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The Russian regulator is developing a remote GMP inspection process in connection with the pandemic

The State Institute of Drugs and Good Practices (FSI “SID and GP”), as a representative of the Russian state GMP inspectorate, authorized by the Ministry of Industry and Trade of Russia to conduct inspections of foreign drug manufacturers for compliance with good manufacturing practice standards, recently conducted the first remote GMP inspection of site owned by an international pharmaceutical company. The COVID-19 restrictive “social distancing” measures are limiting the number of workers at production sites, requiring an alternative approach. This article presents the experiences of both parties to provide guidance to both manufacturers and regulators around the world as they move towards this new form of inspection (1).

Many regulators have postponed or completely abandoned inspections due to the COVID-19 pandemic (2-5). Alternative inspection methods have been proposed by both the PIC / S and the FDA, using remote audits, as an exceptional temporary measure during COVID-19 quarantine and movement restrictions (6,7).

FBU "SILS and NP" quickly adapted to the current situation in order to avoid a shortage of medicines, offering to temporarily conduct remote inspections of foreign manufacturers of medicines. This approach involves a thorough examination of the submitted documentation and a risk assessment at the production site. The internal procedures of the inspectorate have been revised to include a detailed description of the inspection process based on documents provided by the drug manufacturer.

The management of FBU "SILS and NP" must provide permission for remote inspection. The decision on further action is based on a risk-based approach, taking into account many factors, such as the results of previous inspections, the complexity of the site and the criticality of the products (7). For example, if a site received a GMP certificate after a previous inspection by FBU "SILS and NP", the body may allow an inspection to be carried out remotely, which will even allow new products to be included in the previously issued GMP certificate. However, if criticism was identified during the previous inspection, then the documentary re-inspection will include a detailed review of corrective actions, including revision of documents, validation reports and confirmation of personnel training. The decision to conduct a remote survey should be documented in the form of a protocol. Under this new approach, representatives of the site to be inspected must also provide written confirmation that they agree to a remote inspection.

To begin with, 10 working days before the inspection, FBI "SILS and NP" sends a plan to a foreign manufacturer of medicines, including a list of documents that will be considered within the framework of the inspection. A foreign manufacturer of medicinal products, as a rule, through its official representative, submits the requested documents in the agreed form. Typically, paper copies of documents are delivered to FBU "SILS and NP" by a representative of the Russian branch, however, during restrictions due to a pandemic, electronic copies are accepted. (Examples of documents requested by FBU "SILS and NP" for remote verification are given at the end of the article).

Basically, the information requested is provided by email or any other agreed method. The best way to transfer documents is to place documents in the "cloud storage", access to which is limited to specific participants, and is also provided only during the inspection. For documentary inspection, a different level of virtual security is required, since documents are sent in full, while during site inspections, documents are sent only to inspectors. If it is necessary to translate documents, additional time may be required, especially if the translation of a large document must be completed within a specified time frame. The Panel of Inspectors will review the documentation received in detail and decide whether follow-up action is required. If necessary and upon agreement of the parties, it is possible to hold a teleconference to provide answers to questions. The Panel of Inspectors may request missing documentation or additional information to clarify any questions that may arise during the remote inspection.

Be aware that remote inspections inevitably take longer than site inspections. This is due to several factors, including different time zones and the lack of direct contact between the inspector and the site representatives. When changing the survey format (to remote), the survey algorithm remains "classic", i.e. The first day of the inspection begins with an introductory meeting in the form of a presentation in English with brief information about the FBI "SILS and NP", the composition of the commission and the objectives of the inspection. Further, the inspection continues according to the Plan sent to the production site. On average, unlike on-site inspections, remote inspections can take two to three times longer from start to finish. there will be some breaks during remote inspections as information is transmitted and reviewed. At the end of the inspection, the commission of inspectors sums up the results and introduces them to the site representative in Russia by sending information by e-mail and holding a final meeting in the format of a teleconference. The result of the inspection is a report, which is sent to the applicant within thirty days, in accordance with the terms established by the legislative acts of the Russian Federation.

