Russia’s State Institute of Drugs and Good Practices (SID&GP) recently conducted its first remote GMP inspection of a manufacturing facility for an international pharmaceutical company. The “social distancing” restrictions in place due to Covid-19 limit the number of staff on site, necessitating an alternative. This article presents both sides of the experience to provide guidance for both manufacturers and regulators around the globe as they migrate to this new form of inspection (1).
Many regulatory agencies have postponed or completely discontinued GMP inspections due to the COVID-19 pandemic (2–5). Alternative inspection practices have been proposed by both PIC/S and the U.S. FDA using remote audits as an extraordinary interim measure during Covid-19 quarantines and travel restrictions (6,7).
SID&GP quickly adapted to the current situation in order to avoid medicine shortages, proposing to temporarily conduct remote inspections of foreign pharmaceutical manufacturers. This approach involves a thorough review of submitted documentation and a risk assessment of the manufacturing site. The inspectorate’s internal procedures were revised to include a detailed description of the inspection process based on the documents provided by the pharmaceutical manufacturer.
The SID&GP management must provide approval before a remote inspection can be conducted. Their decision to proceed is a risk-based approach, accounting for several factors including results of previous inspections, complexity of the site and criticality of products manufactured at the site (7). For example, if a facility received a GMP certificate from a previous SID&GP inspection, the Agency could allow for a remote inspection that would even allow for a new product to be included in a previously granted GMP certificate. If a previous inspection revealed critical findings, however, then a remote repeat inspection will include a thorough review of corrective actions, including revised documents, validation reports and proof of personnel training. The decision to conduct a remote inspection must be documented in the form of a protocol. Under this new approach, representatives of the manufacturing site to be inspected must also provide written agreement to undergo the remote inspection.
To begin, 10 working days before the inspection, the SID&GP sends the foreign manufacturer a plan including a list of documents that will be assessed. The manufacturer, usually through its Russian affiliate, forwards the requested documents in an agreed-upon form. Normally, paper copies of documents would be delivered to the SID&GP office by the Russian affiliate representative but due to restrictions caused by the pandemic, electronic copies are acceptable. (An example of documents requested for a remote inspection by SID&GP are provided following the article.)
In general, requested information can be sent via email or by any other agreed-upon means. The best way to deliver the documents is to use a secured cloud storage solution restricted to specific participants and made available only during the inspection. Remote inspections require a different level of virtual security as documents are shared in their entirety, whereas during site inspections, the documents are just presented locally to inspectors. Extra time may be required for this should documents need to be translated, especially if translation of a large document must be completed within a defined timeframe. The inspection team will evaluate these documents and decide if follow up will be required. If necessary, and agreed upon by both parties, a teleconference can be set up to answer questions. The inspectors may request additional documentation or information to clarify any questions that may have come up during the remote review.
Keep in mind that remote inspections inevitably take a longer time than onsite inspections. This can be attributed to several factors, including different time zones and lack of direct real-time contact between inspectors and manufacturing site representatives. When the inspection format is changed to be remote, the inspection routine remains “classic,” that is, the first day of the inspection opens with a presentation in English introducing SID&GP, the inspection team members and the purpose of the inspection. From there, the inspection follows the plan sent to the manufacturing site. On average, a remote inspection can take two to three times longer than an onsite inspection from start to finish, although there will be some breaks during the remote inspection as information is transferred and considered. Once an inspection is completed, the team summarizes the potential findings and shares them with the Russian affiliate representative either through email or a close-out meeting via teleconference. The inspection concludes with a report, which is submitted to the applicant within thirty days, the timeframe established by Russian legislation.
