial and other economic activity or illegal imposition of any duties on them, creation of other obstacles to carrying out entrepreneurial and other economic activity.

Thus, in one case, a Company applied to the arbitration court with a statement challenging the refusal to send an assignment to an expert institution to conduct a quality examination of an active pharmaceutical ingredient. Upon consideration of the case, the court agreed with the position of the state body that the documents attached to the application for registration in the SRMP did not comply with the requirements of Article 34 of the Law on Circulation of Medicinal Products, namely: the characterization of impurities was not presented in full, documentary confirmation (validation) of analytical methods was absent, results of the analysis of batches of the API were presented for only one instead of two batches of the substance, the presented stability study contradicted other information, etc. The court refused to satisfy the application. At the same time, it indicated that the applicant is not deprived of the possibility to re-submit the application to the state body after eliminating the deficiencies [1].

Requirements for the Production of Active Pharmaceutical Ingredients

Production of an API includes all stages of the technological process allowing to obtain a finished product, from the acceptance of materials, operations directly for the production of the substance (fermentation, extraction, purification, isolation, recrystallization, drying, grinding), quality control, issuance of release permission, storage, and up to sale.

The main requirements for the production of active pharmaceutical ingredients are contained in the Rules of Good Manufacturing Practice (GMP) of the Eurasian Economic Union [2] (the "GMP EAEU Rules").

The GMP EAEU Rules establish that in the production of medicinal products, only those APIs that are produced in compliance with the said Rules may be used. Furthermore, by virtue of Part 4 of Article 45 of the Law on Circulation of Medicinal Products, only active pharmaceutical ingredients included in the SRMP are used in the production of medicinal agents.

The GMP EAEU Rules detail the requirements for premises and equipment used in production, personnel, documentation maintenance, and quality control measures. Let us consider the main requirements for the production of APIs:

1. Requirements for buildings and premises.

The design of premises, equipment, and decoration must facilitate the minimization of the risk of contamination of raw materials, materials, and finished products. Buildings used in the production of intermediate products should be properly maintained, repaired, and kept clean. Written procedures defining the conduct of sanitation, disinfection, and disinfestation must be developed.

Premises must be divided into zones: acceptance, storage, production zones, laboratory zones. Production zones for substances with infectious properties, high pharmacological activity, or toxicity are specifically allocated.

All engineering systems should be controlled, and measures taken if permissible limits are exceeded. If necessary, appropriate ventilation and air filtration systems, as well as exhaust devices, should be provided to minimize the risk of contamination and cross-contamination. They must also be equipped with equipment to control air pressure, the presence of microorganisms (if necessary), dustiness, humidity, etc.

2. Requirements for process equipment.

Main equipment and technological lines used in production should be appropriately identified. Equipment is positioned in such a way that personnel can carry out cleaning, disinfection (if necessary), and maintenance. Written procedures regarding the order of preventive maintenance of equipment must be developed and observed.

3. Requirements for personnel.

There is a requirement for a sufficient number of personnel having appropriate education, training, and (or) practical experience to carry out the production of active pharmaceutical ingredients, as well as supervision over their production. The duties of all personnel engaged in production must be precisely defined and set out in writing. It is necessary to regularly conduct personnel training involving qualified specialists, at a minimum, on issues related to specific operations performed by the employee.

4. Requirements for documentation.

All production, control, and distribution records should be stored for at least 1 year after the expiration of the batch shelf life. Records containing data on re-tests of API should be stored for at least 3 years after the full sale of the batch.

Requirements for various stages of production and records made at these stages are regulated in detail.

A mandatory condition for granting a license for the production of medicinal agents is the attachment to the license applicant's application of a list of types of active pharmaceutical ingredients that the manufacturer of medicinal agents intends to produce (Part 2 of Article 8 of the Law on Circulation of Medicinal Products). At the same time, in accordance with the Regulation on Licensing of Production of Medicinal Agents approved by Decree of the Government of the Russian Federation No. 686 dated July 6, 2012 (the "Decree No. 686"), the following production operations with APIs are subject to licensing:

• Production of active pharmaceutical ingredients by chemical synthesis method.
• Production of APIs by isolation from natural sources (separately by types of sources: plant, animal, mineral origin, from human organs (tissues)).
• Production of active pharmaceutical ingredients using biological processes.
• Production of sterile APIs.
• Final stages of production of active pharmaceutical ingredients (packaging), quality control tests, storage, and sale.

