GMP Inspections in Russia and the EAEU: Procedures and Rules

 

Anna Ivanova, Associate at BRACE Law Firm ©

March 20, 2023

 

In 2023, the global pharmaceutical industry will celebrate an important anniversary—60 years since the introduction of the first Good Manufacturing Practice (GMP) rules. This abbreviation has become as firmly established in the lexicon of Russian pharmaceutical market participants as its Russian translation — Nadlezhashchaya proizvodstvennaya praktika.

In Russia, the first attempt to harmonize with European GMP rules was made in 2004 with the introduction of GOST R 52249-2004. Subsequently, Order of the Ministry of Industry and Trade of Russia No. 916 dated June 14, 2013, On Approval of the Rules of Good Manufacturing Practice, was adopted [1]. In 2016, to harmonize the legislation of the Eurasian Economic Union (EAEU) Member States, the Board of the Eurasian Economic Commission adopted the Rules of Good Manufacturing Practice (Decision of the EEC Board No. 77 dated November 3, 2016).

Currently, the Rules of Good Manufacturing Practice of Russia, approved by the Ministry of Industry and Trade of the Russian Federation (the "GMP Russia"), and the Rules of Good Manufacturing Practice of the EAEU (the "GMP EAEU") are effectively in force. Certificates of GMP compliance are necessary for the state registration of medicinal products on the pharmaceutical markets of Russia and/or the EAEU. Currently, Order of the Ministry of Industry and Trade of Russia No. 1987 dated May 18, 2022, extended the validity of conclusions on the compliance of a medicinal product manufacturer with GMP Russia requirements for medicinal products with conclusions expiring between January 1, 2022, and December 31, 2022, by one year, essentially until the end of 2023 [2].

The Eurasian Economic Commission decided to automatically extend the validity of all permits issued under EAEU law, i.e., marketing authorizations for medicinal products and GMP compliance certificates, until the end of 2023. Simultaneous performance of inspections of manufacturing sites for compliance with GMP requirements, including through remote inspection, and registration of medicinal products under EAEU rules, as well as conducting such GMP inspections in the post-registration mode, is also permitted [3].

However, verifying the compliance of medicinal product manufacturing with both GMP Russia and GMP EAEU requires an inspection. Russia and the EAEU have established different procedures for conducting inspections, although they are similar in many respects.

The Rules for Organization and Conduct of Inspection of Medicinal Product Manufacturers for Compliance with the Requirements of the Rules of Good Manufacturing Practice, as well as the Issuance of Conclusions on the Compliance of the Medicinal Product Manufacturer with Said Requirements, were approved by Decree of the Government of Russia No. 1314 dated December 3, 2015. This document was adopted to inspect pharmaceutical manufacturers to confirm compliance with GMP Russia (the "Rules for Inspection for Compliance with GMP Russia"). Clause 2 of said Rules for Inspection for Compliance with GMP Russia defines "inspection" as the activity of the Ministry of Industry and Trade of Russia (Minpromtorg Russia) or a federal state budgetary institution subordinate to Minpromtorg Russia, aimed at confirming the compliance of a medicinal product manufacturer with the requirements of the rules of good manufacturing practice of the Russian Federation.

Within the EAEU framework, Decision of the Council of the Eurasian Economic Commission No. 83 dated November 3, 2016, approved the Rules for Conducting Pharmaceutical Inspections. According to Clause 5 of these rules, an inspection is a stage of a pharmaceutical inspection during which an inspection team carries out measures in accordance with the inspection program (the "Rules for Inspection for Compliance with GMP EAEU"). The term "pharmaceutical inspection" is used as defined in the General Requirements for the Quality System of Pharmaceutical Inspectorates of the Member States of the Eurasian Economic Union, approved by Decision of the Council of the Eurasian Economic Commission No. 82 dated November 3, 2016 (the "Requirements for the Quality System of EAEU Pharmaceutical Inspectors"). These Requirements define "pharmaceutical inspection" as the assessment of medicinal product circulation entities, including healthcare organizations, to establish the compliance of pharmaceutical manufacturing and other activities regarding the circulation of medicinal products with acts constituting EAEU law. Thus, this term implies that a pharmaceutical inspection may also be conducted to verify compliance with other requirements established by the EAEU. Nevertheless, according to Clause 1 of the Rules for Inspection for Compliance with GMP EAEU, they establish a unified procedure for the pharmaceutical inspectorate to conduct pharmaceutical inspections of medicinal product manufacturing for compliance with GMP EAEU requirements.

