26 May 2024

Packaging of Medicinal Products in Russia

May 26, 2024

Packaging is a crucial component of a medicinal product and performs a significant number of functions, including protection against external factors (light, air, moisture, temperature changes, mechanical damage), ensuring safety during transportation, storage, and use, and informing consumers about the medicinal product.

Furthermore, packaging design can play a role in promoting the medicinal product on the market, contributing to its recognizability and popularity.

Understanding the importance of ensuring the quality of medicinal product packaging, the legislator establishes sufficiently high requirements for its materials and elements. Moreover, in recent years, these requirements have frequently been replaced and supplemented due to changes in production technologies and the expansion of the range of materials and devices used.

In this article, we will examine the current requirements for the packaging of medicinal products in Russia and the liability for violating these requirements.

Concept and Elements of Medicinal Product Packaging

The main regulatory acts governing requirements for medicinal product packaging in the Russian Federation are:

Federal Law No. 61-FZ dated April 12, 2010, "On the Circulation of Medicinal Products" (hereinafter, the "Law on Medicinal Products," "FZ No. 61-FZ");
Pharmacopoeia of the Eurasian Economic Union, approved by Decision of the Board of the Eurasian Economic Commission No. 100 dated August 11, 2020 (hereinafter, the "EAEU Pharmacopoeia");
General Pharmacopoeia Article "Packaging of Medicinal Products," approved by Order of the Ministry of Health of Russia No. 377 dated July 20, 2023 (hereinafter, "1.1.0035").

The EAEU Pharmacopoeia is harmonized with the requirements of the national pharmacopoeias of the EAEU member states. In particular, its provisions are similar to OFS.1.1.0035; therefore, further in this article, we will rely primarily on the norms of the EAEU Pharmacopoeia.

According to Section 2.4.2.1 of the EAEU Pharmacopoeia, packaging is a material or device guaranteeing the preservation of the quality of a medicinal product throughout the established shelf life (storage period), ensuring its protection from damage and loss, and protecting the environment from pollution.

Packaging elements include the container, closures, components, and other auxiliary packaging elements. The container (tara) is the main element of the packaging intended directly for holding the medicinal product. For example, an ampoule for a solution for injection, or a blister for tablet dosage forms.

The design of the container and the specific features of the medicinal product may provide for closures to create hermeticity or a closed space. Closures come in various shapes and types. The main types of closures are stoppers, lids, and caps. They may also be equipped with protective or sealing devices (membranes, safety rings, etc.).

A component ("komplektuyushchee sredstvo") is an item placed in the consumer packaging of a medicinal product and used for the correct dosing, administration, or application of the medicinal product. The EAEU Pharmacopoeia classifies items such as dosing nozzles, measuring spoons, pipettes, and eye and nasal droppers as components.

Auxiliary elements are used to maintain and improve the packaging's performance of its intended functions: protecting the contents from destruction and contact with environmental factors. Examples include liners, gaskets, desiccants, etc.

It should be noted that permissible types of packaging elements, as well as requirements for materials used in the production of packaging and packaging elements, are regulated in detail in the EAEU Pharmacopoeia and OFS.1.1.0035.

Types and Selection Criteria for Medicinal Product Packaging

The EAEU Pharmacopoeia identifies several classifications of packaging types:

1. Based on direct contact with the medicinal product, packaging is classified into primary, secondary, intermediate, and group packaging.

Primary packaging is packaging that is in direct contact with the medicinal product. Examples include blisters, ampoules, bottles, vials, etc. In some cases, primary packaging may represent a specialized delivery system for the medicinal product, such as an aerosol or a dosing device adjusted to dispense a single dose of the medicinal product. Types of primary packaging are listed in the Annex to the Nomenclature of Dosage Forms, approved by Decision of the Board of the Eurasian Economic Commission No. 172 dated December 22, 2015.

Secondary packaging contains one or more units of primary packaging (e.g., cardboard packs) and, in some cases, may also contain components. Secondary packaging must contain a significant amount of information about the medicinal product for its intended use; therefore, it is also called consumer packaging.

For additional protection of the medicinal product, primary packaging may be placed in intermediate packaging.