Site approach to remote inspections

On the part of the receiving sites, it is very important to properly prepare for a remote inspection. As with traditional on-site inspections, it is very important to have an integrated approach and carefully coordinate work between the applicant company's Russian office and the host production site. Often, the production sites of international companies produce a large number of product units intended for many countries. There may be cases when the production site has misinterpreted the requirements of the Russian Regulatory Dossier, which may lead to additional questions and comments from the inspectors. Before the start of the inspection, it is necessary to hold a teleconference between the employees of the Russian department and the production site. This will help the production site understand the content of the Regulatory Dossier, as well as familiarize itself with the information on Form 3 submitted for the inspection. An example of Form 3 is shown below. In addition, the receiving party must have a clear understanding of the production route of the products outside the production site, and the relationship between the various legal entities involved in the production, testing, release, labeling and distribution of the product in Russia.

During remote inspection, it is necessary to establish effective operation in conditions of different time zones and a limited number of personnel at the plant, due to the pandemic. The inspection support group should include not only the personnel of the production site, but also a representative of the site in Russia and employees responsible for the quality of products to clarify local requirements and answer questions related to a specific type of product or regulatory documents (ND). The manufacturer's representatives in Russia play a particularly important role in remote inspection, as there is no personal contact between the inspector and the receiving site, and Russian representatives play the role of a “bridge” between the receiving site and the inspection team. This representative should foster a positive working relationship with the inspectors. All inquiries and clarifying questions must be sent in Russian to the manufacturer's representative in Russia, who will then arrange for their translation and redirect to the production site.

A coordinator at the host production site is appointed who receives inspection requests and distributes them to the various subject matter experts. After receiving the relevant documents and / or reports, the coordinator can also track the due diligence and translation of documents. It is important to provide answers in an organized manner, for example, accompanied by an explanatory letter that clearly links the question to the answer. It is necessary to establish prompt translation of documents and accompanying letters. Since these steps can take some time, it is good practice to keep communicating with the inspectors so that they know that their documents are being reviewed and not ignored. A manufacturer's representative in Russia can call the inspector to set a time frame and answer any questions.

A recent off-site inspection showed that Russian GMP inspectors may request further clarification. After the initial documents (see table at the end of the article) were reviewed by the inspectors, clarifying questions were asked on the line used to manufacture the product under evaluation and a production protocol request was made for the batch. In addition, a list of non-conformities and complaints related to the product, a list of computerized GMP systems in use at the site, and the title page of the audit report of the contract manufacturing site were requested. The original list included thirty-one requests (see table below), and twenty-three more questions arising from them. Since then, five more requests have been received. The inspection resulted in two insignificant remarks.

It should be noted that FBU "SILS and NP" considers the conduct of a remote inspection a forced measure, taken only in relation to production sites that are being re-inspected. The on-site inspection process will be restored after the end of the COVID-19 pandemic. FBU "SILS and NP" does not have standard approaches to all industries that ask for a GMP check without visiting the site itself. Before making such a decision, FBI "SILS and NP" will carefully study the dossier on the drug produced by the applicant for risk assessment. For example, sterile production is associated with high risks, in all likelihood, FBU "SILS and NP" is unlikely to choose the approach of documentary inspection. FBU "SILS and NP" believes that documentary verification still contains a number of restrictions. In order to make an objective decision on the compliance or non-compliance of the production site with the requirements of the rules of good manufacturing practice, with the help of documentary inspection, FBU SILS and NP will apply a comprehensive approach that was developed during the COVID-19 pandemic.

The COVID-19 pandemic has put manufacturers, site representatives in Russia and inspectors in a new and challenging situation in which it is in the public interest to continue supplying medical products with demonstrated compliance. Fortunately, recent examples of documentary inspection show that with the correct organization and well-coordinated work of the production site and the employees of the Russian representative office, the success of inspections is real and achievable.

