Pharmaceutical Manufacturing under GMP in Russia and EAEU

 

Anna Ivanova, Lawyer at BRACE Law Firm

February 28, 2023

 

In most countries worldwide, the manufacturing of medicinal products must comply with established regulations. International documents also exist to regulate drug manufacturing, typically applying to states cooperating within interstate unions, such as the European Union or the Eurasian Economic Union (the "EAEU"). These legal acts primarily aim to introduce universal procedures for the movement of drugs within union territories and unified rules for drug quality control.

Good Manufacturing Practice (the "GMP") is one such document. The development of GMP is driven by the increasing complexity of manufacturing processes and continuous improvement. GMP refers to a set of international rules developed for the pharmaceutical industry to guarantee the quality, purity, efficacy, and safety of medicinal products released for sale.

These rules were first adopted in the United States in 1963 and gained international status in 1968, having been revised with the participation of the World Health Organization (the "WHO"). One year later, the WHO recommended the GMP standard to all countries.[1] In 1991, new EU GMP rules (GMP EU) appeared, approved by Directive 356/91, which was later amended by Directive 2003/94 in 2003. That same year, the USSR attempted to harmonize Russian rules with international practice by introducing the RD 64-125-91 standard, which had fundamental differences from EU and WHO GMP. Only after the collapse of the USSR did CIS countries independently begin creating a regulatory framework for GMP rules.[2]

The general objective of all Good Manufacturing Practice rules is to establish an obligation for the manufacturer of medicinal products (the Marketing Authorization Holder) to manufacture them so that they guaranteedly comply with their intended use, the registration dossier, or the clinical trial protocol, and consequently do not create risks for consumers due to violations of safety, quality, or efficacy conditions. Quality assurance (quality management) is a comprehensive task covering all factors that, individually or collectively, affect product quality. The quality system includes manufacturing and quality control rules. The scope of GMP rules includes lifecycle stages such as the manufacturing of investigational medicinal products, technology transfer, and commercial manufacturing until the discontinuation of the product.[3]

The Russian Federation also has several standards for the manufacturing of medicinal products. Thus, according to Part 1, Article 45 of Federal Law No. 61-FZ dated April 12, 2010, On the Circulation of Medicinal Products (the "Law on Circulation of Medicinal Products" or "Law No. 61-FZ"), the manufacturing of medicinal products must comply with the requirements of the good manufacturing practice rules approved by the authorized federal executive body.

Under Clause 11, Part 2, Article 18 of the Law on Circulation of Medicinal Products, the registration of medicinal products in Russia requires the consent of the manufacturer of the medicinal product manufactured abroad to undergo an inspection for compliance with the good manufacturing practice rules. Alternatively, the registration application must contain information regarding the date of issue and the registration number of the conclusion on the manufacturer's compliance with the good manufacturing practice rules issued (provided) by the Ministry of Industry and Trade of Russia regarding the manufacturing site of the registered medicinal product for domestic production.

Thus, state registration of drugs strictly requires confirmation of compliance with good manufacturing practice rules. Currently, newly registered drugs are subject to registration under EAEU rules. According to Paragraph 184 of the Rules for Registration and Examination of Medicinal Products for Medical Use, approved by Decree of the Council of the Eurasian Economic Commission No. 78 dated November 3, 2016 (the "EAEU Registration and Examination Rules"), since 2021, drug registration in Russia has been conducted according to these EAEU rules. Furthermore, the registration dossier of an already registered medicinal product must be brought into compliance with EAEU requirements by December 31, 2025. According to the EAEU Registration and Examination Rules, the applicant must provide a valid document confirming that the manufacturer (manufacturing site) of the medicinal product submitted for registration complies with the EAEU good manufacturing practice rules.

Presently, both the Good Manufacturing Practice rules adopted directly in Russia, approved by Order of the Ministry of Industry and Trade of Russia No. 916 dated June 14, 2013 (the "Russian GMP Rules"), and the EAEU Good Manufacturing Practice rules, approved by Decree of the Council of the Eurasian Economic Commission No. 77 dated November 3, 2016 (the "EAEU GMP Rules"), are in effect. However, there is a policy shift toward the exclusive application of EAEU GMP in Russia, supported by several transition provisions.

