05 February 2022

The Legal Status of the Qualified Person of a Medicinal Product Manufacturer and the Responsible Person of a Wholesale Organization

December 5, 2022

BRACE Law Firm ©

Pharmaceutical industry products must comply with all quality and safety standards. Currently, ensuring the quality and safety of medicinal product circulation largely depends on manufacturers, wholesale organizations, and retail organizations complying with the rules of good practice.

These rules require such organizations to appoint a Qualified Person of a medicinal product manufacturer and a Responsible Person of a wholesale organization, both of whom bear personal liability. Furthermore, the presence of these individuals at a pharmaceutical manufacturing site or within a wholesale organization is a mandatory licensing requirement.

This article examines who may serve as a Qualified Person for a medicinal product manufacturer and a Responsible Person for a distributor, as well as the functions, powers, and liabilities imposed on them by law.

Qualified Person of a Medicinal Product Manufacturer

In global practice, the institution of the Qualified Person of a medicinal product manufacturer emerged in the 1970s alongside the development of Good Manufacturing Practice (GMP) rules. Russian legislation adopted this institution from European law. Specifically, the concept of a "Qualified Person" is established in Part 7 of Article 45 of Federal Law No. 61-FZ dated April 12, 2010, On the Circulation of Medicinal Products (the "Law on Circulation of Medicinal Products"). However, the definition provided in the specified legal provision does not clarify the role assigned to this individual in medicinal product manufacturing, but instead focuses on education and qualification requirements.

In turn, the Good Manufacturing Practice Rules of the Eurasian Economic Union (the "GMP Rules")[1] define a Qualified Person ("Qualified Person") as an individual appointed by a medicinal product manufacturer who performs the confirmation of medicinal product compliance with the requirements established during state registration and guarantees that medicinal products are manufactured in accordance with the GMP Rules (Paragraph 7 of Annex No. 16 to the GMP Rules).

The GMP Rules classify Qualified Persons as key management personnel. A manufacturer must employ a sufficient number of such persons, but no fewer than one. It is permitted for the heads of quality or production departments to combine their duties with those of a Qualified Person. Additionally, Article 45 of the Law on Circulation of Medicinal Products requires the Qualified Person to be an employee of the manufacturing organization, meaning they must maintain an employment relationship with the manufacturer. At the same time, the GMP Rules emphasize the independence of the Qualified Person from production site managers and management and sales departments to ensure objective decision-making regarding each batch of products released.

Education, Qualification, and Work Experience Requirements for the Qualified Person

Regulations establish requirements for the education, qualification, and work experience of a Qualified Person. Notably, the requirements under Russian national legislation and Eurasian Economic Union (EAEU) legislation differ. These differences are detailed in Table 1 below:

Table 1: Comparison of Requirements for Qualified Persons

Requirement	Russian Legislation (Part 7, Art. 45 of the Law on Circulation of Medicinal Products)	EAEU Legislation (Eurasian Economic Commission Council Decision No. 73 dated November 3, 2016)
Education	Higher education in: biology, biotechnology, veterinary medicine, veterinary-sanitary expertise, clinical medicine, radiation, chemical and biological protection, pharmacy, fundamental medicine, chemical technology, or chemistry.	Higher education in the fields of: chemistry, chemical technology, chemical-pharmaceuticals, biology, biotechnology, microbiology, pharmacy, medicine, or veterinary medicine.
Additional Education	–	Courses (disciplines/modules) in: applied (medical and biological) physics, general and inorganic chemistry, organic chemistry, analytical chemistry, pharmaceutical chemistry (including medicinal product analysis), biological chemistry, physiology, microbiology, pharmacology, pharmaceutical technology, toxicology (toxicological chemistry), and pharmacognosy.
Work Experience	At least five years in medicinal product manufacturing or quality control.	At least three years in medicinal product manufacturing, quality assurance, or quality control.

Furthermore, due to the specific nature of certain production processes, the EAEU regulations provide special education requirements for Qualified Persons:

At enterprises manufacturing medical gases, individuals with higher education in physical and technical sciences may also serve as Qualified Persons.
At enterprises manufacturing radiopharmaceuticals, individuals with higher education in nuclear physics and radiophysics may serve as Qualified Persons.

