02 February 2022

Concept and Types of Medicinal Products

BRACE Law Firm ©

February 2, 2022

Modern medicine cannot function without medicinal products, and their global volume continues to grow annually. Navigating this diversity is becoming increasingly difficult. However, understanding the definition of a medicinal product and its various types is a vital tool for making informed pharmaceutical selections.

Pursuant to Clause 1 of Article 4 of Federal Law No. 61-FZ dated April 12, 2010, On Circulation of Medicinal Products (the "Law No. 61-FZ" or the "Law on Circulation of Medicinal Products"), medicinal products (the "MP" or the "medicinal products") are defined as "substances or combinations thereof that come into contact with the human or animal body, penetrate the organs and tissues of the human or animal body, and are used for the prevention, diagnosis (excluding substances or combinations thereof that do not contact the human or animal body), treatment of disease, rehabilitation, for the preservation, prevention, or termination of pregnancy, and are obtained from blood, blood plasma, organs, or tissues of the human or animal body, plants, minerals, by synthesis methods, or through the application of biological technologies".

Pharmaceutical Substances and Medicinal Products

Medicinal products include pharmaceutical substances and medicinal products (as dosage forms). For a detailed analysis, we provide their precise definitions from Article 4 of the Law on Circulation of Medicinal Products:

"Pharmaceutical substance — a medicinal product in the form of one or more active substances possessing pharmacological activity, regardless of the nature of their origin, which is intended for the production or manufacturing of medicinal products and determines their efficiency";
"Medicinal products — medicinal products in the form of dosage forms used for the prevention, diagnosis, treatment of disease, rehabilitation, for the preservation, prevention, or termination of pregnancy".

Russia maintains a state standard establishing requirements for the production and quality control of medicinal products for humans and animals: GOST R 52249-2009, Rules for the Production and Quality Control of Medicinal Products (the "GOST R 52249-2009"), as well as the Rules for the Production of Medicinal Products of the EAEU.[1] and the Russian Federation.[2]. Pursuant to Clause 20 of the aforementioned GOST, an active pharmaceutical ingredient (the "API") is "any substance or mixture of substances intended for the production of medicinal products that, in the process of manufacturing a medicinal product, becomes an active ingredient of that medicinal product". Such substances are intended to exhibit pharmacological activity or other direct effects in the diagnosis, treatment, symptom relief, or prevention of disease, or to affect the structure or function of the body.

Note that medicinal products, under Clause 4 of Article 4 of Law No. 61-FZ, may be used for:

prevention, which is a set of measures aimed at preserving and strengthening health, including the formation of a healthy lifestyle, prevention of the occurrence and (or) spread of diseases, their early detection, identification of the causes and conditions of their occurrence and development, as well as measures aimed at eliminating the harmful influence of environmental factors on human health (Clause 6 of Article 2 of Federal Law No. 323-FZ dated November 21, 2011, On the Fundamentals of Health Protection of Citizens in the Russian Federation(the "Law No. 323-FZ"));
diagnosis, which, pursuant to Clause 7 of Article 2 of Law No. 323-FZ, is a set of medical interventions aimed at recognizing conditions or establishing the presence or absence of diseases, carried out by collecting and analyzing patient complaints, medical history, and physical examinations, as well as conducting laboratory, instrumental, pathological, and other studies to determine a diagnosis and choose treatment measures and (or) monitor their implementation;
treatment of a disease — a set of medical interventions performed by appointment of a medical worker, the goal of which is to eliminate or alleviate the manifestations of a disease or condition, restore or improve health, working capacity, and quality of life.[3];
rehabilitation, which is a set of medical and psychological measures aimed at the full or partial restoration of impaired functions and (or) compensation for lost functions of an affected organ or body system, maintaining body functions during the completion of an acute pathological process or exacerbation of a chronic process, as well as the prevention, early diagnosis, and correction of potential functional impairments, reducing the degree of potential disability, improving quality of life, and maintaining the patient's ability to work and social integration.[4];
preserving, preventing, or terminating pregnancy.