Specifically, Decree of the Council of the Eurasian Economic Commission No. 96 dated June 10, 2022, approved temporary measures establishing specific features for the circulation of medicinal products for medical use. These measures include granting EAEU member states the right to establish a temporary procedure for the circulation of medicinal products (including drug registration and amendments to the registration dossier) effective until December 31, 2023, while maintaining the possibility of registration in accordance with the EAEU Registration and Examination Rules. Applicants are also granted the right to register drugs if it is impossible to submit a valid document confirming the manufacturing site's compliance with EAEU GMP requirements. If a registration application is submitted by December 31, 2023, the applicant may instead provide an application for an inspection of the manufacturing site(s) during the registration period. Based on this, such an inspection may be conducted during registration procedures or included in the inspection plan by the pharmaceutical inspectorate of the member state. Additionally, according to Decree of the EEC Board No. 42 dated March 23, 2021, drug manufacturers may submit national documents confirming GMP compliance until the end of 2024 when registering under the EAEU Registration and Examination Rules. This transition period was previously planned to end in 2020 but was extended until the end of 2024.

Several differences exist between the Russian GMP Rules and the EAEU GMP Rules. The EAEU pursues standardization and harmonization in a broader format of good pharmaceutical practices in the sphere of medicinal product circulation. These are defined as rules covering all stages of drug circulation, including good laboratory practice, good clinical practice, manufacturing practice, distribution practice, pharmacy practice, pharmacovigilance practice, and other good practices.[4]

For instance, the EAEU GMP Rules define the procedure for the transfer (transmission) of testing methodologies from the transferring laboratory to the receiving laboratory. Additionally, Paragraph 2.5 of the EAEU GMP Rules establishes that, depending on the size and structure of the organization, a head of the quality assurance department or a head of the quality department may be separately appointed. Management must ensure that their duties and powers are clearly and unambiguously defined. This provision is absent in the Russian document. The EAEU also more clearly specifies the procedure for preventing cross-contamination during drug manufacturing, specifically suggesting risk assessments to control potential cross-contamination.

Furthermore, the EAEU GMP Rules place responsibility for the functioning of the quality system on the manufacturing license holder, whereas the Russian rules state that "the manufacturer must develop and ensure the proper functioning of the pharmaceutical quality system, which includes fulfilling the requirements of these Rules and implementing quality risk management." Russian GMP rules also specify that the manufacturer must have a sufficient number of personnel with the necessary qualifications and experience, while the EAEU GMP Rules more broadly describe management's duties: "Senior management must determine and provide sufficient and appropriate resources (human, financial, material, as well as premises and equipment) to implement and maintain the quality management system and continuously improve its effectiveness." Additionally, the EAEU GMP Rules note that appropriate risk management principles using suitable tools must be included in the pharmaceutical quality system structure.

Nonetheless, Russia is currently transitioning to operating within the unified EAEU legislation, including the application of GMP. Most pharmaceutical companies have begun gradually adapting their manufacturing to EAEU GMP. Despite the legal differences between Russia and the EAEU, both sets of GMP rules share many similar provisions. Therefore, to avoid duplication in presenting the requirements of Russian and EAEU GMP, this article focuses specifically on the EAEU GMP as the legal act that will inevitably be fully integrated into Russian legislation.

The requirements of the EAEU GMP Rules are detailed below.