Medicinal products in secondary (consumer) packaging may be placed in group packaging, which typically consists of cardboard boxes subsequently wrapped in paper, film, etc. Group packaging is generally used for convenience and preservation during the transportation of medicinal products.

2. By type (material and design) and form (shape), there is a significant number of packaging types: ampoules, cylinders, bottles, bags, tubes, vials, etc. The concept of each is contained in the EAEU Pharmacopoeia.

3. By protection against opening, packaging is distinguished as tamper-evident and child-resistant.

4. By protection against external factors, packaging is divided into well-closed, tightly closed, hermetically closed, hermetically sealed, airtight, moisture-proof, light-resistant, isometric, and vacuum packaging.

5. By number of uses and number of doses, packaging is divided into single-use, multi-use, single-dose, and multi-dose.

6. By mechanical properties, packaging can be rigid, soft, fragile, or flexible.

The manufacturer selects the type of packaging during the development stage of the medicinal product, taking into account the following criteria formulated in the EAEU Pharmacopoeia:

The purpose of the packaging;
The intended use of the medicinal product being packaged and its quantity;
The properties of the active pharmaceutical substance and the components of the medicinal product, including active substances and excipients;
The properties of the dosage form of the medicinal product;
The compatibility of each element of the primary packaging with the components of the medicinal product;
The required degree of protection of the medicinal product from the influence of external factors (atmospheric, microbiological, physical) at all stages of circulation, including storage, transportation, and sale;
The protective characteristics of packaging materials, containers, closures, packaging design, etc.;
The shelf life of the medicinal product;
The filling method;
The labeling method of the medicinal product;
The convenience of using the packaging for the consumer (number of doses, packaging parameters, method of opening/closing, legibility of labeling, method of dosing and administration of the medicinal product).

The EAEU Pharmacopoeia also establishes specific packaging selection features for certain types of medicinal products. In particular, special requirements are defined for solid, soft, and liquid dosage forms, sterile dosage forms, volatile medicinal products, light-sensitive medicinal products, and several others. These specific packaging requirements are determined by the characteristics of the medicinal product, the technological process of its manufacture, as well as storage and use. For example, medicinal products containing volatile substances must be packaged in jars or vials sealed with screw caps and equipped with sealing elements. Light-sensitive products must have light-resistant packaging. Packaging for soft dosage forms must ensure protection against microbiological contamination; the preferred packaging is tubes made of flexible materials.

General Requirements for Medicinal Packaging

In addition to requirements for the design and materials of packaging, the EAEU Pharmacopoeia also provides general requirements for the packaging of medicinal products. The main requirements are as follows:

The packaging of the medicinal product must be of appropriate quality.
The packaging must be uniform for each batch of packaged medicinal products.
The packaging of medicinal products must be clean, dry, and free of foreign odors.
The packaging must ensure the preservation of the efficacy, quality, and safety of the medicinal product at all stages of its circulation: it must not lead to the loss of the medicinal product; it must be strong enough to hold the contents during normal use; and it must not change under the influence of the medicinal product's components.
The packaging must possess properties that protect the medicinal product from the adverse effects of environmental factors capable of affecting its quality or efficacy, such as light, temperature, atmospheric gases, and air vapors, and prevent the permeation (penetration) of said factors to the medicinal product through packaging materials and closures.
The packaging must protect the medicinal product from physical (mechanical) damage.
The packaging must ensure compliance with the storage conditions of the medicinal product.
The packaging must contribute to protecting the consumer from counterfeiting and falsification, preventing the opening of the medicinal product before use, and ensuring convenience and safety during its use.
The packaging must have an aesthetic appearance, be convenient for transportation and storage, be economical, comply with modern environmental standards, and require minimal disposal costs.

As we can see, most of these requirements are quite obvious and are observed in the packaging of modern medicinal products.

Specific Packaging Features for Narcotic Drugs and Psychotropic Substances

Special packaging requirements are established regarding narcotic drugs and psychotropic substances. According to Article 27 of Federal Law No. 3-FZ dated January 8, 1998 "On Narcotic Drugs and Psychotropic Substances", primary packaging of narcotic drugs and psychotropic substances, as well as the transport container in which they are placed, must exclude the possibility of their extraction without violating the integrity of said packaging.