Furthermore, according to GOST R 52249-2009, a medicinal (medical) product is a "dosage form of a medicinal product in primary final packaging intended for sale".

Thus, these definitions clarify that medicinal products are finished dosage forms (solutions, ointments, tablets, etc.) ready for administration, whereas a pharmaceutical substance is essentially the active ingredient used for producing medicinal products.

A clear understanding of the difference between a medicinal product and a pharmaceutical substance is crucial in practice, as administrative decisions may depend on it.

For example, in Case No. A07-43115/19, JSC NPO Microgen filed a claim against the Interregional Administration of Rosalkogolregulirovanie to invalidate a resolution imposing administrative liability under Article 14.19 of the CAO RF. The case files reveal a discrepancy in the concepts applied. The authority believed the company had purchased a pharmaceutical substance of ethyl alcohol (ethanol) and should have applied Federal Law No. 171-FZ dated November 22, 1995, On the State Regulation of the Production and Circulation of Ethyl Alcohol, Alcoholic and Alcohol-Containing Products and on the Restriction of the Consumption (Drinking) of Alcoholic Products (the "Law No. 171-FZ"). Conversely, the company purchased an alcohol-containing product — the medicinal product "Ethyl alcohol, concentrate for preparation of solution for external use and preparation of dosage forms 95%" — for use as an auxiliary material in the production of non-alcohol-containing products or for technical purposes. The medicinal product purchased by the company was not an ingredient in the company's final non-alcohol-containing output. The product used by JSC NPO Microgen in its business activities was a medicinal product and not a pharmaceutical substance of ethyl alcohol (ethanol) within the meaning of Clause 2.1 of Article 2 of Law No. 171-FZ; consequently, the provisions of Law No. 171-FZ did not apply to the company's activities in the disputed episodes, as they were governed by the norms of Law No. 61-FZ. The Arbitration Court sided with JSC NPO Microgen, granting its claims and invalidating the administrative resolution.[5].

Medicinal Products for Medical and Veterinary Use

Based on the definition in Law No. 61-FZ, a "medicinal product" consists of "substances or combinations thereof that come into contact with the human or animal body, penetrate organs and tissues of the human or animal body". However, despite this unified definition, the application of medicinal products differs for humans and animals. Veterinary medicinal products are governed by a separate standard, GOST R 52682-2006, Medicinal Products for Veterinary Use (the "GOST R 52682-2006"). Section 2.1 of this standard defines a medicinal product for veterinary use as a substance or mixture of substances of natural, plant, animal, or synthetic origin possessing pharmacological action. The circulation of veterinary medicinal products is a broad concept covering development, research, production, manufacturing, labeling, packaging, storage, transport, state registration, sale, application, and other actions, including the disposal of substandard or falsified medicinal products for veterinary use.

Furthermore, the state registration of medicinal products for humans and animals is conducted by different executive authorities based on separate regulatory documents.

State registration of medicinal products for medical use is conducted by the Ministry of Health of Russia pursuant to Order of the Ministry of Health of Russia No. 725n dated September 21, 2016, and is performed by the Ministry of Health.[6], whereas the release into civil circulation of medical medicinal products is governed by Decree of the Government of the Russian Federation No. 1510 dated November 26, 2019.[7]. In contrast, the state registration of medicinal products for animals is performed by the Federal Service for Surveillance in Veterinary and Phytosanitary Oversight.[8].

Original and Generic Medicinal Products

To understand this issue, one must examine the concepts of original and generic medicinal products. Pursuant to Clause 10.1 of Article 4 of Law No. 61-FZ, an original medicinal product is a "medicinal product with a new active substance that is the first to be registered in the Russian Federation or in foreign states based on results of preclinical studies of medicinal products and clinical trials of medicinal products confirming its quality, efficiency, and safety".