This article examines the specifics of conducting inspections in both Russia and the EAEU in accordance with the aforementioned Rules.

Rules for Conducting Inspections for Compliance with GMP Russia

According to Order of the Ministry of Industry and Trade of Russia No. 4184 dated December 21, 2015, the Federal Budgetary Institution "State Institute of Drugs and Good Practices" (the "FSI 'SID & GP'") is authorized to inspect manufacturers of medicinal products whose manufacturing is carried out outside the Russian Federation for compliance with GMP Russia requirements to issue conclusions on their compliance. However, in accordance with Decision of the Council of the Eurasian Economic Commission No. 34 dated April 23, 2021, On Amendments to the Rules for Registration and Expertise of Medicinal Products for Medical Use, the issuance of conclusions on the compliance of medicinal product manufacturers with good manufacturing practice requirements under the national procedure ceased on January 1, 2022. In this regard, we will briefly review the inspection rules under the national procedure and focus in more detail on inspections under EAEU legal acts.

The Rules for Organization and Conduct of Inspection approved by Decree of the Government of Russia No. 1314 dated December 3, 2015, established that to issue a conclusion, the manufacturer submitted an application for the issuance of a conclusion with a copy of the site master file, information on identified non-conformities of medicinal product quality with established requirements, including the recall of medicinal products from civil circulation for a period of at least 2 years prior to the application, a list of manufactured medicinal products, and a copy of the license and a consent letter from the foreign manufacturer for the inspection. Conclusions were to be issued for each manufacturing site. Their validity period was 3 years from the date the inspection ended.

The organization and conduct of inspections of manufacturers under the national procedure were carried out within the framework of licensing control.

Costs associated with the authorized institution conducting an inspection of a foreign manufacturer are borne by the foreign manufacturer. An agreement on conducting the inspection is concluded with the foreign manufacturer.

The inspection term shall not exceed 160 working days from the date the decision to conduct the inspection is made.

If non-conformities with GMP Russia requirements were identified during the inspection of a foreign manufacturer, the commission of inspectors compiled an inspection report and issued an invoice for additional inspection services within a period not exceeding 25 working days from the date the inspection ended. The manufacturer then formulated a plan of corrective and preventive actions (CAPA) indicating measures to eliminate the identified non-conformities.

The commission of inspectors evaluated the CAPA plan and prepared the final part of the inspection report containing final recommendations and conclusions no later than 25 working days from the receipt of the CAPA plan.

If no non-conformities were identified during the inspection, the inspection report was compiled no later than 25 working days from the date the inspection ended.

Thus, under the domestic procedure, the function of inspecting medicinal product manufacturers is divided into two types in terms of ideology, organization, and financing. Manufacturing facilities located in Russia are subject to licensing control, within which compliance with good manufacturing practice is confirmed [4]. These enterprises are inspected by employees of Minpromtorg Russia, with expenses for control measures paid from the state budget. This approach corresponds to international experience, as it excludes any financial influence of the inspected organization on the inspection results. In turn, foreign manufacturing sites, to obtain the state service for issuing a conclusion on compliance with GMP requirements, must first conclude an agreement with FSI "SID & GP" for the provision of inspection services, with the institution's expenses paid by the foreign manufacturer. Thus, the inspection of foreign manufacturers is conceptually interpreted as a service, not as a type of state control (supervision) [5].

Rules for Inspection for Compliance with GMP EAEU

According to Decree of the Government of Russia No. 1446 dated September 15, 2020, Minpromtorg Russia is designated as the authority empowered to implement Decision of the Council of the Eurasian Economic Commission No. 83 dated November 3, 2016, On Approval of the Rules for Conducting Pharmaceutical Inspections (the "EAEU Inspection Rules") regarding the organization and (or) conduct of pharmaceutical inspections for compliance of medicinal product manufacturing with the requirements of the EAEU Rules of Good Manufacturing Practice.

According to the EAEU Inspection Rules, inspections are conducted by the pharmaceutical inspectorate according to an inspection plan (schedule) in accordance with the manufacturing inspection program. Inspections may be conducted on both a scheduled and unscheduled basis.

The basis for conducting an inspection is a decision by Minpromtorg Russia and (or) an application by the inspected entity (e.g., for licensing, registration, and other procedures related to registration, or conducting investigations related to the quality of medicinal products).

Resident and non-resident organizations provide different packages of documents to initiate an inspection.

A manufacturer organization (resident) located in Russia submits:

• an application for inspection;
• a copy of the manufacturing site dossier (Master File) according to Part III of the Rules of Good Manufacturing Practice, containing a copy of the license to carry out activities for the manufacturing of medicinal products (if available);
• a list of medicinal products manufactured (planned for manufacturing) at the manufacturing site.