Primary packaging and secondary (consumer) packaging of narcotic drugs and psychotropic substances listed in List II and used for medical purposes and/or veterinary medicine must be marked with a double red stripe.

In cases where primary packaging and secondary (consumer) packaging of narcotic drugs and psychotropic substances do not comply with the requirements of the law, they are subject to destruction.

Specific Packaging Features for Alcohol-Containing Medicinal Products

In accordance with Part 4.1 of Article 45 of the Law on Medicinal Products, authorized federal executive bodies are empowered to approve a list of medicinal products for which requirements regarding container volume, packaging, and completeness are established. In exercising these powers, Order of the Ministry of Health of Russia No. 778n dated July 31, 2020 [1] approved a list of medicinal products for medical use (tinctures, balms, drops, elixirs, etc.) that may be produced in containers with a volume of no more than 25, 50, and 100 ml.

Labeling and Packaging of Medicinal Products

Legislation also establishes requirements for labeling applied to the packaging of a medicinal product. These are provided for by Article 46 of the Law on Medicinal Products and the Requirements for the Labeling of Medicinal Products for Medical Use and Veterinary Medicinal Products, approved by Decision of the Council of the Eurasian Economic Commission No. 76 dated November 3, 2016 (hereinafter, the "Requirements").

In accordance with Article 46 of FZ No. 61-FZ, medicinal products, except for medicinal products manufactured by pharmacy organizations, veterinary pharmacy organizations, and individual entrepreneurs, must enter circulation in compliance with the following labeling requirements:

Their primary packaging (except for herbal preparations) must indicate the name of the medicinal product (INN, or grouping, or chemical, or trade name), batch number, release date (for immunobiological medicinal products), expiration date, dosage or concentration, volume, activity in units of action, or number of doses;
Their secondary (consumer) packaging must indicate the name of the medicinal product (INN, or grouping, or chemical and trade names), the name of the manufacturer of the medicinal product, batch number, release date (for immunobiological medicinal products), registration certificate number, expiration date, method of administration, dosage or concentration, volume, activity in units of action or number of doses in the package, dosage form, dispensing conditions, storage conditions, and warning labels.

The procedure for indicating each element of information is regulated in detail in Section III of the Requirements.

Certain medicinal products must also bear warning labels on their secondary (consumer) packaging:

Antibodies to HIV-1, HIV-2, hepatitis C virus, and hepatitis B surface antigen are absent – for products derived from human blood, blood plasma, organs, and tissues;
Homeopathic – for homeopathic preparations;
Product has passed radiation control – for herbal medicinal preparations;
For veterinary use – for medicinal products for veterinary use;
Radiation hazard symbol – for radiopharmaceutical medicinal products.

As a general rule, medicinal product labeling is applied in the Russian language, must be legible, understandable, and truthful, and must not mislead consumers. Important information for the correct and safe use of the medicinal product must be indicated in the largest possible font size (Clauses 2, 3, 40 of the Requirements). The color of inscriptions, signs, and symbols must contrast with the background on which the labeling is applied. The method of applying labeling must ensure its preservation throughout the entire shelf life of the medicinal product.

Due to the implementation of the medicinal product monitoring system in the Russian Federation, a barcode is applied to the secondary (consumer) packaging of the medicinal product. More details on the procedure for its application can be found in our article on this topic [2].

Correct labeling is a crucial indicator of the quality of medicinal product packaging.

GMP Requirements for Medicinal Product Packaging

Requirements for the production of medicinal products are regulated by the Rules of Good Manufacturing Practice of the EAEU, approved by Decision of the Council of the Eurasian Economic Commission No. 77 dated November 3, 2016 (hereinafter, "GMP Rules"). Since the packaging process constitutes one of the production stages, the GMP Rules also regulate requirements for packaging materials, supplier selection, and the technological process itself. Let us examine them in more detail.

GMP Requirements for Packaging Materials

The purchase, handling, and control of primary and printed packaging materials shall be accorded attention similar to that given to starting materials (Clause 5.45 of the GMP Rules).