The majority of the modern pharmaceutical market consists of generic medicinal products. This is due to several factors, primarily the complexity and duration of developing original products and their high cost.

In medical practice, various other names for generic medicinal products are common, such as "generics", "generic medicinal products", or "multi-source medicinal products". A generic medicinal product (Generic) is a medicinal product for medical use that has a qualitative and quantitative composition of active substances and dosage form equivalent to a reference medicinal product, or a veterinary medicinal product with the same composition and form as its reference counterpart, provided its bioequivalence or therapeutic equivalence to the reference product has been confirmed by relevant studies.[9].

Generics enter the pharmaceutical market much more easily because they rely on equivalence studies. Thanks to these studies, "generics" generally skip three stages of clinical trials required for the registration of reference medicinal products, making the process significantly less labor-intensive and expensive.

The term "reference" is associated with the specifics of medicinal product registration and studies of bioequivalence or therapeutic equivalence. Pursuant to Clause 11 of Article 4 of Law No. 61-FZ, a reference medicinal product is a "medicinal product used to assess the bioequivalence or therapeutic equivalence, quality, efficiency, and safety of a generic medicinal product or a bioanalogous (biosimilar) medicinal product (bioanalog). An original medicinal product is used as the reference product for medical use; however, if the original product is not registered or in circulation in the Russian Federation or foreign states, the generic or bioanalog registered first among those in circulation in the Russian Federation is used, provided its equivalence and safety were assessed against the original product and are confirmed by pharmacovigilance results and quality compliance checks".

Historically, the concept of a "reference medicinal product" was first introduced into Russian legislation in 2014, defined then as "a medicinal product first registered in the Russian Federation, the quality, efficiency, and safety of which are proven based on preclinical and clinical studies conducted in accordance with Clause 3 of Article 18 of Law No. 61-FZ, and which is used to assess the bioequivalence or therapeutic equivalence of a generic or bioanalogous product".[10].

While original and generic products contain the same active substance in the same dosage and form, their efficiency and safety may differ significantly due to manufacturing technologies, auxiliary substances, packaging, and storage or transport conditions. Typically, the cost of a generic is lower than that of the original.

Biological Medicinal Products

Since ancient times, humans have used natural substances, primarily herbs, for healing. With the advancement of science and medicine, the ability to cure diseases has expanded. Beyond simple chemical compounds, humans have learned to isolate proteins from living cells, which form the basis of some biological medicinal products. Some biologicals today are very similar to proteins naturally formed in the human body, such as insulin, growth hormones, and growth factors that control blood cell production. Other biologicals are not copies of natural proteins but are enhanced in laboratory settings to increase bioavailability, specificity, and efficiency. The most well-known examples are antibodies, which bind to cell surfaces and are widely used in oncology.

Pursuant to Clause 6.2 of Article 4 of Law No. 61-FZ, biological medicinal products are those whose active substance is produced or isolated from a biological source, requiring a combination of biological and physicochemical methods to determine their properties and quality.

Biological medicinal products include:

immunobiological medicinal products(ILP), which are intended to form active or passive immunity, diagnose the presence of immunity, or diagnose specific immunological responses to allergens. ILPs include vaccines, toxoids, toxins, sera, immunoglobulins, and allergens (Clause 7 of Article 4 of Law No. 61-FZ). Additionally, regarding infectious diseases, Federal Law No. 157-FZ dated September 17, 1998, On the Immunoprophylaxis of Infectious Diseases(the "Law No. 157-FZ"), defines immunobiological medicinal products for immunoprophylaxis as "vaccines, toxoids, immunoglobulins, and other medicinal products intended to create specific immunity to infectious diseases". Using these products, humanity has nearly eradicated diseases such as smallpox, cholera, and diphtheria. Pharmacy organizations dispense ILPs for immunoprophylaxis to citizens only upon prescription.[11];
medicinal products derived from human or animal blood or plasma (excluding whole blood). This category has been known to medicine for a long time. For example, a diphtheria treatment was invented based on blood serum immunoglobulins (antibodies). This enabled new drugs for dangerous diseases like Hepatitis B, tick-borne encephalitis, and tetanus;
biotechnological medicinal products— medicinal products produced using biotechnological processes and methods, including recombinant DNA technology, controlled gene expression technology, hybridoma methods, and monoclonal antibody methods.[12]. The active substance has a biological origin, is derived from living cells, and possesses a complex heterogeneous molecular structure. The starting substrate consists of animal cells or microorganisms;
gene therapy medicinal products— medicinal products whose pharmaceutical substance is or includes recombinant nucleic acid, allowing for the regulation, repair, replacement, addition, or deletion of a genetic sequence.[13]. This is a relatively new field. For diseases that previously had no therapy, gene therapy may offer a cure for conditions such as hemophilia, HIV, diabetes, and cancer.