EAEU GMP Rules

The EAEU GMP Rules establish the general rule that the manufacturer must manufacture medicinal products to ensure they comply with their intended use, registration dossier requirements, and/or the clinical trial protocol, while minimizing risks to patients related to safety, quality, and efficacy. Senior management is responsible for fulfilling these requirements, which necessitates the participation and responsibility of personnel across various departments at all levels of the manufacturer, as well as suppliers and wholesale organizations. To this end, a quality management system is implemented at all stages of the product lifecycle: manufacturing for clinical trials, technology transfer, industrial manufacturing, and discontinuation of drug manufacturing. The pharmaceutical quality system may also extend to the pharmaceutical development stage. The quality system must be documented. Within this system, Good Manufacturing Practice is highlighted and must meet the following requirements:

• All manufacturing processes are defined and systematically reviewed in light of experience, confirming the ability to consistently manufacture medicinal products of the required quality in accordance with specifications;
• Critical stages of the manufacturing process and significant process changes must undergo validation;
• All necessary conditions for GMP compliance must be provided, including trained personnel, appropriate premises and space, equipment and maintenance, materials, containers and labels, approved procedures and instructions according to the pharmaceutical quality system, and appropriate storage and transportation conditions;
• Instructions and procedures must be written in clear and unambiguous language and must be specifically applicable;
• Procedures must be strictly followed, and personnel must be trained to perform them correctly;
• Records must be made during manufacturing to confirm that the quantity and quality of products meet the established standards;
• Any significant deviations must be fully documented and investigated to determine the cause and implement appropriate corrective actions;
• Records related to a batch (e.g., in a batch file), including distribution documentation, must be stored in a clear and accessible form to allow for a full batch history trace;
• Wholesale distribution of products must minimize risks to their quality and take into account the Good Distribution Practice rules approved by the EEC;
• A system for recalling any batch from sale or supply must be available;
• Complaints regarding supplied products must be reviewed, the causes of defects investigated, and appropriate measures taken both for substandard products and to prevent such occurrences.

To ensure these requirements, the EAEU GMP Rules establish requirements for personnel, the quality system, premises and equipment, documentation, manufacturing procedures, raw materials and technological operations, finished products, outsourced activities, product recalls and similar actions, and self-inspection.[5]

These requirements are examined in more detail below.

1. Personnel Requirements (Chapter 2 of the EAEU GMP Rules):

• The manufacturer must have a sufficient number of employees with the necessary qualifications and practical experience. Senior management must provide appropriate resources to maintain the quality management system.
• The duties and corresponding powers of employees must be defined and specified in job descriptions. Management personnel may delegate duties to designated deputies (Para. 2.1).
• Senior management must establish a quality policy defining the overall direction of the company's activities (Para. 2.3).
• The manufacturer must provide training for personnel whose job duties involve presence in manufacturing and storage areas or control laboratories (Para. 2.10).
• In addition to basic training covering the theory and practice of the quality management system and GMP, each employee must undergo initial training according to their job duties. The manufacturer must maintain training records (Para. 2.11).
• Detailed occupational hygiene programs must be developed at the enterprise, considering the specifics of the particular production. These programs must contain procedures regarding health, hygiene rules, and clothing requirements. Every employee whose duties involve presence in manufacturing and control zones must understand and strictly follow these procedures. Enterprise management should promote hygiene programs, which should be discussed during training (Para. 2.15).
• Persons hired must undergo a medical examination. The manufacturer must approve instructions ensuring its awareness of the health status of personnel that may affect product quality. Regular subsequent medical examinations must be conducted after the initial one (Para. 2.16).

2. Requirements for Premises (Chapter 3 of the EAEU GMP Rules):

• The manufacturing environment, considering all protective measures, must present a minimal risk of contamination of materials or products (Para. 3.1).
• Lighting, temperature, humidity, and ventilation must not adversely affect medicinal products during their manufacturing and storage (Para. 3.3).
• The layout of work areas and in-process storage areas must ensure a sequential placement of equipment to prevent cross-contamination and minimize the risk of missing or incorrectly performing any manufacturing or control step (Para. 3.8).
• Storage areas must ensure the orderly storage of various categories of materials and products: raw materials and packaging materials, intermediate, bulk, and finished products, as well as products in quarantine, products approved for release, and rejected, returned, or recalled products (Para. 3.18).
• Raw materials, other materials, and products must be protected from weather conditions in receiving and shipping areas (Para. 3.20).
• Storage areas for rejected, recalled, or returned materials or products must be isolated (Para. 3.23).
• Quality control laboratories must be separated from manufacturing areas and designed to meet the requirements of the work conducted therein (Para. 3.26).
• Staff break rooms and dining areas must be separated from other zones. Changing rooms, toilets, and showers must be easily accessible and must not communicate directly with manufacturing or storage areas (Paras. 30, 3.31).