List of quality documents to be reviewed during inspection

Requested Document
Pharmaceutical quality system documentation
1 Copy of the production site license
2 Copy of GMP site certificate (issued by local Notified Body)
4 CAPA for observations from previous inspections
5 Description of the production route for the production of product XXX - name, address and production stages for each site involved. Information on quality agreements between the respective sites and the status of the agreements.
6 Analysis of the functionality of the pharmaceutical quality system by management to assess effectiveness (latest report) - Quality report for management review
7 2019 Annual Product Review for Product XXX and the procedure for creating a quality review (sections: FPP quality review, claims review, nonconformity review, change review). Procedure for creating an annual product quality review.
8 Product release procedure. List of persons responsible for the release of products.
9 Change control management procedure and list of significant changes for Product XXX for 2019/2020
10 Non-Conformity Management Procedure and Non-Conformity List for Product XXX 2019/2020
11 Self-inspection procedure. List of persons who conduct self-inspections. Self-inspection information for production facilities used in the production process of Product XXX with self-inspection status (dates, results, responsible inspectors)
12 Procedure for managing complaints. 2019/2020 Claim List for Product XXX (if applicable)
13 Procedure for managing product recalls. Review List 2019/2020 for Product XXX (if applicable)
14 Description of job functions of key personnel: Head of production, Head of quality control
15 Detailed schematic description of the production site XXX with the designation of the categories of premises, personnel and material flows, the location of the equipment, indicating the production line used to produce Product XXX
16 Detailed schematic description of quality control laboratories used to test Product XXX
17 Detailed HVAC system drawings for the production site of Product XXX
18 Detailed schematic description of the storage facilities used to manufacture Product XXX
19 Procedure for handling intermediate and finished pharmaceutical products in warehouses (receipt, storage)
20 A copy of the batch maintenance protocol for packaging Product XXX (the decision on the batch number is at the discretion of the production site)
21 Intra-production control of the production process of Product XXX (procedure defining the implementation of intra-production control)
22 Storage Conditions for Product XXX (procedure defining storage conditions)
23 List of planned validation and qualification activities for 2020 (related to equipment and production facilities used to manufacture Product XXX)
24 Report and protocol of qualification of the production facility used for the production of Product XXX
25 Report and protocol of qualification of the production line used to produce Product XXX
26 Specification for FPP for the production of Product XXX
27 Specification for ZhLS (before packing) for the production of XXX Product
28 Stability study report for Product XXX, including data throughout the shelf life of the product. Procedure for testing product stability.
29 Stability Study Plan for Product XX
30 Analytical Method Validation (or Method Transfer Report) for Product XXX (methods will be selected upon receipt of specifications)
31 Procedure for managing non-conformities to specifications. 2019/2020 Specification Non-Conformity List for Product XXX



1. Federal Law "On the Circulation of Medicines" dated 12.04.2010 N 61-FZ (as amended on 04.03.2020) http://www.consultant.ru/document/cons_doc_LAW_99350/
2. https://www.fda.gov/news-events/press-announcements/coronavirus-disease-2019-covid-19-update-foreign-inspections
3. https://mhrainspectorate.blog.gov.uk/2020/03/23/mhra-good-practice-gxp-inspections-during-the-covid19-outbreak/
4. https://www.sukl.sk/hlavna-stranka/slovenska-verzia/inspekcia/posobnost/vykon-inspekcii-pocas-pandemie-covid-19?page_id=5339
5. Procedure for inspection mutual confidence from PIC / S, PIC / S June 2018
6. MDSAP Shipment Number: 2020-05, https://www.fda.gov/media/136441/download
7. «Recommended Model for Risk Based Inspection Scheduling in GMP Conditions» by PIC / S, January 1, 2012.

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