Release of Medicinal Products into Civil Circulation in Russia

 

February 2, 2024

BRACE Law Firm ©

 

Russian legislation does not define the concept of "release into civil circulation" (or "putting into civil circulation"). Courts classify this as any action aimed at transferring goods from one person to another, for example, importing goods into the territory of the Russian Federation, offering for sale and selling, or delivering goods to a buyer.

For a long time, the procedure for releasing medicinal products into civil circulation differed little from that of other goods. Mandatory confirmation of conformity of medicinal products in the form of a declaration or certification was required.

The procedure for releasing medicinal products into civil circulation changed in November 2019, when, pursuant to instructions from the President of Russia, they were removed from the scope of legislation on technical regulation [1]. Instead, a procedure was established for submitting specific documents and information to Roszdravnadzor, and in some cases, obtaining a permit from the control body for release into circulation. These changes aimed, on the one hand, to increase control over the quality of medicines by introducing special regulation, and on the other hand, to reduce the financial burden on manufacturers and importers of medicinal products.

However, the changing international situation and the need for timely provision of expensive medicinal products required further adjustments. Effective September 1, 2024, amendments to the legislation will enter into force, concerning, inter alia, the procedure for releasing medicinal products.

This article examines the current procedure for releasing medicinal products into civil circulation and the upcoming changes.

Regulatory Regulation of Release of Medicinal Products into Circulation

The rules for releasing medicinal products for medical use into civil circulation are regulated by Article 52.1 of Federal Law No. 61-FZ dated April 12, 2010, "On the Circulation of Medicinal Products" (hereinafter, the "Law on Circulation of Medicinal Products" or "Law No. 61-FZ") and the Procedure for releasing medicinal products for medical use into civil circulation adopted pursuant thereto by Decree of the Government of Russia No. 1510 dated November 26, 2019 (hereinafter, "Decree No. 1510"). The release procedure varies depending on whether the medicinal product is classified as an immunobiological product or not.

Article 52.2 of the Law on Circulation of Medicinal Products is dedicated to the release of medicinal products for veterinary use. It entered into force on September 1, 2023 [2]. The procedure for their release was approved by Decree of the Government of Russia No. 565 dated April 8, 2023 [3] (hereinafter, "Decree No. 565"). These norms do not apply to batches of medicines released into civil circulation before September 1, 2023, and apply until their expiration date [4].

Below, we examine the specifics of releasing medicinal products for medical use and provide an overview of the specifics for medicinal products for veterinary use.

Procedure for Releasing Medicinal Products into Circulation

Before releasing a batch or lot of a medicinal product into civil circulation, the manufacturer/importer of the medicinal product must submit the following documents and information to Roszdravnadzor.

1. Regarding medicinal products manufactured in the Russian Federation:

• A manufacturer's document confirming the quality of the medicinal product;
• Confirmation of conformity of the medicinal product with the requirements established during its state registration.

2. Regarding medicinal products imported into Russia:

• A certificate from the manufacturer of the medicinal product regarding the compliance of the imported product with the requirements of the pharmacopoeial monograph, or if none exists, with the requirements of the normative documentation;
• Confirmation of conformity of the imported product with the requirements established during its state registration.

Roszdravnadzor has issued several explanatory materials regarding the drafting of these documents. Thus, in accordance with Roszdravnadzor clarifications set out in Letter No. 01I-2906/19 dated November 28, 2019, "On Release into Civil Circulation," the manufacturer's certificate for imported medicinal products is provided in the form of a scanned original and a certified translation into Russian.

Confirmation of conformity of the medicinal product with the requirements established during its state registration is issued by the authorized person of the manufacturer / representative of the importer authorized by the foreign manufacturer. The confirmation must contain information allowing the identification of the manufacturer's authorized person (Full Name, number and date of the Order of the Ministry of Health of Russia on attestation) or the responsible person of the distributor and their authority (Full Name, number and date of the power of attorney or other document defining their authority). Based on the nature of the work performed and the responsibility imposed, the manufacturer's authorized person must possess the necessary information and be knowledgeable about issues of medicinal product quality and requirements for quality documentation.

A foreign manufacturer of a medicinal product may authorize a specific representative of the importer (an individual) directly or the organization importing the medicinal product into Russia, and the head of the importer locally issues a power of attorney to their employee.

When entering information about medicinal products entering civil circulation, provision is made for entering information about the authorized (responsible) person of the manufacturer/importer, including personal contact details and attaching a document confirming their authority.