A Site Perspective on Remote Inspections
For the manufacturer, it is very important to thoroughly prepare for a remote inspection. As with traditional onsite inspections, it is crucial to develop an integrated approach and to carefully coordinate work between the company’s Russian affiliate office and the receiving manufacturing site. Quite frequently international companies’ manufacturing sites produce many product categories, destined for multiple countries. There could be instances where a manufacturing site has misinterpreted requirements of the Russian regulatory dossier, potentially leading to additional questions and findings by inspectors. Prior to an inspection, it is advisable to schedule a teleconference between the hosting site and the Russian affiliate office. This will help the site to understand the content of a Regulatory Dossier as well as information within a Form 3, submitted before an inspection. An example of a Form 3 is provided below. Additionally, a host should have a clear understanding of a product flow beyond the manufacturing site, and a relationship between different legal entities involved in manufacturing, testing, release to market and distribution of a product in Russia.
During a remote inspection, it is necessary to establish an effective work pattern considering the different time zones involved and limited number of employees at the manufacturing facility due to pandemic. The inspection support group should include not only the site’s personnel, but also the Russian affiliate representative and the company’s Quality groups to clarify local requirements and answer questions related to specific product flow or Analytical Normative Documents (AND). Russian affiliate representatives play a key role because there is no direct face-to-face contact between inspectors and a hosting site, and the affiliate representatives can serve as a “communication bridge” between a hosting site and inspection team. This representative should establish a positive working relationship with the inspectors. All requests and follow up questions must be submitted in Russian to the affiliate representative, who will then arrange for translation and then forward the questions to a hosting site.
An inspection manager within the hosting site should receive inspection requests and triage them to various Subject Matter Experts. After receiving the corresponding documents and/or records, an inspection manager may have to coordinate legal review and translation of documents. It is important to provide answers in an organized manner, e.g., accompanied by an explanatory letter linking each request to a corresponding response document. It is imperative to establish a mechanism to swiftly translate documents and cover letters. Since these steps can take some time, it is good practice to continue communication with the inspectors, so they know documents are being worked on and not ignored. The Russian affiliate representative can call an inspector to provide timelines and answer any questions.
A recent remote inspection showcases what Russian GMP inspectors might request for further clarification. After initial documents (see box below article) were reviewed by inspectors, follow up questions were asked to clarify which line is used to manufacture product under evaluation along with a request for an executed batch record. Additionally, inspectors requested a list of deviations and complaints related to the product, a list of GMP computerized systems used on the site and a cover page of an audit report for a contract manufacturing site. The initial list contained 31 requested items (see box below), followed by an additional twenty-three questions. Five more queries were received after that. The inspection resulted in two minor findings.
Ultimately, SID&GP considers conducting remote inspections a contingency measure, undertaken only with respect to manufacturing sites subject to reinspection. Onsite inspections will be resumed once the COVID-19 pandemic is over. SID&GP does not have a standard approach for all manufacturers requesting a remote GMP inspection. Before electing to conduct a remote inspection, SID&GP would study the drug master file carefully to assess the risk. For example, sterile manufacturing is a high-risk process, and most likely, SID&GP will likely not elect to conduct a remote inspection. From SID&GP’s point of view, a remote inspection has a number of limitations. In order to reach an objective decision on a manufacturing site’s compliance or non-compliance subject to GMP requirements via remote inspection, SID&GP will apply a comprehensive approach that has been developed during the COVID-19 pandemic.
COVID-19 pandemic has put manufacturers, affiliates and inspectors in a new and challenging situation where it is in the public interest to continue to supply medicines while ensuring demonstrated compliance. Thankfully, recent examples of remote inspections show that with good organization and coordination between the manufacturing site and Russian affiliate representatives, success is realistic and achievable.
List of Medicinal Products
List of Quality Documents to be Reviewed During Inspection
- Federal Law dated 12.04.2010 N 61-ФЗ (as amended on 04/03/2020) “On Circulation of Medicines”http://www.consultant.ru/document/cons_doc_LAW_99350/
- The PIC/S Inspection reliance procedure, PIC/S June 2018
- MDSAP Transmittal Number: 2020-05, https://www.fda.gov/media/136441/download
- The PIC/S “A Recommended Model on Risk-Based Inspection Planning in GMP Environment”, 1 January 2012