As demonstrated, EAEU legislation has expanded and clarified the education and qualification requirements for Qualified Persons compared to Russian national law. Given that Russia and other EAEU member states are currently forming a unified goods market, EAEU regulatory requirements should serve as the primary benchmark.

Attestation Procedure for the Qualified Person of a Medicinal Product Manufacturer

To perform duties as a Qualified Person, an individual must undergo attestation. The attestation procedure is regulated by Eurasian Economic Commission Council Decision No. 73 dated November 3, 2016,[2] and the implementing Ministry of Health of Russia Order No. 7n dated January 12, 2021 (the "Order No. 7n").[3]

The Ministry of Health of Russia's attestation commission conducts attestation once every five years. The process includes an assessment of the employee's professional activity report, a knowledge test, and an interview.

Candidates submit attestation applications via their personal accounts on the state register of medicinal products portal. The following documents must be attached to the application:

An attestation sheet (following the template in Annex No. 1 to Order No. 7n), certified by the manufacturer's HR department and head, and bearing the organization's seal.
A professional activity report, approved by the head and certified by the seal of the manufacturing organization. This report describes the applicant's professional activity over the past three years, detailing their job functions and specializations, and provides data on employers, including medicinal product manufacturing license numbers.
Copies of educational documents, certificates of additional professional training or advanced training within the last five years, and copies of the labor book (or an electronic labor book extract).
A copy of the document confirming any change to the applicant's surname, first name, or patronymic.

Within three business days of application registration, the documents are sent to the attestation commission's expert group for review, or a reasoned notification of refusal is sent to the applicant's personal account.

The Ministry of Health of Russia approves and publishes the knowledge test questions on its website. The test involves at least 120 questions for a single specialization and is considered successful if the applicant answers at least 80% correctly. For multiple specializations, the number of questions and the testing time increase accordingly.

The interview covers theoretical and practical aspects of the candidate's professional activity, taking their specialization into account.

Following these steps, the commission decides whether to grant or refuse attestation, and the results are posted in the participants' personal accounts. Information regarding attested Qualified Persons is entered into the EAEU Unified Register of Qualified Persons of Medicinal Product Manufacturers.

Qualified Persons previously attested under national legislation submit an attestation application using a specific template provided in Annex No. 3 to Order No. 7n.[4] In such cases, the attestation decision is based on the application alone, without a report assessment, testing, or an interview.

In practice, manufacturers have attempted to challenge decisions refusing attestation under Chapter 24 of the APC RF ("Proceedings for Challenging Non-normative Legal Acts, Decisions, and Actions (Inaction) of Government Bodies..."). However, courts have refused these claims, ruling that the manufacturing organization is not the applicant (attested person) within the context of the attestation procedure. Consequently, a refusal to attest does not violate the manufacturer's rights or legitimate interests in the sphere of entrepreneurial or other economic activity.[5]

Duties of the Qualified Person of a Medicinal Product Manufacturer

The primary function of a Qualified Person is to determine the suitability or unsuitability of each batch of finished medicinal products after manufacturing is complete. No batch of products may be released for sale or supply until the Qualified Person certifies its compliance.

The core duties of a Qualified Person are outlined in Chapter 2 of Part I and Annex No. 16 to the GMP Rules. Specifically, the Qualified Person:

For medicinal products manufactured within EAEU member states, confirms that the products were manufactured and tested in compliance with all requirements of applicable legislation, regulatory documentation, and the registration dossier.
For medicinal products from other countries, confirms that each batch has undergone full qualitative and quantitative analysis in an EAEU member state, at least for all active substances, and all other tests or checks necessary to ensure quality in accordance with the registration dossier.
Prior to the release of any batch, must document that all necessary operations were performed and that each batch meets established requirements.
If a computerized system is used to document compliance confirmation and authorize batch release, it must provide access only to the Qualified Person and clearly identify and record the employee who approved and released the batch for sale.

