Biological Medicinal Products

 

March 31, 2023

BRACE Law Firm ©

 

The production of medicinal products (the "medicinal products", the "medicines") is developing rapidly, with a significant number of new drugs registered every year. Since the 1980s, biological medicinal products, in which the active substance is derived from materials of biological origin (organs and tissues of plant or animal origin, cells, blood, plasma, microorganisms, etc.), have become widespread. The prevalence of these products is growing; according to some data, the global market for biological medicines could exceed $250 billion.

The reasons for this situation lie in the advantages of products of biological origin over those created through chemical synthesis, such as targeted action and non-toxicity of treatment. Furthermore, a range of genetic, autoimmune, and oncological diseases can only be treated with biological medicinal products. The ever-increasing number of such products requires special legal regulation for their circulation.

In this article, we will examine the basic terminology established by Russian legislation regarding biological medicinal products and consider the problems of the regulatory framework governing their production, registration, and quality control.

Concept and Types of Biological Medicinal Products

The fastest and most detailed legal formalization of the circulation of biological medicinal products is occurring in the EU and the USA. As early as 2003, EU legislation defined the concepts of "biological medicinal product" and "biological sources". Thus, according to Annex I to Directive 2001/83/EC, a biological medicinal product is a product containing a biological pharmaceutical substance. Biological sources include microorganisms, organs and tissues of plant or animal origin, cells or fluids (including blood and plasma) of human or animal origin, and biotechnological cell constructs (cell substrates, whether or not they are biotechnological, including primary cells).

In the Russian Federation, the definition of a biological medicinal product is provided in Article 4 of Federal Law No. 61-FZ dated June 12, 2010, On the Circulation of Medicinal Products (the "Law on Circulation of Medicinal Products"). According to this definition, biological medicinal products are medicinal products whose active substance is produced or isolated from a biological source and for the determination of the properties and quality of which a combination of biological and physicochemical methods is required.

The Law on Circulation of Medicinal Products classifies the following as biological medicinal products:

• Immunobiological medicinal products;
• Medicinal products derived from blood or blood plasma of humans and animals (except for whole blood);
• Biotechnological medicinal products;
• Gene therapy medicinal products.

Immunobiological medicinal products (the "ILP") are medicinal products intended to form active or passive immunity, or to diagnose the presence of immunity, or to diagnose a specific acquired change in the immunological response to allergenic substances. These include vaccines, toxoids, toxins, sera, immunoglobulins, and allergens.

Medicinal products derived from blood or blood plasma of humans and animals are products manufactured by industrial methods from human blood components. Examples include human albumin products, human immunoglobulins, and blood coagulation factor products.

Biotechnological medicinal products are medicinal products whose production involves biotechnological processes and methods (including recombinant DNA technology, technology for controlled expression of genes encoding biologically active proteins in prokaryotes and eukaryotes), the hybridoma method, and the monoclonal antibody method. This group includes monoclonal antibodies, cytokines, etc.

Gene therapy medicinal products are medicinal products whose pharmaceutical substance is a recombinant nucleic acid or includes a recombinant nucleic acid that allows for the regulation, repair, replacement, addition, or removal of a genetic sequence. Put simply, a gene therapy product contains a specific DNA fragment that determines the product's therapeutic effect. Its principle of action consists of delivering new genetic material to target cells. We note that there are currently few gene therapy products approved for use, as the process of their creation and testing is complex and expensive. Currently, only about 10 such products (including "Luxturna®", "Zolgensma®", and others) have been approved worldwide, while a number of other products are undergoing phase II and III clinical trials. According to researchers of this issue, this situation is due to the complex and expensive process of creation, testing, and state registration of serial products.[1]

Production and Quality Control of Biological Products

The production of biological medicinal products has its own specifics, determined by the nature of the products and the manufacturing technology. It is characterized by the complexity and diversity of technological processes, as well as variability, since, unlike conventional medicines which have a high degree of stability, biological products are variable. In addition, the nature of the starting materials used requires special precautions due to the risk of contamination. Let us consider the requirements for production and quality control in more detail.