A manufacturer organization (non-resident) submits:

• an application for inspection;
• a copy of the manufacturing site dossier (Master File) according to Part III of the Rules of Good Manufacturing Practice;
• a certified copy or electronic copy of the valid authorization (license) for the manufacturing of medicinal products issued by the authorized body of the third country where the manufacturing site is located, or an extract from the relevant register of the third country where the inspected entity is located;
• a certified copy of the document issued by the authorized body of the country where the medicinal products are manufactured, regarding the compliance of the manufacturing (manufacturing site) with the requirements of good manufacturing practice applicable in the country of manufacture (if available);
• a list of medicinal products manufactured (planned for manufacturing) at the manufacturing site.

An inspection may be refused in the following cases:

• the information contained in the application for inspection and (or) documents submitted upon request of Minpromtorg Russia is incomplete and (or) unreliable;
• the applicant has not ensured conditions for conducting the inspection, making the inspection procedure impossible;
• the costs for conducting the inspection have not been paid within the established period (if applicable).

The inspection procedure consists of the following stages:

• acceptance and expertise of submitted documents;
• agreement on inspection dates with the inspected entity or its authorized representative;
• formation of the inspection team;
• compilation and sending of the inspection program to the inspected entity or its authorized representative;
• inspection of the manufacturing site, including sampling of materials or products (if necessary) and conducting laboratory tests thereof;
• compilation of the report on the pharmaceutical inspection (the "Report");
• evaluation (if necessary) of the plan of corrective and preventive actions (CAPA), the report on its implementation, and evidence of the elimination of identified non-conformities;
• adoption of a decision to issue or refuse to issue a certificate of manufacturer compliance with the Rules of Good Manufacturing Practice;
• issuance of the certificate.

The inspection team must consist of at least two pharmaceutical inspectors.

At the beginning of the inspection, an opening meeting is held with representatives of the inspected entity. During this meeting, the lead inspector introduces the inspection team members, meets the management and responsible persons of the inspected organization, informs them of the purpose and scope of the inspection, clarifies the inspection program and schedule, makes a confidentiality statement, and answers questions from the inspected party.

The inspection agreement establishes the following rights of the inspector:

• to access (enter) any premises in accordance with the inspection program and access the manufacturing site dossier (Master File);
• to obtain evidence such as documentation, photographic materials (video recordings) of premises and equipment;
• to access any object (item) within the scope of the inspection and study it;
• to take measures or demand measures regarding items (material evidence) that may allegedly testify to non-compliance with GMP EAEU requirements, including restricting access to such items and ensuring their preservation for further proceedings in the established order;
• to inspect audited objects, review documentation and records, interview responsible persons of the inspected entity, and observe activities at workplaces;
• to terminate the inspection if obstructed in exercising the specified rights.

If a risk to the life and health of the population (including potential critical non-conformities) is identified, the lead inspector immediately informs the head of the pharmaceutical inspectorate (by phone, email, or other means of communication within 24 hours of identifying the non-conformity) and the head of the inspected entity, and, if necessary, takes actions provided for by the pharmaceutical inspectorate's quality system.

If necessary, sampling of materials or products may be carried out during the inspection, which are sent by the inspected entity for testing to a testing laboratory. The cost of samples is not subject to compensation.

Expenses related to transportation, customs operations, and customs control regarding samples of materials and products moved across the customs border of the EAEU, as well as testing of samples, are borne by the inspected entity.

The lead inspector ensures the compilation of the report. If no non-conformities were identified during the inspection, or only other (minor) non-conformities that are not critical or major were identified, the report is compiled in 2 copies and signed by the lead inspector and inspection team members no later than 30 calendar days from the date of inspection completion.

If critical and (or) major non-conformities were identified during the inspection:

• Part I of the report is compiled in 2 copies and signed by the lead inspector and inspection team members no later than 30 calendar days from the date of inspection completion;
• Part II of the report is compiled in 2 copies and signed by the lead inspector and inspection team members no later than 30 calendar days from the date the inspected entity submits the CAPA plan, the report on its implementation, and documentary evidence of the elimination of all non-conformities.

If other (minor) non-conformities were identified during the inspection, the inspection team evaluates the CAPA plan and the report on its implementation during the next inspection.

The manufacturing of medicinal products is recognized as complying with GMP EAEU requirements in one of the following cases:

• absence of non-conformities;
• absence of critical and major non-conformities;
• elimination of all critical and major non-conformities based on the evaluation of the response.