The Guideline on Compliance with Mandatory Requirements of Legislation in the Sphere of Circulation of Medicinal Products Concerning the Release of Medicinal Products for Medical Use into Civil Circulation (hereinafter, the "Guideline") identifies the following frequent violations when checking documents submitted by manufacturers and importers:

• The information contained in the manufacturer's document does not allow the identification of the medicinal product taking into account data from the state register of medicinal products (lack of a full description, including information on the primary and secondary packaging of the batch (lot) of the medicinal product, manufacturer's name);
• Absence of an indication of the normative documentation for the medicinal product according to which it was produced and controlled;
• Records are limited to indicating the number of the registration certificate for the medicinal product;
• Data on testing the product for compliance with established requirements for the indicators "Packaging", "Labeling", and "Shelf Life" are not indicated or are not specific, limited to the text "in accordance with requirements";
• Data on test results are designated formally;
• Documents lack signatures of responsible persons, as well as details (date, number) ensuring the principle of traceability regarding the production and quality control of a specific batch of a specific product;
• Absence of proper confirmation of the authority of authorized persons [5].

The specified documents and information are submitted via the personal account of the Roszdravnadzor Automated Information System (hereinafter, "AIS"). Within 3 business days from the date of receipt of documents and information in the AIS, Roszdravnadzor publishes information on batches or lots of medicinal products being released into civil circulation on its official website. The fact of data entry can be verified on the website in the electronic service "Information on Medicinal Products Released into Civil Circulation in the Russian Federation."

Subsequently, manufacturers and importers of medicinal products are required to submit to Roszdravnadzor a test protocol for one batch of the medicinal product of each trade name (taking into account the dosage form and strength) that entered civil circulation during the calendar year, annually, no later than February 1 of the year following the calendar year. The protocol confirms the compliance of the medicinal product with the requirements of normative documentation. Tests must be conducted in an accredited testing laboratory (center).

Specifics of Releasing First-Time Manufactured and Imported Products

For the first three batches or lots of products that are manufactured in or imported into Russia for the first time, with the exception of immunobiological ones, it is additionally necessary to submit to the AIS a test protocol on compliance with quality indicators provided for by the normative documentation (Part 4 of Article 52.1 of Federal Law No. 61-FZ dated April 12, 2010, "On the Circulation of Medicinal Products").

According to Roszdravnadzor Letter No. 01I-2906/19 dated November 28, 2019, medicinal products that received registration certificates after November 28, 2019, are considered first-time manufactured or first-time imported.

The test protocol is issued by accredited Federal State Budgetary Institutions subordinate to the Ministry of Health and Roszdravnadzor (hereinafter, "FSBI"). Currently, there are two such institutions:

• FSBI "Scientific Center for Expert Evaluation of Medicinal Products" of the Ministry of Health of Russia;
• FSBI "Information and Methodological Center for Expertise, Accounting and Analysis of Circulation of Medical Products" of Roszdravnadzor.

The rules for issuing the protocol are approved by Decree of the Government No. 1510. To obtain it, the applicant sends an application on paper or in electronic form to the selected FSBI. The application indicates:

• Information about the applicant: name, TIN (INN), PSRN (Registration number), email address;
• Information about the medicinal product: name (trade name, TIN or grouping or chemical name), number and date of the registration certificate;
• Details of the document confirming the fact of payment for the issuance of the test protocol. The fee is currently 1,200 rubles.

The application must also be accompanied by:

• A manufacturer's document confirming the compliance of the quality of the batch or lot with the requirements established during its state registration;
• A copy of the normative documentation for the medicinal product certified by the applicant.

Upon receipt of the documents and information, the FSBI requests from the applicant the quantity of samples of the medicinal product necessary for testing, and if necessary, samples of the pharmaceutical substance, strains of microorganisms, and cell cultures (hereinafter, "samples"), and notifies regarding the fee amount for conducting tests. The fee amount is calculated in accordance with the methodology approved by the Ministry of Health of Russia [6].

Within 30 business days, the applicant must submit the requested samples and details of the payment document.

The testing period is 30 business days from the date of receipt of medicinal product samples. For medicinal products derived from blood, human or animal blood plasma, biotechnological medicinal products, and gene therapy medicinal products, this period may be extended.

Issuance of the test protocol will be refused in case of failure to submit documents and information in full, the required quantity of samples, or details of the document confirming payment for conducting tests.