According to Article 45 of the Law on Circulation of Medicinal Products, the production of medicines must comply with the requirements of the rules of good manufacturing practice. Currently, both the Rules of Good Manufacturing Practice approved by Order of the Ministry of Industry and Trade of Russia No. 916 dated June 14, 2013, and the EAEU Rules of Good Manufacturing Practice approved by Decision of the Council of the Eurasian Economic Commission No. 77 dated November 3, 2016 (the "GMP Rules"), apply in Russia. Both documents are similar in content, but since a transition to uniform rules for the circulation of medicinal products within the EAEU is currently underway, let us consider the production requirements established by the GMP Rules.

During production, manufacturers must comply with both the general requirements for the production of any medicinal products and the additional rules for the production of biological medicinal products, from the control of seed cultures and cell banks to final operations and testing. Let us examine them in more detail.

The general principle established by the GMP Rules is as follows: the manufacturer must produce medicinal products in such a way as to guarantee their compliance with their intended use, the requirements of the registration dossier and the clinical trial protocol, and to minimize the risk to patients associated with the safety, quality, and efficacy of the medicinal products.

To implement this, a pharmaceutical quality system must be developed and function, including good manufacturing practice and quality risk management. This system must be documented and its effectiveness monitored. The basic requirements of good manufacturing practice consist of the following:

• The manufacturer systematically reviews all production processes in light of accumulated experience and confirms the ability to produce medicinal products of the required quality in accordance with specifications;
• The manufacturer must validate critical stages of the production process and significant changes to the process;
• The manufacturer must provide all necessary conditions for compliance with the GMP Rules (availability of properly trained personnel with the necessary qualifications; availability of appropriate premises and areas, equipment and maintenance, materials, containers, and labels; approved procedures and instructions in accordance with the pharmaceutical quality system; appropriate storage and transportation conditions);
• The manufacturer must state instructions and procedures in writing clearly and unambiguously, and they must be specifically applicable to the facilities available;
• Personnel must strictly follow procedures and receive training in their correct execution;
• The manufacturer must maintain records during production;
• The manufacturer must fully document and investigate any significant deviations to determine the cause of the deviation and implement appropriate corrective and preventive actions;
• The manufacturer must maintain records relating to the batch, including distribution documentation, in a clear and accessible form to allow the complete history of the batch to be traced;
• During wholesale distribution of products, it is necessary to minimize risks to their quality and take into account the rules of good distribution practice;
• A system must be in place to recall any batch of product from sale or supply;
• The manufacturer must consider complaints about supplied products, investigate the causes of defects, and take appropriate measures both in relation to substandard products and to prevent similar occurrences.

Annex 2 to the GMP Rules establishes additional special requirements for the production and quality control of biological medicines, in particular:

1. Personnel Requirements.

To ensure product safety, the manufacturer must take the health of personnel into account. Employees engaged in production, maintenance, testing, and animal care must be vaccinated with appropriate specific vaccines and undergo regular medical examinations. To minimize the possibility of cross-contamination, it is necessary to control the restriction of personnel movement based on quality risk management principles.

2. Premises and Equipment.

Designers must plan production and storage facilities taking into account requirements for cleanliness classes, and plan processes to prevent product contamination by foreign substances. Work with live cells that are stable in the environment must take place in dedicated production areas. If the manufacturer uses pathogenic microorganisms in production, it must also conduct such production only in dedicated production facilities. Air conditioning systems must be designed, constructed, and maintained in a way that excludes the risk of cross-contamination between different production zones. It is recommended to use "sterilization-in-place" systems where possible.

3. Documentation.

For starting raw materials and materials, additional information is required regarding the source, origin, supply chain, production method, and applied quality control methods. For medicinal products whose production involves human cells or donor tissues, full traceability must be ensured, starting from the raw materials and materials to confirmation of receipt of the medicinal product at the site of its use. At the same time, the manufacturer must ensure patient anonymity and the confidentiality of their health information. Records must be preserved for thirty years after the expiry date of the medicinal product.