Each delivery or batch of primary or printed packaging materials must be given a specific reference number or identification mark (Clause 5.47 of the GMP Rules).

Outdated or obsolete primary packaging material or printed packaging material shall be destroyed and this disposal recorded (Clause 5.48 of the GMP Rules).

GMP Requirements for Packaging Operations

Before packaging operations begin, steps should be taken to ensure that the work area, packaging lines, printing machines, and other equipment are clean and free from any products, materials, or documents previously used, if these are not required for the current operation (Clause 5.50).

Upon arrival of products and packaging materials at the packaging station, checks should be made to ensure that the quantity, identity, and conformity to the packaging instructions are correct (Clause 5.52).

Labeling should be applied as quickly as possible after filling and sealing. Prior to applying labeling, necessary measures should be taken to prevent mix-ups or mislabeling (Clause 5.54).

GMP Requirements for Documentation

There must be appropriately authorized specifications for packaging materials, including the date of approval (Clause 4.13 of the GMP Rules).

Specifications for primary or printed packaging materials should include the following information:

Description of the materials, including: name and internal code reference; reference to a pharmacopoeial monograph or other normative documentation or standard; the approved suppliers and, if possible, the original producer of the starting and packaging materials; a specimen of printed materials;
Directions for sampling and testing;
Qualitative and quantitative requirements with acceptance limits;
Storage conditions and precautions;
The maximum period of storage before re-examination (Clause 4.14).

For every medicinal product and for each batch size and type of packaging, there should be packaging instructions. Normally, these should include the following:

Name of the product and the batch number of the bulk and finished product;
Description of its pharmaceutical form and strength, where applicable;
The pack size expressed in terms of the number, weight, or volume of the product in the final container;
A complete list of all the packaging materials required, including quantities, sizes, and types, with the code or reference number relating to the specifications of each packaging material;
Where applicable, an example or reproduction of the relevant printed packaging materials, and specimens indicating where to apply batch number references and shelf life of the product;
Checks that the equipment and work station are clear of previous products, documents, or materials not required for the planned packaging operations (line clearance), and checks for cleanliness of the equipment and its readiness for the next process;
Precautions to be observed (including a careful examination of the area and equipment) in order to ensure that the packaging line is cleared before the start of the operation;
Description of the packaging operation, including any significant subsidiary operations and equipment to be used;
Details of in-process controls with instructions for sampling and acceptance limits.

Additionally, other documents may be developed to specify the provisions of the manufacturing formula and processing instructions (Clause 4.19).

The GMP Rules also state that manufacturers of finished products are responsible for all testing of packaging materials as described in the marketing authorization dossier (Clause 5.35). Thus, one can agree with researchers on this topic [3] that GMP Rules guarantee that packaging means are produced in a consistent manner according to standards appropriate for their use.

It should be noted that in accordance with the rules for registration and examination of medicinal products for medical use [4], the dossier for a medicinal product includes information on the characteristics and properties of packaging materials and closures, as well as mock-ups of the primary and secondary packaging of the medicinal product. All this information is provided as part of the documents for the registration and examination of the medicinal product. Information on all permitted types of packaging is entered into the State Register of Medicinal Products (GRLS). Thus, as a general rule, the circulation of medicinal products is allowed only in the packaging indicated in the GRLS.

An exception to this rule is formulated in Article 47 of the Law on Medicinal Products. According to Part 3.2 of said norm, until December 31, 2024, the importation into the Russian Federation and circulation of registered medicinal products for medical use in packaging intended for circulation in foreign countries is permitted in the event of a shortage (defectura) of medicinal products or a risk thereof due to the introduction of restrictive economic measures against the Russian Federation. The procedure for the circulation of such preparations is defined in Decree of the Government of Russia No. 593 dated April 5, 2022 [5].

According to said decree, the importation and circulation of such medicinal products are allowed based on a permit from the interdepartmental commission of the Ministry of Health of Russia, provided they comply with the requirements established during registration, with the exception of requirements for primary and secondary (consumer) packaging.