According to the Law on Circulation of Medicinal Products, a bioanalogous (biosimilar) medicinal product (bioanalog) is a "biological medicinal product similar in quality, efficiency, and safety to a reference biological product in the same dosage form and with an identical administration route".[14]. The circulation of generic and bioanalogous products is governed by Decree of the Government of the Russian Federation No. 1583 dated October 1, 2020.

This group of products cannot be analyzed without defining an interchangeable medicinal product, which, pursuant to Clause 12.3 of Article 4 of Law No. 61-FZ, is a medicinal product with proven therapeutic or bioequivalence to a reference product, having equivalent qualitative and quantitative composition, excipients, dosage form, and administration route. The interchangeability of medicinal products for medical use is determined by the Ministry of Health of Russia within a single International Nonproprietary Name (INN) based on the conclusion of an expert commission.[15]. The procedure is regulated by Decree of the Government of the Russian Federation No. 1360 dated September 5, 2020.

Narcotic and Psychotropic Medicinal Products

This is a special category because such products can provide medical benefits but may also cause irreparable harm or addiction (e.g., drug addiction) if used without control.

Narcotic medicinal products are "medicinal products and pharmaceutical substances containing narcotic drugs included in the List of narcotic drugs, psychotropic substances, and their precursors subject to control in the Russian Federation in accordance with Russian legislation and international treaties, including the Single Convention on Narcotic Drugs of 1961".[16];

Psychotropic medicinal products are "medicinal products and pharmaceutical substances containing psychotropic substances included in the List of narcotic drugs, psychotropic substances, and their precursors subject to control in the Russian Federation in accordance with Russian legislation and international treaties, including the Convention on Psychotropic Substances of 1971".[17];

The circulation of narcotic and psychotropic substances is under strict state control and regulated by Federal Law No. 3-FZ dated January 8, 1998, On Narcotic Drugs and Psychotropic Substances (the "Law No. 3-FZ"). For narcotic and psychotropic substances permitted for medical use, the legislation on the circulation of medicinal products also applies unless it contradicts Law No. 3-FZ. Additionally, to use these substances for medical purposes, medical organization officials must obtain a certificate of no criminal record for employees who will have direct access to precursors.

Herbal Medicinal Products

Herbal mixtures formed the basis of medical care for centuries and remain widespread today. While herbal treatment is often viewed as alternative medicine, practicing physicians frequently prescribe them.

Pursuant to Clause 14 of Article 4 of Law No. 61-FZ, a herbal medicinal product is a "medicinal product produced or manufactured from one or several types of herbal medicinal raw materials and sold in pre-packaged form in secondary (consumer) packaging".

Such products are typically used to achieve an additional medical effect. However, a physician must precisely know which herbal products to prescribe alongside primary therapy, as some herbal products can produce adverse effects when taken, for example, with antibiotics.

Homeopathic Medicinal Products

Homeopathy is another field, involving the use of extremely small doses prepared for specific patients using specialized technologies. Unlike allopathy (classical pharmacotherapy), homeopathy lacks a standard evidence base.