4. Starting Raw Materials and Materials.

The manufacturer should clearly define the source, origin, and suitability of biological starting raw materials and materials for their subsequent use. For human tissues (cells) used as starting materials, the following requirements must be met:

• Acquisition, donation, and testing must be carried out in accordance with legislation;
• In cases of importation from other countries, appropriate quality and safety control standards must be met;
• Transportation to the production site must be carried out in accordance with a written agreement between the responsible parties;
• Production sites must have documentary evidence of compliance with relevant specific storage and transportation conditions;
• An agreement must exist between the responsible parties defining the spheres of responsibility of each party (including the designation of responsible and Qualified Persons).

5. Operating Principles.

• Critical operational (technological) or other starting parameters affecting the quality of the medicinal product must be defined, validated, documented, and maintained in accordance with established requirements.
• The strategy for controlling the entry of raw materials and materials into production zones should be based on quality risk management principles.
• The manufacturer should maintain constant monitoring of certain production processes, entering the monitoring results into the batch production records.
• In the event of an accidental spill, especially of live microorganisms, immediate safety measures must be taken. Specific decontamination measures must be provided for each type or group of microorganisms.

6. Quality Control.

• The manufacturer must conduct a continuous assessment of the effectiveness of the quality assurance system, including the maintenance of records that allow for the evaluation of trends.
• A procedure must be in place describing the necessary actions (including interaction with medical professionals) in case test results are obtained that fall outside the specifications. Such cases must be investigated in full.
• Appropriate corrective and preventive actions aimed at preventing the possibility of recurrence of such cases must be recorded in the form of a written document.

The GMP Rules also contain additional guidance on production for certain types of biological medicinal products, such as allergens, vaccines, recombinant products, etc.

Features of Registration of Biological Medicinal Products

Like any other medicinal products, biological medicinal products are subject to state registration and entry into the State Register of Medicinal Products. At the same time, despite their specifics, no separate procedure for their registration was provided for in Russia. Regarding features, the Law on Circulation of Medicinal Products only indicated the need to present additional documents:

• A risk management plan containing a detailed description of measures aimed at identifying, evaluating, and preventing or minimizing risks associated with the use of the product;
• Documents containing information on the entities involved in the circulation of donor blood and its components, the criteria and methods for the selection, transportation, and storage of donor blood and its components; technical characteristics of the packaging for the collection of donor blood and (or) blood plasma – for a product derived from human blood or blood plasma.

Since 2021, the registration of medicinal products in Russia has been carried out according to EAEU rules. The procedure for registration and expertise was approved by Decision of the Council of the Eurasian Economic Commission No. 78 dated November 3, 2016 (the "EAEU Registration Rules").[2] Products registered under the rules of Russian legislation may circulate until the end of their marketing authorizations' validity period, but no later than December 31, 2025. The registration dossiers for such medicinal products must be brought into compliance with EAEU requirements by December 31, 2025.

We note that the EAEU Registration Rules also do not provide for any special procedure for the registration and expertise of biological medicinal products. Among the specifics for forming a registration dossier, the following are specified:

1) additional requirements are established for documents provided in the registration dossier regarding substances, such as:

• Describe production premises and equipment;
• Provide a description and documentary evidence of the origin and history of the acquisition of starting materials;
• Confirm that the active substance meets the requirements of the EAEU Pharmacopoeia for minimizing the risk of transmitting these pathogens with the manufactured medicinal products;
• When using cell banks, provide evidence that the characteristics of the cells remained unchanged;
• Study seed materials, cell banks, serum or plasma pools, and other materials of biological origin for the presence of foreign agents;
• In the production of bacterial and viral vaccines, demonstrate the characteristics of the infectious agent on the seed material;
• For medicinal products derived from human blood or plasma, describe and document the origin, criteria, and methods for the selection, transportation, and storage of starting materials.