Procedure for Releasing Immunobiological Medicinal Products

In accordance with Article 4 of the Law on Circulation of Medicinal Products, immunobiological products are understood as medicinal products intended for the formation of active or passive immunity, or the diagnosis of the presence of immunity, or the diagnosis of a specific acquired change in the immunological response to allergenic substances. Immunobiological medicinal products (hereinafter also "ILP") include vaccines, anatoxins (toxoids), toxins, serums, immunoglobulins, and allergens.

To release immunobiological medicinal products into civil circulation, it is necessary to obtain a Roszdravnadzor permit for each batch or lot (Part 7 of Article 52.1 of Law No. 61-FZ). The permit is issued in the form established by Roszdravnadzor Order No. 8966 dated November 29, 2019 [7], based on the conclusion of an accredited FSBI on the compliance of the batch or lot of the immunobiological medicinal product with the requirements established during its state registration (hereinafter, the "Conclusion"). No fee is charged for issuing the permit.

The procedure for issuing these documents is also regulated by Decree No. 1510. To obtain the Conclusion, the manufacturer or importer of the ILP sends an application for the issuance of the Conclusion on paper or in electronic form to the selected FSBI. The application must be accompanied by:

• A certified copy of the ILP manufacturer's document containing information on the stages of production and quality control of the batch or lot of the product in accordance with the registration dossier documents;
• A certified copy of the ILP manufacturer's document confirming the compliance of the quality of the batch or lot of the product with the requirements established during its state registration;
• Confirmation of conformity of the batch or lot of the ILP with the requirements established during state registration, executed by the applicant's authorized person;
• A certified copy of the normative documentation for the medicinal product.

The fee for issuing the Conclusion is 2,000 rubles.

Upon receipt of the documents, the FSBI notifies the applicant of the quantity of samples necessary for testing and the fee amount for conducting tests. The fee amount is calculated in accordance with the methodology approved by the Ministry of Health of Russia [8]. The applicant must submit the requested samples and details of the document confirming payment for the testing service within 30 business days from the date of receipt of the request.

The testing period is 30 business days from the date of receipt of samples. It may be extended, but by no more than 30 business days. Upon completion of the tests, the FSBI sends the Conclusion with the attached quality test protocol to the applicant and Roszdravnadzor.

The applicant fills out an application for the issuance of a permit via the AIS personal account, including information about the ILP, and attaches the Conclusion and test protocol as scanned documents in PDF format.

Within 3 business days, the Roszdravnadzor permit for release into civil circulation or refusal to issue a permit is posted in the personal account and published in the public domain on the Roszdravnadzor website in the section "Services" / "Register of Roszdravnadzor permits for the release of a batch (lot) of ILP into civil circulation" with the possibility of printing.

In What Cases is Compliance with Rules for Release of Medicines into Circulation Not Required?

In accordance with Part 9 of Article 52.1 of the Law on Circulation of Medicinal Products, compliance with the established procedure for release into civil circulation is not required regarding:

• Medicinal products intended for conducting clinical trials of medicinal products, expertise of medicinal products for the purpose of state registration of medicinal products;
• Unregistered medicinal products intended for providing medical care based on life-saving indications for a specific patient or group of patients, imported into the Russian Federation based on a permit from the Ministry of Health of Russia.

The rules for importing said medicinal products are regulated by Decree of the Government of Russia No. 853 dated June 1, 2021 [9].

Please also note that the specifics of medicinal product circulation in the event of a shortage of medicinal products or the risk thereof, approved by Decree of the Government of Russia No. 593 dated April 5, 2022 [10], apply until December 31, 2024, inclusive. In accordance with Clauses 3 and 4 of the said act, introduction into civil circulation in the manner established by Article 52.1 of Law No. 61-FZ is not required for:

• Medicinal products not registered in the Russian Federation that have a permit from the Ministry of Health of Russia for temporary circulation;
• Medicinal products in packaging intended for circulation in foreign countries that have received a conclusion from the interdepartmental commission of the Ministry of Health of Russia.

Consequences of Violating the Procedure for Release into Civil Circulation

If medicinal products are detected in circulation for which the aforementioned documents and information were not submitted / a permit was not obtained, the control body makes a decision to terminate civil circulation. The decision to terminate civil circulation is formalized by an order.

After its adoption, Roszdravnadzor:

• Sends a corresponding notification to the manufacturer/importer of the medicinal product within 5 business days;
• Posts information about the termination of circulation on its official website within 3 business days.

The decision is canceled upon receipt of information about the entry of the established documents and information into the AIS. The manufacturer/importer is also notified of the cancellation of the decision, and it is posted on the official website.