Licensing of activities for the production of medicinal agents for medical use is carried out by the Ministry of Industry and Trade of the Russian Federation.

The main requirements for license applicants are set forth in Clause 4 of Decree No. 686:

• availability of premises, buildings, and other objects, technical means, equipment, and technical documentation belonging on the right of ownership or other legal basis, necessary for performing the declared works;
• compliance of production with the rules of good manufacturing practice (GMP);
• availability of industrial regulations (promyshlenny reglament) approved by the manufacturer's head and including data on the equipment used and a description of the technological process and control methods at all stages of production;
• availability of a Qualified Person responsible for the implementation and maintenance of the quality system, who is certified and included in the register of Qualified Persons;
• availability of employees who have concluded employment contracts, having respectively higher or secondary vocational pharmaceutical, chemical, chemical-technological, biological, biotechnological, medical, or veterinary education, responsible for production, labeling, and quality control of medicinal agents.

In addition to the above, increased requirements are imposed on the licensee:

• prohibition on the production and sale of falsified, substandard, and counterfeit medicinal agents, or with violation of the GMP EAEU Rules;
• compliance with the rules for storage of medicinal agents;
• compliance with the rules for the destruction of substandard, falsified, and counterfeit medicinal agents;
• professional development of Qualified Persons at least once every 5 years.

For applicants and licensees carrying out the production of the active pharmaceutical ingredient of ethyl alcohol (ethanol), additional requirements are established, such as:

• containers for receiving ethyl alcohol must be equipped with automatic means of measurement and accounting for the concentration and volume of anhydrous alcohol in ethyl alcohol, and the volume of ethyl alcohol;
• equipment for accounting for the volume of turnover and use of ethyl alcohol or its API must be equipped with technical means for fixing and transmitting information on the volume of production and turnover to the USAIS (EGAIS).

Non-compliance with GMP requirements is regarded by controlling bodies as a violation of license requirements and entails administrative liability under Parts 3 and 4 of Article 14.1 of the CAO RF. The maximum penalty for carrying out activities with a gross violation of license requirements for individual entrepreneurs is up to 8,000 rubles or administrative suspension of activity for up to 90 days; for officials – up to 10,000 rubles; for legal entities – up to 200,000 rubles or administrative suspension of activity for up to 90 days.

Let us consider an example from judicial practice. A control body conducted a scheduled inspection of an Enterprise carrying out the production of medicinal agents. Based on the results of the inspection, non-compliance with GMP Rules was revealed: the raw material and material acceptance zone was not equipped, an isolated zone for rejected, recalled products was absent, a procedure for quality risk management was not presented, and training of enterprise employees was not organized. Based on the fact of violation of license requirements, the administrative body drew up a protocol on an administrative offense provided for by Part 4 of Art. 14.1 of the CAO RF and sent it to the arbitration court. The court decided that in accordance with Clause 5 of Decree No. 686, compliance with GMP Rules is one of the license requirements. The Enterprise was held administratively liable under Part 4 of Art. 14.1 of the CAO RF, and a penalty was imposed in the form of an administrative fine in the amount of 100,000 rubles [3].

Requirements for Packaging and Labeling of Active Pharmaceutical Ingredients

Requirements for the packaging and labeling of APIs entering circulation are established in Part 2 of Article 46 of the Law on Circulation of Medicinal Products and the pharmacopoeial monograph "Pharmaceutical Substances" [4].

Thus, the primary packaging must indicate in a clearly legible font in Russian: the name of the active pharmaceutical ingredient (INN or grouping, or chemical and trade names), the name of the manufacturer, batch number and date of manufacture, quantity in the package, shelf life, and storage conditions. Information on the purpose of the substance and precautionary measures must be present. Packaging and storage conditions must ensure the quality of the substance during the established shelf life.

Discrepancy in labeling and packaging is also regarded by controlling bodies as a violation of license requirements and conditions. At the same time, not only manufacturers of substances but also wholesale and retail trade organizations may be held administratively liable. Thus, in one case, the Territorial Body of Roszdravnadzor, while exercising control over pharmaceutical activities, revealed that the labeling of APIs in circulation at a Pharma Organization did not comply with the Rules for manufacturing and dispensing medicinal products for medical use. It applied to the arbitration court with a statement to hold the Pharma Organization administratively liable under Part 4 of Article 14.1 of the CAO RF for a gross violation of license requirements. The court agreed that the actions of the Pharma Organization contained signs of the composition of the imputed administrative offense, but did not find a significant threat to protected public relations, and recognized the offense as insignificant [5].