2) special requirements are established for the documents of the registration dossier for biological medicinal products derived from plasma, and vaccines.

Biosimilars: Legal Issues of Circulation

Speaking of biological products, it is worth considering the issue of biosimilar (biopurified) medicinal products (the "biosimilar"). According to Article 4 of the Law on Circulation of Medicinal Products, a biosimilar is a biological medicinal product that is similar in parameters of quality, efficacy, and safety to a reference biological medicinal product in the same dosage form and having an identical route of administration. We clarify that "reference" refers to the original medicinal product, and if such is not registered or is not in circulation in Russia and is not in circulation in foreign states – the biosimilar that was first registered in the Russian Federation. Thus, a biosimilar is a medicinal product that is similar in parameters to an original biological product.

The appearance of biosimilars begins after the patent protection period for the original product expires. At the same time, it is necessary to understand that in modern conditions, reproducing a medicinal product obtained through chemical synthesis is not so difficult, which cannot be said about biosimilars. Since they are produced using "living" sources, a biosimilar cannot be an exact copy of the original biological product; moreover, biosimilars may have significant differences in activity, efficacy, and immunogenicity. For instance, in studies of 11 erythropoietin biosimilars conducted by scientists, differences were identified in the content of the active substance, activity, and composition, as well as inter-batch differences.[3] At the same time, these differences may be identified during long-term clinical use. All this creates significant problems in confirming their safety and interchangeability. Let us consider how these procedures are currently carried out.

The registration of biosimilars in Russia is carried out according to the general rules for the registration of medicinal products. An application for the state registration of a biosimilar may be submitted after 3 years from the date of state registration of the reference medicinal product in the Russian Federation (Part 21 of Article 18 of the Law on Circulation of Medicinal Products).

To evaluate the quality, safety, and efficacy of a biosimilar before registration, the Rules for Conducting Research of Biological Medicinal Products of the EAEU apply.[4]

Interchangeability of Biological Medicinal Products

When considering the legal regulation of biological medicinal products, one cannot ignore the topic of their interchangeability. The problem of determining the interchangeability of medicinal products stood sharply for a long time among the medical and pharmaceutical community. And even the introduction in 2014 of the institution and principles of interchangeability into the Law on Circulation of Medicinal Products did not fully eliminate existing disagreements and doubts.

According to Article 4 of the Law on Circulation of Medicinal Products, an interchangeable medicinal product is a medicinal product with proven therapeutic equivalence or bioequivalence in relation to a reference medicinal product, having equivalent qualitative and quantitative composition of active substances, composition of excipients, dosage form, and route of administration.

Thus, the criteria by which the interchangeability of products is determined are: therapeutic equivalence (i.e., achieving a clinically comparable therapeutic effect and indicators of efficacy and safety) and bioequivalence (i.e., achieving comparable indicators of the rate of absorption, degree of entry to the site of action, and rate of excretion of active substances).

The specifics of determining the interchangeability of biological medicinal products are established by Decree of the Government of Russia No. 1360 dated September 5, 2020, On the Procedure for Determining the Interchangeability of Medicinal Products for Medical Use (the "Decree No. 1360").

For biological medicinal products, the interchangeability of medicinal products is established on the basis of the following criteria (characteristics):

• Identity of the INN (in its absence – the grouping or chemical name);
• Equivalence of dosage forms;
• Equivalence of qualitative and quantitative characteristics of pharmaceutical substances included in the products (if any);
• Identity of indications and contraindications for use;
• Equivalence of pharmacokinetics and (or) pharmacodynamics indicators;
• Comparability of safety, efficacy, and immunogenicity indicators based on the results of therapeutic equivalence studies.

For biosimilars, for the reasons mentioned above, what is determined is not equivalence, but the comparability of qualitative and quantitative characteristics of pharmaceutical substances / comparability of the antigenic composition of vaccines. Also, paragraph 13 of Decree No. 1360 presumes that biosimilars that are interchangeable with respect to one reference medicinal product are interchangeable among themselves.

