Russian GMP Inspections Present Challenges, Opportunities: Part I What to Expect from a Russian GMP Inspection

[Editor’s Note: Part II of this article addresses the ongoing harmonization activities in the field of GMP inspections within the Euroasian Economic Union (EAEU).]

Over the past two years, many international companies have hosted Russian inspectors at their manufacturing sites (1). Below is information describing the general regulatory landscape in Russia, history of the Russian GMP inspectorate and common observations made by Russian inspectors. This can help companies prepare for Russian inspections, anticipate the types of findings that may be delivered and understand how to address these findings.

General Regulatory Landscape

There are four regulatory bodies concerned with the field of manufacturing, control and distribution of medicine in Russia: The Ministry of Health (MoH), the Ministry of Industry and Trade (MoIT), the Federal Service for Surveillance in Healthcare (Roszdravnadzor), and the Federal Service for Veterinary and Phytosanitary Surveillance (Rosselkhoznadzor). The responsibilities for each are outlined below.

MoH:

• Registration of drugs
• Control of clinical trials
• Expert evaluation of drugs (Federal National State-financed Institution “Scientific Center for Expert Evaluation of Medicinal Products” of the Russian Ministry of Health)
• Issuing of marketing authorizations
• Maintenance of registry for medicinal products

MoIT:

• Licensing of drug manufacturers and maintaining the register of licenses
• Licensing control
• GMP inspections of Russian drug manufacturers
• GMP inspections of foreign drug manufacturers (Federal State Institute of Drugs and Good Practices (“SID and GP”) of the Russian Ministry of Industry and Trade)

Roszdravnadzor:

• Field surveillance of medicinal products and medical devices circulation
• State control over the quality and safety of medical activitie
• GDP inspections
• Pharmacovigilanc

Rosselkhoznadzor:

• Registration of veterinary drugs
• State supervision in the field of veterinary drugs circulation
• Licensing of veterinary drug manufacturers and maintaining the registry of licenses
• Licensing supervision
• GMP inspections of Russian veterinary drug manufacturers
• GMP inspections of foreign veterinary drug manufacturers

In addition, in-country certification is required in Russia (2).

Establishment of the Russian GMP Inspectorate

The establishment of the Russian GMP inspectorate is directly connected with introducing GMP rules in Russia. The very first version of Russian GMP guidelines, Rules of Organization of Drug Manufacture and Quality Control, were drafted and enacted in 1991. While these became effective regional and national standards, they still had fundamental differences from accepted EU GMP.

Then, in 1998, the Russian industry standard, Rules of Organization of Drug Manufacture and Quality Control (GMP), was approved. This standard embraced the principles of EU GMPs to the greatest extent possible. It became effective July 1, 2000, covering all manufacturing facilities, regardless of their legal status or form of ownership. Under this standard, when registering a newly built or reconstructed facility or importing drug products into the Russian Federation, a manufacturer must provide a GMP certificate for the manufacturing site issued by the manufacturer’s inspectorate.

Today, the following documents regulate the manufacturing of medicines:

1. Federal law No. 61-FZ dated April 12, 2010, “On Circulation of Medicines”
2. Federal law No. 99-FZ dated May 4, 2011, “On Licensing of Certain Types of Activity”
3. RF Government Decree No. 1314 dated Dec. 3, 2015, “On Determination of Compliance of Medicinal Product Manufacturers with the Requirements of the Good Manufacturing Practice” (together with “Rules for Organization of Inspections of Drug Manufacturers for Compliance with Good Manufacturing Practice and Issuance of GMP Certificates”)
4. Order No. 916 dated June 14, 2013, “On Approval of Good Manufacturing Practice Standards for Medicinal Products”
5. Order No. 1997 dated Dec. 12, 2013, “On Approval of Recommendations for Organization of Manufacture and Quality Control of Medicinal Products”

Currently, two different groups of inspectors are responsible for the inspection of local Russian and foreign manufacturers. The MoIT’s Department of Pharmaceutical and Medical Industry Development Section of Drug Manufacture Licensing and Inspections is charged with the licensing of Russian manufacturers, including GMP inspections. Additionally, the MoIT makes decisions on issuing GMP certificates to both Russian and foreign manufacturers. In 2017, there were 13 inspectors in this subdivision.

The State Institute of Drugs and Good Practices (SID and GP), which began in 2016, conducts inspections of foreign pharmaceutical manufacturers(3). These inspectors must meet the following requirements: hold a graduate degree in science or pharmacy, have more than five years of work experience in manufacturing or quality assurance and have knowledge of a foreign language.

The first group of inspectors underwent specialized training, conducted by experienced inspectors, that consisted of three modules: classroom review, observation of an inspection conducted by one of the trainers and, then, conducting their own independent inspection under a trainer’s supervision. After the training, the newly minted inspectors were awarded specialized diplomas and received international WHO certificates to support their capacity to act as inspectors. As of 2017, SID and GP included 58 inspectors.

Since then, between Dec. 18, 2015 and April 23, 2018, 896 foreign manufacturing sites have been inspected by Russian inspectors; 684 certificates have been issued and 196 have been denied. As the Russian GMP inspectorate has become better established, more than 9,000 deficiencies have been identified, including 2,500 critical violations, 3,203 major deficiencies and 3,375 minor deficiencies.

