Russian GMP Inspections Present Challenges, Opportunities: Part II Harmonization in the field of GMP inspections within the EAEU

[Editor's Note: Read Part I for background on Russian GMP inspections.]

A substantial part of activities by the Russian GMP inspectorate involves integrating Russia into the global pharmaceutical community, participating in development of a regulatory framework for the common pharmaceutical market among Eurasian Economic Union (EAEU) member countries, and creating an international independent expert board of inspectorates. The latter is the most promising, as this project suggests establishment of trust in the inspectorate along with increased numbers of inspections and mutual GMP recognition to decrease the burden on pharmaceutical manufacturers, all of which substantially improve the quality of production.

Implementing good practices and working with experts in the pharmaceutical industry to create a professional system of values is another important goal of the Russian GMP inspectorate. The Federal State Institute of Drugs and Good Practices (SID & GP) is making a determined effort to support Russia’s integration into the global pharmaceutical community. To that end, harmonizing EAEU legislation with global best practices and gaining accord with EAEU member state inspectorates to PIC/S remain high priorities.

The EAEU intends to create a common market of drugs. In December 2014, Russia, Belarus and Kazakhstan signed the Agreement for Unified Principles and Rules of Drugs Circulation within the EAEU. Armenia and Kyrgyzstan entered into the agreement in 2015. A number of important measures are covered by this agreement, which applies to all countries within the EAEU territory, including:

• Implementing good practices at all steps of drug circulation
• Creating controls by means of pharmaceutical inspections
• Developing a common EAEU pharmacopeia
• Maintaining a key element of GMP compliance supervision—accreditation of qualified persons and maintaining a registry of them
• Establishing unified rules of registration, expert evaluation, etc.

In August 2016, during a meeting of the Eurasian intergovernmental council, leaders from Union member states approved the EAEU GMP, a set of documents regulating the field of drug circulation, which concurs with EU GMP. Creation of a common market for drugs recognizes the results of inspections conducted throughout the EAEU territory.

In this regard, all EU member states face major efforts to harmonize legislation, solicit experts, train inspectors, encourage good practices, create an inspectorate, access PIC/S and invest in technological advancement of the resource base for the testing of drugs, among others.

Implementation of a common inspection system within the EAEU territory is preceded by a transition period. Until the end of 2018, submission of a “national” document (i.e., the document issued by the national authority of an EAEU member state) is allowed for confirmation of compliance with GMP. Also, until that time, parallel inspections of manufacturers for compliance with EAEU GMP can be conducted for the purposes of registering drugs. By the end of 2020, manufacturers within EAEU member states will be able to confirm GMP compliance in two ways: by a document from EAEU and by a document issued by an EAEU member state’s regulatory body.

Harmonization Issues

Even with availability of a robust, thoroughly controlled system of drug manufacturing, it remains impossible to control 100% of all pharmaceutical manufacturers worldwide. This is often due to varying approaches to GMP regulation in different countries. Throw in a multitude of national pharmacopeias and recognizing results of inspections in different countries can be complicated. For example, when entering new markets, manufacturers must be inspected repeatedly by various inspectorates.

There is a pressing need to reduce import/export barriers and harmonize approaches in addition to implementing mutual recognition of the results of inspections.

At the heart of developing GMP inspection standards in the EAEU region lie two major priorities: accession of EAEU regulatory bodies to PIC/S and harmonization of EAEU legislation with best global practices.

PIC/S Accession

All EAEU member states, except Kyrgyzstan, have attempted PIC/s accession. Belarus, Kazakhstan, Armenia and Russia have all submitted applications to join PIC/S.

Belarus, the most advanced country among the EAEU member states, is now in the process of joining PIC/S. With assistance from the European Union, the Belarus inspectorate developed its laboratory facilities and a structure for its pharmaceutical regulatory framework.

In support of its PIC/S application, Kazakhstan implemented organizational changes within its pharmaceutical inspectorate along the model of the U.S. FDA. This inspectorate would report to the Ministry of Health. Inspections and expert evaluations of drugs would be carried out by a separate regulatory body.

Armenia also has plans to reorganize its pharmaceutical regulatory framework. A regulatory agency is expected to be created soon that would report directly to the prime minister of the country. This agency would be responsible for carrying out inspections, issuing registration dossiers and providing expert evaluation of drugs and medical devices, much like the FDA.

Kyrgyzstan has not attempted to access PIC/S, although they plan to form an inspectorate similar to that of Kazakhstan. As the pharmaceutical market in this country is rather small and there are only a few pharmaceutical manufacturers, the number of inspectors will be limited.

Finally, Russia submitted a PIC/S accession application in August 2017. Now, major efforts are being made to harmonize the regulatory approaches. The SID & GP inspectorate was pre-audited by an independent party for compliance with PIC/S requirements and found that all internal documents comply with the PIC/S requirements. To implement the plans for PIC/S accession, however, it will first be necessary to amend federal legislation.

Harmonization within the EAEU

Toward the end of 2016, EAEU member states approved the standards and principles of its shared common pharmaceutical market. And on Nov. 3 of that same year, they signed the documents that would regulate that market, including:

• Rules for registration and expert evaluation of drugs
• Good pharmaceutical practices in the sphere of drug circulation
• Rules for carrying out pharmaceutical inspections
• Procedures for carrying out joint pharmaceutical inspections
• General requirements for the quality system of pharmaceutical inspectorates

Six key challenges to harmonization have been identified:

1. The need for further advancement of joint GMP regulation in EAEU countries
2. Establishment of unified approaches to regulation and positions in inspection issues, both internally and globally, for carrying out inspections, classifying nonconformities and developing educational standards and training programs for inspections
3. Cooperation of inspectorates (carrying out joint inspections, conducting joint training sessions, consulting on applying GMP regulations)
4. Drawing up recommendations for EAEU member states’ inspectorates
5. Initiation of improvements of GMP regulations under a simplified procedure in relevant EAEU authorities
6. Exchange of inspection reports and creation of a unified base of such reports

Based on a meeting of the Eurasian Economic Commission held Nov. 16–17 2017, a decision was made to create a standing Pharmaceutical Inspections Committee within the EAEU. This committee will facilitate:

1. Strengthening of trade, economic and professional relationships among EAEU member states
2. Cutting disreputable manufacturers from the market
3. Increasing drug safety by improving the quality of manufacturing
4. Creating conditions to increase export opportunities
5. Enhancing the quality of inspections
6. Promoting transparency in mutual GMP recognition issues
7. Reducing requirements on pharmaceutical manufacturers

EAEU rules and procedures were initially developed based on PIC/S requirements. Currently, a working group is being formed within the Eurasian Economic Commission to address conducting pharmaceutical inspections for compliance based on good pharmaceutical practices. The working group first met Feb. 1, 2018, with plans to hold monthly briefing sessions and expanded quarterly sessions. The group is tasked with coordinating activities and harmonizing and developing procedures and methods (i.e., detailed SOPs).

The Russian inspectorate was formed and developed relatively recently. While 2018 marks only its third year of inspecting pharmaceutical manufacturers, the inspectorate plays an essential role in the Russian regulatory system. Inspections of foreign manufacturers have uncovered many findings, making clear the need for harmonization. The Russian inspectorate maintains an open dialog with industry and leads the way for creation of unified inspectorates in the EAEU.