The confirmation procedure is detailed in Annex No. 16 to the GMP Rules. When confirming compliance, the Qualified Person must guarantee, at a minimum, that:

The finished product batch and its manufacturing process comply with the medicinal product's registration dossier.
The finished product batch was manufactured in accordance with the GMP Rules or, for products imported from third countries (non-EAEU members), in accordance with good manufacturing rules equivalent to the GMP Rules.
The main manufacturing processes and control methods are validated.
Any deviations or planned changes in the process or quality control were approved by responsible persons in accordance with a defined system.
All necessary checks and tests (including additional sampling, inspections, and checks due to process deviations or planned changes) were conducted.
Manufacturing process and quality control documentation was prepared and approved by authorized personnel.
All audits were conducted in accordance with the quality assurance system requirements.
All factors that the Qualified Person considers significant for the quality of the specific batch were taken into account.

Qualified Person duties may only be transferred to another Qualified Person(s). ⁷²For example, this occurs when batch production is split into several stages performed at different locations or by different manufacturers, or when a batch of intermediate or bulk products is divided into two or more finished product batches. In such cases, one Qualified Person may not be able to thoroughly examine every production stage. Therefore, the GMP Rules allow a Qualified Person to rely on the documented conclusions of other Qualified Persons regarding the compliance of intermediate production stages.

To formalize the transfer of a portion of the Qualified Person's powers, a written agreement must be executed. This agreement must comply with Chapter 7 of the GMP Rules ("Activities Transferred to Another Person (Outsourcing)"), which requires:

Outsourced activities must be properly defined, agreed upon, and controlled to avoid discrepancies that could lead to unsatisfactory quality.
Prior to transferring activities, the Customer must ensure the Contractor's legality, suitability, and competence, and include provisions in the agreement to ensure compliance with these requirements.
The Contractor must have the necessary premises, equipment, knowledge, experience, and competent personnel.
The agreement must clearly define the duties of each party.
The agreement must specify who is responsible for each stage of the outsourced activity, including in-process control, sampling, and analysis.
The Contractor must not make unauthorized changes beyond the scope of the agreement.
The Contractor must not transfer work assigned under the agreement to a third party without the Customer's prior review and approval.
The Customer must monitor and verify the Contractor's actions, including reviewing and evaluating records and results. All records must be kept by or accessible to the Customer.
The Customer must have the right to audit the activities performed by the Contractor or an agreed-upon third party.

Such an agreement may take the form of a Standard Operating Procedure (SOP) within a single manufacturing enterprise or a formal contract between different enterprises, even if they belong to the same corporate group.

Regardless of the number of sites and Qualified Persons involved, the manufacturing process must be under the general supervision of a single Qualified Person who bears full responsibility for the release of the finished product batch.

Once a Qualified Person has confirmed the compliance of a finished product batch, this procedure does not need to be repeated in countries that have mutual recognition agreements with EAEU member states.

In practice, Qualified Persons are also assigned duties such as:

Participating in the investigation of quality claims and defects and making decisions regarding necessary measures.
Reviewing the enterprise's quality system, identifying potential threats, and proposing measures to eliminate or prevent them.
Maintaining business contacts with regulatory authorities.

Thus, the Qualified Person is a key figure in pharmaceutical manufacturing, guaranteeing the safety of products released into civil circulation.

Concept and Duties of the Responsible Person of a Wholesale Medicinal Product Organization

The concept of the "Responsible Person of a wholesale organization" is found in the Good Distribution Practice Rules of the Eurasian Economic Union (the "GDP Rules").[6] According to Paragraph 8 of the Rules, a Responsible Person is an individual endowed with the powers and duties to ensure the implementation and maintenance of the quality system.

While both the Qualified Person and the Responsible Person aim to ensure medicinal product quality, there are several fundamental differences between them:

First, qualification requirements for the Responsible Person are broader and partly advisory. According to Paragraph 17 of the GDP Rules, the Responsible Person must meet the qualification requirements established by the national legislation of the EAEU member state and possess the necessary qualifications, experience, and knowledge in good distribution practice. Pharmaceutical education is recommended but not mandatory. The distributor may set the educational profile based on its product range. Furthermore, the Responsible Person does not undergo attestation, and no register of Responsible Persons is maintained.

Second, a distributor typically has one Responsible Person who reports to the head of the organization. Unlike the Qualified Person, there is no declared principle of independence in decision-making and activities.

Third, the Responsible Person of a wholesale organization has the right to delegate their duties to subordinates. Although they should generally perform their duties personally, they may delegate a portion of them, which is not permitted for a Qualified Person (whose duties can only be partially transferred to other attested Qualified Persons via contract).