Failure to comply with the procedure for releasing medicinal products into civil circulation may result in administrative liability under Article 19.7.8 of the Code of Administrative Offenses of the Russian Federation "Failure to submit information or submission of knowingly unreliable information to the federal executive body exercising control and supervision functions in the sphere of healthcare." The fine for officials is from 10,000 to 15,000 rubles, and for legal entities from 30,000 to 70,000 rubles.

Let us illustrate with an example from judicial practice. In one case, Roszdravnadzor revealed that a manufacturer had shipped a batch of a medicinal product to a distributor. However, the documents and information were posted in the AIS later than the actual date of release into circulation. The control body held the business entity administratively liable under Article 19.7.8 of the Code of Administrative Offenses of the Russian Federation with a fine of 50,000 rubles. The company attempted to challenge the ruling in court, citing extreme necessity: supply for the purpose of executing a state contract to provide patients with cystic fibrosis. The court concluded that the elements of the imputed administrative offense were proven, but taking into account the nature of the committed offense, reduced the fine to 30,000 rubles [11].

Specifics of Releasing Medicinal Products for Veterinary Use

The procedure for releasing medicinal products for veterinary use is largely similar to that for products for medical use. Let us consider the specifics.

The body authorized to accept documents and information, as well as issue permits for the release of immunobiological veterinary products into circulation, is Rosselkhoznadzor.

To release an imported veterinary product into civil circulation, a Conclusion of compliance with GMP requirements issued after an inspection of the manufacturing site will also be required.

A test protocol for compliance with quality indicators must be submitted regarding the first two batches of first-time manufactured or first-time imported medicinal products.

The law explicitly provides requirements for the authorized person. They must:

• Be attested in the manner established by the Ministry of Agriculture;
• Have a higher education in one of the specialties and/or one of the areas of training: biology, biotechnology, veterinary medicine, veterinary-sanitary expertise, clinical medicine, radiation, chemical and biological defense, pharmacy, fundamental medicine, chemical technology, chemistry;
• Have at least 5 years of work experience in the field of production and/or quality control of medicinal products or in the field of monitoring the efficacy and safety of medicinal products for veterinary use.

The permit for release of immunobiological products into civil circulation is issued based on the results of tests of the first two batches of the product in an accredited testing laboratory. The permit will be considered valid for the entire circulation period of the batch of the product for which it was issued. For subsequent batches, such a permit is issued for a period of three years.

Compliance with the specified release procedure is not required for products intended for:

• Export from the Russian Federation;
• Conducting preclinical and clinical trials, expertise for the purpose of state registration or introducing amendments to the registration dossier;
• Import for the purpose of treating specific animals in zoos, zoological gardens, circuses, oceanariums, dolphinariums, treating wild animals belonging to species listed in the Red Data Book, as well as animals imported into the Russian Federation for participation in sports and entertainment events.

Regulatory Changes in the Sphere of Releasing Medicinal Products into Civil Circulation

Effective September 1, 2024, amendments to the Law on Circulation of Medicinal Products will enter into force, introducing significant changes to the procedure for releasing medicinal products for medical use into civil circulation [12]. Let us examine them in more detail:

1. The procedure for release into civil circulation will also apply to pharmaceutical substances.

Before releasing each batch or lot of a Russian pharmaceutical substance into civil circulation, the manufacturer will be required to submit to Roszdravnadzor:

• A manufacturer's document confirming the quality of the pharmaceutical substance;
• A document confirming the compliance of the pharmaceutical substance with the requirements established during its state registration or registration, executed by the manufacturer's authorized person.

For a foreign pharmaceutical substance, the following will be required:

• A medicinal product manufacturer's document confirming the quality of the pharmaceutical substance.

2. All documents will be submitted exclusively in electronic form.

3. The deadlines for the annual submission of test protocols for one batch of medicinal products released onto the market are being moved.

It will be possible to submit them to Roszdravnadzor until April 1, rather than until February 1, as established by current norms.

4. The procedure for releasing medicinal products manufactured in Russia for the first time or imported for the first time into circulation is being simplified.

The manufacturer (importer) will be able to submit a test protocol for only one first batch or product (instead of three), provided that:

• Information is submitted on the date of issuance and number of the conclusion of compliance of the medicinal product manufacture with the requirements of good manufacturing practice regarding the manufacturing site where the product was manufactured (GMP certificate of the Russian Federation or EAEU);
• No cases of defects were recorded at any manufacturing sites carrying out the production of the medicinal product and final quality control during the previous three years.