The manufacturing of medicinal products is recognized as non-compliant with GMP EAEU requirements in one of the following cases:

• if critical and (or) major non-conformities are established in the inspection report;
• failure to eliminate all critical and major non-conformities based on the evaluation of the response;
• failure to submit a response no later than 60 calendar days from the date of receipt of Part I of the report if critical or major non-conformities were identified;
• obstruction of the inspector in exercising their rights within the framework of the inspection.

If the manufacturing of medicinal products is recognized as complying with GMP EAEU requirements, Minpromtorg Russia issues a GMP EAEU certificate no later than 10 working days from the date of the decision to issue the certificate.

The validity period of the GMP EAEU certificate cannot exceed 3 years from the date of inspection completion.

The basis for refusal to issue a GMP EAEU certificate is the recognition of manufacturing as non-compliant with GMP EAEU requirements.

Minpromtorg Russia may also decide to terminate a previously issued certificate in the event of:

• refusal of the inspected entity to undergo an inspection at the request of the authorized body (organization);
• failure by the inspected entity to ensure the conduct of an inspection at the request of the authorized body (organization);
• refusal to issue a certificate by the authorized body (organization) of the Member State whose pharmaceutical inspectorate performed the inspection or by the authorized body (organization) of another Member State.

Notably, the pharmaceutical inspectorate carries out and documents an annual internal audit of its activities to assess compliance with the requirements of the pharmaceutical inspectorate's quality system.

Currently, remote inspections are also possible. On February 8, 2021, the Council of the Eurasian Economic Commission (EEC) decided to amend the EAEU Inspection Rules, allowing pharmaceutical inspections using remote interaction means.

According to the document, by decision of the pharmaceutical inspectorate, inspections for compliance with GMP EAEU Rules using remote interaction means (e.g., via audio or video communication), i.e., without visiting the manufacturing site, are permitted in the following cases:

• threat of occurrence, occurrence, and liquidation of an emergency and (or) occurrence of a threat of the spread of epidemic diseases presenting a danger to others, diseases and injuries resulting from exposure to adverse chemical, biological, and radiation factors;
• occurrence of force majeure circumstances or circumstances beyond the parties' control that threaten the life and health of inspectors (e.g., for political, medical, or other reasons) [6].

Order of the Ministry of Industry and Trade of Russia No. 2945 dated September 4, 2020, approved the administrative regulation for issuing certificates of manufacturer compliance with GMP EAEU requirements. According to said administrative regulation, the Department for the Development of the Pharmaceutical and Medical Industry of Minpromtorg Russia directly provides the state service.

The term for providing the state service is calculated from the day of receipt of the application and the full set of attached documents and shall not exceed 90 calendar days after the last day of the last inspection. The list of documents to be submitted by a resident with an application for inspection is similar to the list specified in the EAEU Inspection Rules. However, the list of documents for non-residents differs regarding the need to provide a consent letter for the inspection.

It is also established that if the application for a certificate indicates the need for it to be provided in the form of an electronic document, Minpromtorg Russia sends the certificate to the applicant in the form of an electronic document signed with an electronic signature.

Control over the completeness and quality of the provision of the state service by Minpromtorg officials is carried out in the form of inspections and consideration of complaints against the actions (inaction) of officials.

Inspections can be scheduled and unscheduled. Checks on the completeness and quality of the provision of the state service are carried out by Minpromtorg officials in accordance with the annually approved comprehensive work plan (scheduled inspections) or, in cases where applicants file a complaint against decisions or actions (inaction) taken (carried out) during the provision of the state service, by officials of the Department for the Development of the Pharmaceutical and Medical Industry (unscheduled inspections).

Scheduled inspections are conducted no more than once every 3 (three) years. Unscheduled inspections are conducted by decision of the Director of the Department for the Development of the Pharmaceutical and Medical Industry of Minpromtorg Russia or their deputy.

Appealing of GMP Inspection and Issuance of GMP Certificate

The applicant or their authorized representative has the right to pre-trial (out-of-court) appeal of actions (inaction) and (or) decisions taken (carried out) by Minpromtorg during the inspection and issuance of the compliance certificate.

A complaint may be filed in the following cases:

• violation of the deadline for registering the applicant's request for the provision of the state service;
• violation of the deadline for providing the state service;
• demanding documents from the applicant not provided for by the regulatory legal acts of the Russian Federation;
• refusal to accept documents from the applicant, the submission of which is provided for by regulatory legal acts;
• refusal to provide the state service on grounds not provided for by federal laws and other regulatory legal acts of the Russian Federation adopted in accordance with them;
• demanding payment from the applicant for the provision of the state service not provided for by the regulatory legal acts of the Russian Federation;
• refusal by Minpromtorg or its official to correct typos and errors in documents issued as a result of providing the state service or violation of the established deadline for such corrections.