Fourth, their specific duties differ. According to Paragraph 21 of the GDP Rules, the Responsible Person's duties include:

Ensuring the implementation and maintenance of the quality management system.
Ensuring the implementation and maintenance of initial and ongoing training programs for personnel involved in distribution.
Coordinating and promptly organizing the recall of medicinal products from circulation.
Ensuring effective handling of customer claims.
Approving suppliers and recipients.
Approving the outsourcing of activities that could potentially affect compliance with good distribution practice.
Ensuring self-inspections and the adoption of necessary corrective measures.
Making decisions regarding returned, recalled, rejected, substandard, or falsified medicinal products.
Approving the return of medicinal products to the salable stock.

The Responsible Person's primary sphere of activity is the recall of substandard and falsified medicinal products and the preparation of Standard Operating Procedures (SOPs) for the quality system. However, the GDP Rules provide only general guidelines for quality system documentation, such as requiring regular reviews and that procedures be approved, signed, and dated by the Responsible Person. The lack of detailed regulation regarding which specific SOPs should be developed by the Responsible Person negatively impacts the implementation of quality systems in distribution organizations.

Liability of the Qualified Person of a Manufacturer and the Responsible Person of a Pharmaceutical Distributor

Applicable legislation provides for the following types of liability for the circulation (including manufacturing and sale) of falsified, counterfeit, substandard, or unregistered medicinal products:

Disciplinary liability under Article 192 of the Labor Code of the Russian Federation for breach of duties specified in the job description, with penalties including warnings, reprimands, or dismissal.
Administrative liability under Article 6.33 of the CAO RF for the circulation of falsified, counterfeit, substandard, or unregistered medicinal products, provided such actions do not constitute a criminal offense. Maximum penalties include fines up to 600,000 rubles for officials and up to 5 million rubles for legal entities, or administrative suspension of activities for up to 90 days. If these actions involve the use of mass media or information and telecommunications networks, the maximum fine for legal entities increases to 6 million rubles.
Criminal liability under Article 238.1 of the Criminal Code of the Russian Federation for the circulation of falsified, substandard, or unregistered medicinal products on a large scale. "Large scale" is defined as a value exceeding 100,000 rubles. The maximum penalty is 12 years of imprisonment, potentially with an additional fine of up to 5 million rubles (or five years' salary) and/or a ban on holding certain positions or engaging in certain activities for up to 10 years.

Depending on the specific actions, liability may also arise under other articles of the Criminal Code, such as Article 292 (Forgery by an Official) or Article 293 (Negligence).

While judicial practice has not yet shown cases of Qualified or Responsible Persons being held liable, the possibility cannot be ruled out, especially in cases of intentional violations, such as deciding to release substandard products into circulation despite data to the contrary or using forged documents.

In conclusion, the introduction of the institutions of the "Qualified Person of a manufacturer" and the "Responsible Person of a wholesale organization" should be viewed positively, as their proper functioning is one of the guarantees of the quality of medicinal products entering circulation.

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References

[1] Approved by Eurasian Economic Commission Council Decision No. 77 dated November 3, 2016.

[2] Eurasian Economic Commission Council Decision No. 73 dated November 3, 2016, On the Procedure for Attestation of Qualified Persons of Medicinal Product Manufacturers.

[3] Ministry of Health of Russia Order No. 7n dated January 12, 2021, On the Approval of the List of Documents Submitted by an Attested Qualified Person of a Medicinal Product Manufacturer of a Member State of the Eurasian Economic Union, the Stages of the Procedure and the Order for Making Decisions on the Attestation of Qualified Persons of Manufacturers of Medicinal Products for Medical Use in Accordance with the Procedure for Attestation of Qualified Persons of Medicinal Product Manufacturers, Approved by Eurasian Economic Commission Council Decision No. 73 dated November 3, 2016, On the Procedure for Attestation of Qualified Persons of Medicinal Product Manufacturers.

[4] Letter of the Ministry of Health of the Russian Federation No. 20-0/8 dated February 8, 2021.

[5] Resolution of the Ninth Arbitration Appeal Court No. 09AP-71979/2019 in Case No. A40-11372/2019 dated February 13, 2020.

[6] Approved by Eurasian Economic Commission Council Decision No. 80 dated November 3, 2016.