Additionally, the EEC Expert Committee on Medicinal Products recommends that when performing work according to the EAEU Registration and Examination Rules, a GMP certificate issued following a pharmaceutical inspection is sufficient to confirm the manufacturing site's compliance, without listing the specific drugs produced or planned for production at the site. However, based on the evaluation of the manufacturing documents in the registration dossier, the authorized body may decide to conduct an inspection during the drug registration period or include the site in the inspection plan within the first three years after registration is completed. Thus, confirming the manufacturing site's GMP compliance during registration is recommended to be somewhat simplified.[6]

3. Equipment Requirements (Chapter 3 of the EAEU GMP Rules):

• The design of manufacturing equipment must allow for easy and thorough cleaning according to detailed written instructions. It must be installed to prevent any risk of error or contamination and must not pose a danger to the products (Para. 3.36).
• Parts of manufacturing equipment in contact with products must not react with them or affect the product quality in any way (Para. 3.39).
• Defective equipment must be removed from manufacturing and quality control areas or labeled as defective (Para. 3.44).

4. Documentation Requirements (Chapter 4 of the EAEU GMP Rules).

Two main types of documentation exist for fulfilling GMP requirements and recording compliance:

• Regulatory – instructions (directions, requirements);
• Recording – records (reports).

The appropriate good practice for documentation must be applied depending on the document type.

Main types of regulatory documents include:

• Site Master File: a document describing the manufacturer's activities in fulfilling GMP requirements;
• Specifications: documents containing detailed requirements that raw materials, packaging materials, and products used or obtained during manufacturing must meet;
• Manufacturing formulas, processing instructions, packaging instructions, and testing methodologies: documents containing detailed information on all used raw materials, equipment, and computerized systems (if any);
• Procedures (Standard Operating Procedures): documents containing requirements for performing specific operations;
• Protocols: documents containing requirements for performing and recording individual operations;
• Technical agreements: agreements concluded between customers and contractors regarding work performed by third parties (outsourcing).
• The following types of recording documents (records/reports) are also established:
• Records: evidence confirming the performance of various actions to prove compliance with instructions (e.g., activities, events, investigations). Records contain source data used to form other records;
• Certificates of Analysis: documents (passports, analytical sheets, etc.) containing a summary of sample test results for products or materials along with an assessment of compliance with established specifications;
• Reports: documents reflecting the performance of specific tasks, projects, or investigations along with results, conclusions, and recommendations.

The main requirements of the EAEU GMP Rules are listed above. Note that requirements for specific types of medicinal products and/or pharmaceutical substances are being introduced in addition to these Rules (e.g., requirements for stability studies of herbal pharmaceutical substances and herbal medicinal products, approved by Decree of the EEC Board No. 169 dated December 7, 2021).

As mentioned, GMP compliance is confirmed by a corresponding conclusion. This conclusion is of particular importance not only for state registration but also for participating in procurement.

Under Clause 1(2) of Decree of the Government of Russia No. 1289 dated November 30, 2015, On Restrictions and Conditions for the Admission of Medicinal Products Originating from Foreign States Included in the List of Vital and Essential Drugs for the Purpose of Procurement for State and Municipal Needs, confirmation of compliance is provided by the Bidder declaring information about the document confirming the manufacturer's compliance with EAEU GMP or Russian GMP, as well as information about the document containing details on the drug manufacturing stages carried out within the EAEU.