A complaint against the actions (inaction) of Minpromtorg Russia officials is submitted to the head of Minpromtorg, their deputy, or the acting head.

The complaint must contain:

• the name of the body providing the state service, the official of the body providing the state service, or the civil servant whose decisions and actions (inaction) are being appealed;
• the surname, first name, patronymic (the latter if available), information on the place of residence of the applicant (individual) or the name, information on the location of the applicant (legal entity), as well as the contact telephone number(s), email address(es) (if available), and postal address to which the response should be sent to the applicant;
• information on the appealed decisions and actions (inaction) of the body providing the state service, the official of the body providing the state service, or the civil servant;
• arguments based on which the applicant disagrees with the decision and action (inaction) of the body providing the state service, the official of the body providing the state service, or the civil servant.

The applicant may also submit documents (if available) confirming the applicant's arguments, or copies thereof.

The term for considering a complaint is 15 working days from the date of its registration, and in the case of appealing a refusal by Minpromtorg Russia to accept documents from the applicant or to correct typos and errors in issued documents, or in the case of appealing a violation of the established deadline for such corrections—within 5 (five) working days from the date of complaint registration.

The above briefly describes the main procedures for inspecting pharmaceutical manufacturers. Currently, we can speak of a reorientation of pharmaceutical manufacturers towards GMP EAEU requirements, including regarding inspections. It is important to note that the EAEU Inspection Rules are more adapted to modern operating conditions of pharmaceutical companies. For example, the ranking of non-conformities of a manufacturing site under GMP EAEU into major, critical, and other (minor) makes the procedure for obtaining a GMP EAEU certificate faster and easier for minor violations than if critical or major non-conformities are identified.

Furthermore, the EAEU Inspection Rules implement a quality system for the pharmaceutical inspectorate, whereas under domestic rules, the implementation of such a system was not legislatively established.

Thus, a pharmaceutical inspection for compliance with the requirements of any good practice in the sphere of medicinal product circulation is one of the main components of the state regulatory system. The modern organization of a pharmaceutical inspectorate implies the existence of a quality system [7].

Moreover, while previously a number of scholars noted the orientation of the Russian pharmaceutical industry toward foreign sales markets [8], currently, there is a trend toward the development of the domestic pharmaceutical industry oriented toward domestic markets, as well as the circulation of medicinal products directly within the EAEU.

In addition, currently, the situation with conducting remote GMP inspections continues to be relevant, and such inspections remain a demanded tool for assessing manufacturing sites [9].

Based on the above, it can be concluded that the institution of inspection is actively developing in Russia in accordance with the EAEU Inspection Rules.

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References

[1] Some Aspects of Conducting GMP Inspections in Russia. G.N. Gildeeva, V.I. Yurkov // Sechenov Herald. No. 1(31). 2018.

[2] Order of the Ministry of Industry and Trade of Russia No. 1987 dated May 18, 2022, On Extension of Validity Periods of Conclusions on Compliance of a Manufacturer of Medicinal Products for Medical Use with the Requirements of Rules of Good Manufacturing Practice.

[3] The EAEU Adopts a Package of Temporary Measures to Accelerate the Launch of Medicines to the Market. Eurasian Economic Commission. June 10, 2022.

[4] Cl. 2, Art. 45 of Federal Law No. 61-FZ dated April 12, 2010, On the Circulation of Medicinal Products.

[5] The Role of Inspection of Medicinal Product Manufacturers for Compliance with Good Manufacturing Practice in Ensuring the Quality of Medicinal Preparations. A.P. Meshkovsky. Medical Technologies. Assessment and Choice. 2016. P. 84.

[6] The Possibility of Conducting GMP Inspections in Remote Mode Established in the EAEU. February 20, 2021. Pharmprom.

[7] International Approaches to Forming a Quality System for a Pharmaceutical Inspectorate. N.S. Nikolenko, V.V. Beregovykh. // Remedium No. 12. 2019.

[8] Lakeev A.E. International Legal Standards in the Sphere of Health Protection in the Legal System of the Russian Federation // Medical Law. 2016. No. 3. P. 28 – 33.

[9] Conducting Remote GMP Inspections. View from the Manufacturer's Side. E. Gladyshev, Y. Stepanova. January 16, 2023. Pharmprom.