Interchangeability is determined by the Ministry of Health of the Russian Federation on the basis of the conclusion of a commission of experts from the expert institution FSBI "Scientific Center for Expert Evaluation of Medicinal Products" (the "SCEEMP") of the Ministry of Health of Russia. The evaluation is performed by comparing the normative documentation for the medicinal products, reports on conducted bioequivalence or therapeutic equivalence studies of the medicinal products, comparing instructions for medical use, as well as licenses for the production of medicinal products or conclusions on the manufacturer's compliance with the GMP Rules.

The establishment of interchangeability is formalized by a conclusion, which the Ministry of Health places in the personal account of the marketing authorization holder (owner) within 3 working days from the day of its receipt from the expert institution. In addition, the list of interchangeable medicinal products is posted on the official website of the Ministry of Health of Russia and updated at least once a month.

The conclusion may be appealed to the Ministry of Health of Russia within 20 working days from the date of its placement by filing a complaint through the applicant's personal account. Its consideration is carried out by a commission, which includes representatives of scientific organizations and educational organizations of higher education engaged in activities in the sphere of the circulation of medicinal products.

If the expert institution identifies the absence in the registration dossier for a biosimilar of the results of a bioequivalence study or therapeutic equivalence study in relation to the reference medicinal product, the expert institution reports this to the Ministry of Health of Russia within 3 working days from the date of identifying the absence of the said information. The Ministry of Health sends a request to the marketing authorization holder / owner regarding the need to submit a report on the results of the relevant clinical studies of the medicinal product. The timeframe for providing the report is determined by the expert institution, but shall not exceed 3 years.

The rules for the circulation of biosimilars until the end of the period established for conducting studies of their bioequivalence or therapeutic equivalence are approved by Decree of the Government of Russia No. 1583 dated October 1, 2020 (the "Decree No. 1583").[5]

According to Decree No. 1583, upon receiving a request, the holder or owner must submit an application for the issuance of a permit to conduct a clinical study within 180 working days. A report on the results of the clinical study is submitted to the Ministry of Health within a period not exceeding 3 months from the date of its completion. Next, the Ministry of Health sends its report to the FSBI "Scientific Center for Expert Evaluation of Medicinal Products" within 10 working days for a conclusion.

Until the day of submission to the Ministry of Health of the report on the conducted clinical trials, measures for quality and safety control of medicinal products are taken:

• Selective quality control;
• Submission by the marketing authorization holder or owner to Roszdravnadzor of periodic safety update reports for the medicinal products once every 3 months.

In conclusion, we note that in the context of creating unified conditions for the circulation of medicinal products within the Eurasian Union, it is necessary to harmonize requirements, including those for biological medicinal products. However, this work is still very far from completion. Furthermore, the problem of increasing safety measures for biological products, including by improving regulatory requirements, remains relevant.

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References

[1] Production of Gene Therapy Medicinal Products: Issues of Law and Ethics // Medical Law: Theory and Practice, 2021, No. 2.

 [2] Decision of the Council of the Eurasian Economic Commission No. 78 dated November 3, 2016, On the Rules for Registration and Expertise of Medicinal Products for Medical Use.

[3] Biosimilars in Modern Healthcare: What Does a Clinician Need to Know? // Clinical Pharmacology and Therapy, 2011, 20 (1).

[4] Decision of the Council of the Eurasian Economic Commission No. 89 dated November 3, 2016, On the Approval of the Rules for Conducting Research of Biological Medicinal Products of the Eurasian Economic Union.

[5] Decree of the Government of Russia No. 1583 dated October 1, 2020, On the Approval of the Rules for the Circulation of Generic Medicinal Products, Biosimilar (Biopurified) Medicinal Products (Biosimilars) Until the End of the Period Established for Conducting Research on Their Bioequivalence or Therapeutic Equivalence or Making Changes