For example, in one case involving a challenge to a state Customer's decision to recognize a company without such confirmation as the winner of an electronic auction for drug supply, the supervisory authority found the complaint justified. The complainant explained that the GMP conclusion attached by the auction winner was invalid because the authorized body's inspection took place on February 20, 2019, and the conclusion is valid for three years from the inspection date—until February 20, 2022. Thus, the GMP conclusion had expired by the time the bids were reviewed, as confirmed by the state registry of GMP conclusions on the website of the Ministry of Industry and Trade of Russia. The auction winner's representative argued that the conclusion was extended under Decree of the Government of the Russian Federation No. 353 dated March 12, 2022, On Specifics of Licensing Activities in the Russian Federation in 2022. However, the Moscow FAS rejected this argument because, at the time of the bid review, the Ministry of Industry and Trade had not made the corresponding decision, and no order had been issued to extend GMP conclusions that expired in 2022. This indicated that an invalid GMP conclusion was submitted in the bid.[7]

The procedure for obtaining a certificate of compliance with the EAEU Good Manufacturing Practice rules is examined below.

Procedure for Obtaining EAEU GMP Compliance Certificates in Russia

By Decree of the Government of Russia No. 1446 dated September 15, 2020, the Ministry of Industry and Trade of Russia was designated as the authorized body for implementing EEC Council Decisions No. 83 and No. 82, including the issuance of certificates to drug manufacturers for their compliance with EAEU GMP requirements. The Department for the Development of the Pharmaceutical and Medical Industry of the Ministry of Industry and Trade of Russia directly provides this state service.

The procedure for exercising these powers and for submitting and reviewing relevant applications is established in the Administrative Regulation for the provision of the state service of issuing EAEU GMP compliance certificates, approved by Order of the Ministry of Industry and Trade of Russia No. 2945 dated September 4, 2020 (the "Administrative Regulation").

To obtain a certificate, the manufacturer must submit a hard-copy application to the Ministry of Industry and Trade of Russia, either in person or by registered mail with return receipt and an inventory of contents, along with the following documents:

• A copy of the document confirming the powers of the manufacturer's representative;
• A copy of the Site Master File according to EAEU GMP requirements;
• A list of medicinal products manufactured (planned for manufacturing) at the manufacturing site.

If the manufacturer is a non-resident, it must additionally provide a certified copy of the document granting the right to manufacture medicinal products at the manufacturing site, a certified copy of the document issued by the authorized body of the manufacturing country regarding the site's compliance with the GMP rules applied in that country (if available), and a letter of consent from the non-resident manufacturer to undergo a pharmaceutical inspection.

If the application or attached documents contain incomplete or unreliable information, the Ministry of Industry and Trade of Russia notifies the applicant. The deadline for correcting deficiencies is 20 business days from the date of receipt of the notice.

The timeframe for issuing the certificate starts from the date the application and the full set of documents are received and is carried out in accordance with the Rules for Conducting Pharmaceutical Inspections, approved by Decree of the Council of the Eurasian Economic Commission No. 83 dated November 3, 2016 (the "GMP Inspection Rules"). These rules contain a similar list of documents and establish that an inspection program is prepared within 30 business days of the start of the inspection. The Ministry of Industry and Trade of Russia makes a decision to issue (or refuse to issue) the certificate within a period not exceeding 90 (ninety) calendar days after the last day of the final inspection.

Grounds for refusal to issue a certificate include:

• Failure to submit a properly executed application and set of documents;
• A decision by the authorized institution to refuse the pharmaceutical inspection if the costs associated with the inspection are not paid on time;
• Non-compliance of the manufacturer (including non-resident manufacturers) with EAEU GMP rules.

Fees are charged for conducting pharmaceutical inspections of manufacturers to issue a certificate of compliance with EAEU GMP for medicinal products submitted for registration and intended for circulation on the common market of the EAEU, as well as for non-resident manufacturers. The fee is determined for each applicant individually according to the Procedure and Amount of Fees for Pharmaceutical Inspections, approved by Decree of the Government of the Russian Federation No. 352 dated May 6, 2011, under which the applicant bears the full cost of the inspection.