A homeopathic medicinal product is defined as a "medicinal product produced or manufactured from a pharmaceutical substance or substances in accordance with the requirements of general pharmacopoeial monographs for homeopathic medicinal products or the pharmacopoeia of the manufacturer's country".[18].

Radiopharmaceutical Medicinal Products

Radiopharmaceutical products, pursuant to Clause 10 of Article 4 of Law No. 61-FZ, are medicinal products containing one or several radionuclides (radioactive isotopes) in a ready-to-use form. They are used for biomedical research, radioisotope diagnostics, and the treatment of various diseases, primarily radiotherapy for malignant tumors.

In therapeutic radiopharmaceuticals, the radionuclide is the primary therapeutic agent, allowing the radiation dose to be localized directly in the target organ or affected cells, thereby minimizing exposure to surrounding healthy tissues.

The manufacturing of radiopharmaceutical products directly within medical organizations is regulated by Order of the Ministry of Health of Russia No. 1218n dated November 12, 2020.

Orphan Medicinal Products

Pursuant to Clause 6.1 of Article 4 of the Law on Circulation of Medicinal Products, orphan medicinal products are "medicinal products intended exclusively for the diagnosis or pathogenetic treatment (treatment targeting the mechanism of the disease) of rare (orphan) diseases".

Under Clause 1 of Article 43 of Law No. 323-FZ, rare (orphan) diseases are those with a prevalence of no more than 10 cases per 100,000 population. Examples include hemophilia, cystic fibrosis, and malignant neoplasms of lymphoid tissue.

The list of medicinal products for treating such diseases is approved by Appendix No. 3 to Order of the Government of the Russian Federation No. 2406-r dated October 12, 2019.

The availability of a diverse range of medicinal products on the market allows for higher-quality medical care, reflecting progress in medicine and the integration of both ancient herbal knowledge and modern research using radionuclides.

_______________________

References

[1] Decision of the Council of the Eurasian Economic Commission No. 77 dated November 3, 2016, On Approval of the Rules of Good Manufacturing Practice of the Eurasian Economic Union.

[2] 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.

[3] Clause 8 of Article 2 of Law No. 323-FZ.

[4] Clause 1 of Article 39 of Law No. 323-FZ.

[5] Resolution of the Arbitration Court of the Ural District No. F09-2590/21 dated June 15, 2021, in Case No. A07-43115/2019; Resolution of the Eighteenth Arbitration Appellate Court No. 18AP-15836/2020 dated January 25, 2021, in Case No. A07-43115/2019.

[6] Clause 5.5.23 of the Regulation on the Ministry of Health of the Russian Federation, approved by Decree of the Government of the Russian Federation No. 608 dated June 19, 2012.

[7] Decree of the Government of the Russian Federation No. 1510 dated November 26, 2019, On the Procedure for Release into Civil Circulation of Medicinal Products for Medical Use.

[8] Clause 5.2(1).11 of the Regulation on the Federal Service for Surveillance in Veterinary and Phytosanitary Oversight, approved by Decree of the Government of the Russian Federation No. 327 dated June 30, 2004.

[9] Clause 12 of Article 4 of Law No. 61-FZ.

[10] Federal Law No. 429-FZ dated December 22, 2014, On Amending the Federal Law On Circulation of Medicinal Products.

[11] Clause 3 of Article 12 of Law No. 157-FZ.

[12] Clause 7.1 of Article 4 of Law No. 61-FZ.

[13] Clause 7.2 of Article 4 of Law No. 61-FZ.

[14] Clause 12.2 of Article 4 of Law No. 61-FZ.

[15] Part 1 of Article 27.1 of Law No. 61-FZ.

[16] Clause 8 of Article 4 of Law No. 61-FZ.

[17] Clause 9 of Article 4 of Law No. 61-FZ.

[18] Clause 15 of Article 4 of Law No. 61-FZ.