The following rules for introducing such medicinal products into circulation have been established:

A label containing information about the product in Russian must be affixed to the consumer and primary (if applicable) packaging;
Each package of the batch (lot) of the medicinal product must be accompanied by instructions for medical use of the medicinal product translated into Russian, approved by the authorized body of the manufacturer's country or the marketing authorization holder;
Labeling (a two-dimensional barcode) is applied to the secondary (or in its absence, the primary) packaging.

Liability for Violation of Packaging Requirements

A medicinal product that does not comply with the requirements of a pharmacopoeial article or, in its absence, the requirements of normative documentation or a normative document, is considered substandard; a medicinal product accompanied by false information about its composition and/or manufacturer is considered falsified. This applies, inter alia, to cases where violations of packaging and labeling requirements for medicinal products are identified.

The circulation of falsified and substandard medicinal products, including their production, importation into the Russian Federation, and sale, is prohibited (Articles 47, 57 of the Law on Medicinal Products).

For violation of packaging and labeling requirements during the circulation of medicinal products (in the absence of signs of a crime), parties may be held administratively liable:

Under Part 4 of Article 14.1 of the Code of Administrative Offenses (KoAP) of the Russian Federation: "Conducting entrepreneurial activity with a gross violation of the requirements and conditions provided for by a special permit (license)". The fine for individual entrepreneurs is from 4,000 to 8,000 rubles or administrative suspension of activity for up to 90 days; for officials – from 5,000 to 10,000 rubles; for legal entities – from 100,000 to 200,000 rubles or administrative suspension of activity for up to 90 days.
Under Article 6.33 of the KoAP RF: "Circulation of falsified, counterfeit, substandard, and unregistered medicinal products", containing several independent offenses. Maximum fines are: for citizens – up to 200,000 rubles; for officials – up to 600,000 rubles; for individual entrepreneurs – up to 600,000 rubles or administrative suspension of activity for up to 90 days; for legal entities – up to 6,000,000 rubles or administrative suspension of activity for up to 90 days.

Let us illustrate with an example from judicial practice. The Department of the Ministry of Internal Affairs applied to the arbitration court with a statement to hold a business entity administratively liable for committing an administrative offense provided for by Part 4 of Article 14.1 of the KoAP RF and Part 1 of Article 6.33 of the KoAP RF. As established by the Department during an inspection, 98 capsules of a potent medicinal product were found in the cash register area of a pharmacy organization; they were loose in a cardboard box without packaging. Information about the medicinal product and its manufacturer in a clearly legible font was absent from the capsules. The court indicated that by virtue of Article 46 of Law No. 61-FZ, the dispensing of a medicinal product is carried out in primary and secondary (consumer) packaging, the labeling of which must meet the requirements of Article 46 of Law No. 61-FZ. The court recognized the presence of said offenses in the Company's actions and imposed an administrative fine in the amount of 1,000,000 rubles [6].

Under Article 6.34 of the KoAP RF: "Production or sale of medicinal products for medical use without applying means of identification or with a violation of the established procedure for their application". Under this rule, liability is generally imposed for violations committed during labeling with means of identification in the MDLP system.

The fine for officials is up to 10,000 rubles with confiscation of the subjects of the administrative offense; for legal entities – up to 100,000 rubles with confiscation of the subjects of the administrative offense.

Summing up, it should be noted that the packaging process is an important part of the technological process of manufacturing medicinal products, guaranteeing the quality and safety of preparations. In this regard, compliance with all requirements established by legislation for this stage of production is extremely important.

______________________________

[1] Order of the Ministry of Health of Russia No. 778n dated July 31, 2020, "On approval of the list of medicinal products for medical use for which requirements are established regarding container volume, packaging, and completeness".

[2] Source: https://brace-lf.com/en/analytics/pharmaceutical-and-medical-law/mdlp-system-monitoring-medicinal-product-movement-medical-use.

[3] V. Stolypin, L. Gurariy, "GMP Requirements for Medicinal Product Packaging" // Remedium, 2004, No. 10, pp. 89 – 92.

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

[5] Decree of the Government of Russia 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 shortage of medicinal products due to the introduction of restrictive economic measures against the Russian Federation".

[6] Resolution of the Fifteenth Arbitration Appeal Court dated August 16, 2022, No. 15AP-12605/2022 in case No. A53-14578/2022.