A refusal to issue a certificate may be appealed by filing a complaint with the head of the Ministry of Industry and Trade or their deputy. The timeframe for reviewing the complaint by the authorized official is 15 (fifteen) business days from its registration. If the appeal concerns a refusal to accept documents or a failure to correct errors, the timeframe is reduced to 5 (five) business days.

Paragraph 1.3 of the EAEU Good Manufacturing Practice specifies the content of the Site Master File submitted for the certificate. It must contain sufficient information but, as far as possible, should not exceed 25–30 pages, excluding appendices. The dossier is submitted in hard copy in A4 format.

The dossier must consist of the following sections:

1. General information about the manufacturer (name, address, phone number, Taxpayer Identification Number (INN), copy of the pharmaceutical activity license with a brief description of activities if not covered by the license, data on types of drugs manufactured, and a list of site inspections over the last five years).
2. Manufacturer's quality management system, including:

• Description of the quality management system, responsibility for maintaining the quality system, and information on activities for which the enterprise is accredited and certified;
• Description of the procedure for authorizing the release of finished products and the supplier and contractor management system;
• Quality risk management (description of the methodology);
• Product quality reviews with a description of the methodology.

3. Personnel, including the organizational structure chart indicating positions in quality management, manufacturing, and quality control, as well as the number of personnel.
4. Premises and equipment, including a description and plan of the premises, plans of manufacturing, storage, and other areas, description of product storage conditions, and a list of main equipment with descriptions.
5. Documentation, indicating the description of the documentation system (e.g., electronic, manual) and types of documents.
6. Technological process, indicating types of products manufactured, process validations, material management, and warehousing.
7. Quality control, including a description of quality control activities at the site.
8. Distribution, complaints, product defects, and recalls. This section must list the types of organizations (distribution license holders, manufacturing license holders, etc.) with a description of the system for ensuring appropriate conditions during transportation, distribution organization, and product traceability methods. It also includes a description of the system for handling complaints, defects, and recalls.
9. Self-inspection, including a brief description of the self-inspection system with specific focus on criteria for selecting inspected areas, practical measures, and follow-up actions.

This procedure regulates the specifics of obtaining an EAEU GMP compliance certificate. Despite transition provisions allowing domestic manufacturers to use Russian GMP compliance conclusions, in the near future, all manufacturers selling products on the Russian pharmaceutical market will face the necessity of obtaining an EAEU GMP certificate by submitting documentation to the Ministry of Industry and Trade under the Administrative Regulation. Foreign investors may delegate the duty to obtain such certificates to Russian partners by concluding appropriate agreements.

Contract Manufacturing of Medicinal Products under GMP

In effect, drug registration for sale on the Russian market implies mandatory certification of compliance with Good Manufacturing Practice rules.

Foreign investors may manufacture drugs in Russia by delegating the acquisition of relevant certificates and permits to Russian pharmaceutical companies through contract manufacturing.

Contract manufacturing is a type of production where the Customer instructs a contractor—a Contract Manufacturing Organization (the "CMO")—to manufacture products at the contractor's facilities. it may involve performing individual stages of manufacturing and quality control or the full cycle of product manufacturing.[8]

Thus, under Paragraph 1.6.5 of the EAEU Registration and Examination Rules, a copy of the contract (agreement) between the contract manufacturing site and the manufacturer regarding GMP compliance may be submitted among the manufacturing documentation if the entire process or one stage of drug manufacturing is carried out at a contract site.

Under Paragraph 2.9 of EAEU GMP, the heads of manufacturing and quality control, as well as the head of quality assurance or the quality service (if necessary), generally have shared or jointly performed duties related to product quality assurance, including the development, effective implementation, maintenance, and monitoring of the quality management system. These duties may include approving and monitoring organizations performing work under contract and suppliers of other GMP-related outsourced services.