5. Relaxations are provided for orphan and high-tech medicinal products.

Let us recall how the Law on Circulation of Medicinal Products defines these types of medicinal products:

• Orphan medicinal products – medicinal products intended exclusively for the diagnosis, etiopathogenetic, or pathogenetic treatment (treatment aimed at the mechanism of disease development) of rare (orphan) diseases;
• High-tech medicinal products (Advanced Therapy Medicinal Products) – gene therapy medicinal products, somatic cell therapy medicinal products, or tissue engineered products.

Submission of a test protocol will not be required for orphan medicinal products, or high-tech medicinal products obtained from the biological material of a specific person and intended for use by the same person. For other first-time manufactured or imported high-tech medicinal products, a test protocol for the first batch (lot) obtained through remote testing and submitted to Roszdravnadzor within the first 3 years after the product's market launch will be submitted.

Summarizing, please note that the policy pursued by the state in recent years aims to reduce bureaucratic obstacles for the speedy entry of medicinal products into the Russian market and to prevent shortages, increasing the availability of medicinal products, especially expensive and unique ones. At the same time, the preparation of documents necessary for introducing medicinal products to the Russian market requires careful preparation by a team of professionals, including legal specialists.

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References

[1] Federal Law No. 449-FZ dated November 28, 2018, "On Amendments to Certain Legislative Acts of the Russian Federation Regarding the Release of Medicinal Products for Medical Use into Civil Circulation".

[2] Federal Law No. 317-FZ dated July 2, 2021, "On Amendments to the Federal Law 'On the Circulation of Medicinal Products'".

[3] Decree of the Government of Russia No. 565 dated April 8, 2023, "On the procedure for submitting documents and information on medicinal products for veterinary use released into civil circulation, issuing a permit for the release of an immunobiological medicinal product for veterinary use into civil circulation, and test protocols on the compliance of batches of an immunobiological medicinal product for veterinary use with quality indicators provided for by the normative document".

[4] Federal Law No. 317-FZ dated July 2, 2021, "On Amendments to the Federal Law 'On the Circulation of Medicinal Products'".

[5] Approved by Roszdravnadzor on November 14, 2022.

[6] Order of the Ministry of Health of Russia No. 33n dated January 20, 2020, "On approval of the Methodology for determining the fee amount for the provision by federal state budgetary institutions subordinate to the Ministry of Health of the Russian Federation and the Federal Service for Surveillance in Healthcare of services for conducting tests for the purpose of issuing a test protocol on the compliance of the first three batches or lots of a medicinal product for medical use (excluding an immunobiological medicinal product) manufactured in the Russian Federation for the first time or imported into the Russian Federation for the first time with quality indicators provided for by normative documentation".

[7] Order of Roszdravnadzor No. 8966 dated November 29, 2019, "On approval of the form of the permit for release into civil circulation in the Russian Federation of a batch or lot of an immunobiological medicinal product manufactured in the Russian Federation or imported into the Russian Federation and the form of the conclusion on the compliance of a batch or lot of an immunobiological medicinal product with the requirements established during its state registration".

[8] Order of the Ministry of Health of Russia No. 4n dated January 15, 2020, "On approval of the Methodology for determining the fee amount for the provision by federal state budgetary institutions under the jurisdiction of the Ministry of Health of the Russian Federation and the Federal Service for Surveillance in Healthcare of services for conducting quality tests of a batch or lot of an immunobiological medicinal product for compliance with the requirements established during its state registration, and the maximum fee amount for the provision of this service".

[9] Decree of the Government of Russia No. 853 dated June 1, 2021, "On Approval of the Rules for Importing Medicinal Products for Medical Use into the Russian Federation and Recognizing as Invalid Certain Acts and Certain Provisions of Certain Acts of the Government of the Russian Federation".

[10] Decree of the Government of the Russian Federation No. 593 dated April 5, 2022, "On the specifics of the circulation of medicinal products for medical use in the event of a shortage or risk of a shortage of medicinal products due to the introduction of restrictive economic measures against the Russian Federation".

[11] Resolution of the Arbitration Court of the Moscow District dated March 5, 2022, No. F05-34087/2021 in case No. A40-68861/2021.

[12] Federal Law No. 1-FZ dated January 30, 2024, "On Amendments to the Federal Law 'On the Circulation of Medicinal Products' and Articles 1 and 4 of the Federal Law 'On Amendments to the Federal Law 'On the Circulation of Medicinal Products' and the Federal Law 'On Amendments to the Federal Law 'On the Circulation of Medicinal Products'".