How to Prepare for Russian Inspections

Preparation for an inspection is crucial and should be initiated long before the Russian inspectors arrive at the manufacturing site. For the first step, the manufacturer’s office in Russia submits a set of documents to MoIT that include:

1. GMP application form administration document with manufacturing site details (name, address, contact info), Qualified Person (QP) details (name, position, email, phone, fax—which should be identical to the actual site master file) and manufacturing license details (site number, date, agency contact details)
2. Power of Attorney
3. Site Master File
4. List of complaints within the last two years
5. Product list per manufacturing site
6. Manufacturing license (notarized translation)
7. Letter of agreement for inspection (signed by site)
8. Fee payment confirmation

To prepare for an inspection, the host site needs to complete a Form 3, which describes all products and manufacturing steps at the site. The manufacturing site needs to cooperate fully with the company’s Russian office. If possible, representatives of the Russian office should visit the site before the inspection to become familiar with all the manufacturing steps. If the form is not filled out correctly, inspectors may have additional questions and observations, which has happened in some cases.

Translation is the next critical step. Knowledge of the Russian language is not enough—an interpreter must be a certified translator and familiar with technical terminology. Before the inspection, interpreters must be aware of Russian GMPs. They should also visit the site before the inspection to prevent any potential misunderstandings or inaccurate translation that could result in observations.

Additionally, host site personnel should receive cultural training that explains Russian communication styles and includes a brief presentation on Russian history and culture. Site personnel need to be able to describe the supply chain cycle for a product once it has left the site and is released to the Russian market. Russian inspectors take into account the manufacturing site, in the context of product supply to the Russian market according to the requirements of Normative Documentation (ND); it is crucial for site personnel to understand this perspective when preparing for the inspection. Very often, employees at each site are only aware of their specific tasks due to the decentralized nature of modern manufacturing.

Once an applicant submits the full set of documents, members of the inspection team are assigned within five business days. A lead inspector on this team coordinates the inspection from planning to CAPA evaluation.

The inspection should take no more than ten days. An inspection plan is drafted with a list of documents to be prepared for the inspection. This occurs approximately two weeks before the inspection.

The fee for the onsite inspection is calculated according to a formula approved by the Russian government. This formula is based on the complexity of the production process and the variety of product types to be inspected.

During an inspection of a foreign manufacturing site, findings may be classified into three general categories:

1. Noncompliance with the requirements of the registration dossier approved in the Russian Federation
• One frequent observation is that finished product released by the QP does not comply with the ND. This often occurs when regulatory affairs personnel are not located at the site. Additionally, it is possible that upon initial submission, regulatory files were reflective of the actual manufacturing and testing procedures at that time. Changes in process or methods may not have been reported to MoH, however, and may not be reflected in the Russian dossier.
• Discrepancies between the actual manufacturing and testing practices and the approved regulatory dossier is obviously a breach of GMP requirements. Russian inspections that reveal such deficiencies will result in corrections and amendments to regulatory documents in line with actual processes.
2. General GMP deficiencies related to documentation, personnel training, process, analytical methods, rooms, equipment validation/qualification, etc., including:
• Noncompliance with Annex 1 requirements, for example, no continuous monitoring at the most critical points, and insufficient process validation
• Absence of dedicated isolated areas for storage of rejected/recalled products, as well as of rejected starting materials and excipients (including cases with fully computerized storage systems)
• Maximal allowable carry-over (MAC) calculations for cleaning validation studies not based on toxicological studies
• Absence of traceability of the quantity of printed packaging materials with applied variable data during production
• Absence of verification (i.e., validation) of time intervals between the end of the production process and equipment cleaning, as well as between the executed cleaning and the start of the next process (dirty hold time/clean hold time)
3. Observations related to noncompliance of foreign sites with Russian-specific compendial or other regulatory requirements, particularly the following monographs:
• OFS.1.2.4.0004.15 Abnormal Toxicity. The requirement to carry out this test is usually listed in Russian NDs for sterile drugs as requested by the Federal National State-financed Institution Scientific Center for Expert Evaluation of Medicinal Products. This test is not performed in Europe or the United States, as animal tests are prohibited there, and absence of abnormal toxicity is proved by other methods(4).
• OFS.1.1.0009.15 Shelf Life of Medicinal Products. This pharmacopeial monograph requires a sterility test to be performed at the end of the shelf life. At the same time, many foreign manufacturers perform a sterility test upon product release only and have substituted this test at the end of shelf life with a container closure integrity test.
• OFS.1.2.4.0002.15 Microbial Purity. Interpretation of this monograph can trigger some major and critical observations based on the requirement for sterility of drug substance used for the manufacture of sterile drugs, as well as the requirement for analysis of microbial purity for each batch of nonsterile drugs.

[Editor’s Note: This article continues on the PDA Letter website. It is also the first in a two-part series. Part II will appear in the Nov/Dec issue and can also be found on the Letter website.]

References

1. “One and a Half Years of Russian GMP inspectorate: Yesterday, Today, Tomorrow.” CIS GMP News (August 28, 2017).
2. Meyers, E., Parfenova, N., and Roenninger, S. “Manufacturers Face Certification, Licensing Steps in Russia.” PDA Letter (January 2014) 38–41.
3. State Institute of Drugs and Good Practices website https://urldefense.proofpoint.com/v2/url?u=https-3A__gilsinp.ru_-3Fpage-5Fid-3D656-26lang-3Den&d=DwMF3g&c=Sexio4usKrYWFsrnxgjbcQ&r=bA3DUwBtAot3DithALO7D88HJ0L27ox-WdUeYi2cU_A&m=1sjxc-7-_scOSLosH8DQUZkH-5ezn92OWdTC5X6Kw40&s=4_UfSGYrlbT42ouF72cx9V1vtwL6A5CRJfRMfXaocfk&e=
4. “Rationale for Removing Abnormal Toxicity Testing” EFPIA Position Paper. EFPIA.eu (March 14, 2014) https://www.efpia.eu/media/25713/position-paper-on-rationale-for-removing-abnormal-toxicity-testing-1.pdf