In the pharmaceutical industry, full-cycle contract manufacturing allows for the localization of drug production at a partner's facilities in Russia. This, in turn, enables not only investment optimization but also the acquisition of preferences in state tenders and additional points when including drugs in the List of Vital and Essential Drugs (the "VED List").[9]

Supplement No. 1 to the EAEU GMP Rules establishes requirements for quality risk management methods and tools, introducing a method such as Hazard Operability Analysis (the "HAZOP"). This section of the EAEU GMP Rules provides that HAZOP may be applied to manufacturing processes (including contract manufacturing), as well as to suppliers, equipment, and premises for the manufacturing of active pharmaceutical ingredients and medicinal products. HAZOP is primarily used in the pharmaceutical industry for process safety assessment. The result of HAZOP (like HACCP) is a list of critical operations for risk management. This facilitates regular monitoring of critical points during the manufacturing process. Thus, EAEU GMP explicitly provides for the possibility of contract manufacturing.

Paragraph 1.6.5 of the EAEU Registration and Examination Rules establishes that a certified copy of the contract (agreement) between the contract manufacturing site and the manufacturer regarding GMP compliance must be submitted for registration if the entire process or one stage of drug manufacturing is carried out at a contract site.

According to Paragraph 45 of Decree of the Government of Russia No. 1556 dated December 14, 2018, On Approval of the Regulations on the System for Monitoring the Movement of Medicinal Products for Medical Use, an entity carrying out contract manufacturing in Russia must submit relevant information to the monitoring system within five business days of transferring the medicinal products (finished products) to the customer. The customer of the contract manufacturing must confirm the accuracy of the information regarding the transferred drugs within five business days of receipt and registration in the monitoring system.

These norms indicate that current Russian and EAEU legislation establishes mechanisms for regulating drug circulation considering contract manufacturing.

Furthermore, when pharmaceutical manufacturers participate in state procurement, the "Third is Odd" rule applies, under which the state Customer rejects bids for foreign-made goods if at least two bids meeting the procurement requirements have been submitted. These restrictions will not apply to a drug if its manufacturing stages are sufficiently localized (e.g., full-cycle manufacturing in Russia), regardless of whether production is localized at a plant owned by an investing multinational group in Russia or at the facilities of a third-party Russian manufacturer.[10]

When performing contract manufacturing, it is critical to carefully detail issues related to GMP compliance when using partners' manufacturing sites and personnel, as well as who bears responsibility for obtaining compliance certificates.

This article examined the main legal requirements for pharmaceutical manufacturing under GMP. We believe the primary trend in the legal regulation of pharmaceutical manufacturing under Good Manufacturing Practice is the unification of current legislation with EAEU legislation to create a unified medicinal product market within the Eurasian Economic Union. However, this process is not rapid, which is why transition periods are established and extended to maintain domestic manufacturers on the market that previously confirmed compliance with the national good manufacturing practice adopted before EAEU GMP.

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References

1. History and prerequisites for introducing good manufacturing practice standards into the pharmaceutical industry (review). Toktonalieva N.U., Toktonaliev I.U. // Bulletin of Science and Practice. 2020.
2. GMP Quality Standard. Praksina E.
3. EU GMP Rules 2019.
4. Shakhnazarov B.A. EAEU Pharmacopoeia as a harmonizing basis for medicinal product quality requirements in the EAEU and beyond // Actual Problems of Russian Law. 2022. No. 11. P. 183–193.
5. The right of citizens to medicinal provision: monograph / N.V. Putilo, N.S. Volkova, F.V. Tsomartova et al.; M.: IZiSP, KONTRAKT, 2017. 216 p.
6. Recommendation of the Eurasian Economic Commission No. 77 dated August 17, 2022, On the provision of documents confirming the compliance of the manufacturing site(s) of a medicinal product with good manufacturing practice requirements.
7. Decision of the Moscow FAS Russia dated May 18, 2022, in Case No. 077/06/106-7214/2022.
8. Key GMP elements of contract manufacturing of medicinal products. Morozov K. // Pharmprom.
9. Contract manufacturing at the Servier plant: how it works. October 4, 2021.
10. Contract manufacturing of medicinal products in the Russian Federation: practical aspects. A. G. Odabashyan, A. S. Morozova // Development and Registration of Medicinal Products. 2016. No. 3 (16).