Import of APIs

Production capacities deployed in Russia do not cover the entire need for active pharmaceutical ingredients necessary for the production of domestic medicinal products. In this regard, the issue of importing APIs has not lost its relevance.

The rules for importing medicinal agents into the territory of Russia, including active pharmaceutical ingredients, are regulated by Article 47 of the Law on Circulation of Medicinal Products and Decree of the Government of Russia No. 853 dated June 1, 2021 [6].

As a general rule, medicinal agents imported into the Russian Federation must be contained in the State Register of Medicinal Products. This rule applies, among other things, to APIs.

The import into the Russian Federation of a specific batch of unregistered active pharmaceutical ingredients for its inclusion in the SRMP is permitted based on a permit issued by the Ministry of Health of Russia. The consideration of the application is carried out within a period not exceeding 5 (five) business days. No fee is charged for the issuance of the said permit.

The quality of the imported goods must be confirmed by a medicinal agents manufacturer's certificate, certifying its compliance with the requirements of pharmacopoeial monographs or other normative documents.

For violation of quality requirements, the risk of being held administratively liable for false declaration of imported goods is not excluded. Thus, in one case, a pharmaceutical enterprise was held liable under Part 3 of Article 16.2 of the CAO RF with the imposition of a fine in the amount of 100,000 rubles. The customs authority established that the enterprise carried out the import into the Russian Federation of an active pharmaceutical ingredient, the quality of which was not confirmed by the manufacturer's certificate. It was not possible to challenge the ruling issued by the customs authority in court [7].

In conclusion, the measures of state support for Russian manufacturers of APIs should also be briefly considered. Until recently, the main manufacturers of active pharmaceutical ingredients were China and India. The global situation developed in recent years, the spread of COVID-19, and the introduction of economic sanctions against Russia, have once again highlighted the importance of developing domestic pharmaceutical industry. To overcome dependence on foreign components of medicines, the state has taken a course towards import substitution.

Thus, back in 2014, the State Program "Development of the Pharmaceutical and Medical Industry" was approved [8]. One of the directions of the program is establishing a full cycle of production of medicinal agents in Russia, starting from the production of the API to the release control of the finished medicine. By the end of 2030, it is planned to increase the share of strategically significant medicinal agents, the production of which is carried out according to the full production cycle in Russia, to 90%. The solution of these tasks should be ensured by providing budgetary allocations to capital construction objects for the creation of production and development of production capacities, as well as providing support measures, including granting advantages in state procurement taking into account the depth of production localization.

Undoubtedly, the support measures for pharmaceutical production taken by the state deserve a positive assessment. However, in our opinion, to achieve the indicated indicators, it is necessary to improve regulatory and legal regulation and expand state support measures, including by concluding offset and special investment contracts (SPIC) on a parity basis between business and the state, providing tax incentives, and long-term loans on concessional terms.

____________________

References

[1] Resolution of the Ninth Arbitration Appeal Court dated November 25, 2020, No. 09AP-59175/2020 in case No. A40-99359/20.

[2] Approved by Decision of the Council of the Eurasian Economic Commission No. 77 dated November 3, 2016.

[3] Decision of the Arbitration Court of the Moscow Region dated June 10, 2021, in case No. A41-33576/2021.

[4] OFS. 1.1.0006.15. General Pharmacopoeial Monograph. Pharmaceutical Substances, approved by Order of the Ministry of Health of Russia No. 749 dated October 31, 2018.

[5] Decision of the Arbitration Court of the Vladimir Region dated December 1, 2021, in case No. A11-12185/2021.

[6] Decree of the Government of Russia No. 853 dated June 1, 2021, On Approval of the Rules for Import of Medicinal Agents for Medical Use into the Russian Federation and on Invalidating Certain Acts and Certain Provisions of Certain Acts of the Government of the Russian Federation.

[7] Resolution of the Arbitration Court of the Moscow District dated October 4, 2016, No. F05-13984/2016 in case No. A41-108815/2015.

[8] Decree of the Government of Russia No. 305 dated April 15, 2014, On Approval of the State Program of the Russian Federation 'Development of the Pharmaceutical and Medical Industry'.