GMP-Conference: An array of country flags came to visit us at the GMP workshop

The world pandemic has not only changed everybody’s’ way of life, but also made serious adjustments in the work of regulators. In particular, most countries have introduced a remote format of GMP-inspections, the features of which were described during the workshop, in which the company “Akrikhin” became a partner.

New conditions or an ordinary operation mode, however the most important work of the inspector is not to find violations and to punish, but to prevent these violations, to take a proactive role, so that the manufacturer could find everything himself and identify, prevent serious violations and avoid the manufacturing of low-quality medicines that can harm people, stated Elena Denisova, Deputy Head of the Russian State GMP-Inspectorate, Deputy Director of the Department for the Pharmaceutical and Medical Industry Development of the Ministry of Industry and Trade of the Russian Federation. Therefore, GMP-Inspectorates around the world understand the concern of medicines manufacturers of the new inspection formats. To reduce the level of concern and to explain the peculiarities of work in the new conditions, 12 countries have shared their approaches of conducting remote GMP-inspections. Basically, approaches of many regulators to conduct inspections in the situation related to COVID-19 are almost the same.

The last group of inspectors from “SID&GP” returned from a business trip on March 16, and since that date, without stopping the work, the Inspectorate began to inspect the medicines manufacturers, using the format of desk-top review. Moreover, in May, when the Russian Government Decree № 789 was issued, allowing to use photo, video, the online format or video demonstration of manufacturing sites, the Russian State GMP Inspectorate began to conduct virtual inspections. As of the date of the GMP-Conference, the Russian GMP-Inspectorate has carried out distant inspections of more than 200 foreign manufacturers of medicinal products.

The procedure of carrying out an inspection without travelling begins with obtaining of the foreign manufacturer approval to perform an inspection based on the results of the desk-top review. Then, an inspection is planned using a risk-based approach, and the Inspectorate determines the criticality or significance of the inspections individually for each site/product. The Inspectorate sends out an inspection plan in advance, specifying the list of documents to be considered during the inspection. However, the inspection itself is not limited to reviewing only the documents specified in such plan. “In the course of the inspection, additional documents may be requested for an in-depth and comprehensive assessment of the manufacturer for compliance with the requirements of the GMP rules. Communication during such an inspection is carried out by e-mail and audio- or video-communication”, – explained the Deputy Head of the Expertise Department of “SID&GP” Nadezhda Arkhipova.

The shift from routine on-site inspections to online inspections required changes in internal procedures, elaboration of international documents that set out the main approaches and requirements of regulators for this type of inspection. In this situation, the most important thing is the preparation for the inspection: quite a large number of documents need to be examined by the inspector before the inspection itself, because the inspection is limited in time. “During the pandemic, “SID&GP” faced a situation where the staff at site did not have access to documents or even to the manufacturing facilities by themselves”.

“Remote inspections depend, among other things, on the support of IT specialists – the ability to organize online broadcasting. This raises questions related to the confidentiality of the information received, the possibility to use it during the inspection,” stated Natalia Chadova, Head of Department on Drug Product Inspection and Expert Evaluation of “SID&GP”.

And what about the others?

The National Institute of Pharmacy and Nutrition (OGYÉI) of Hungary has agreed on measures to mitigate the effects of violations caused by COVID-19 during the inspection of manufacturing or other sites related to medicinal products in the EU. In cases where no centralized/relevant national marketing authorization exists, Member States can make use of possibilities foreseen in Directive 2001/83/EC, including resorting to compassionate use, or authorization of the distribution of an unauthorized medicinal product in accordance with Article 5(2).

As in Russia and the EAEU, the validity of GMP certificates for manufacturing/importing sites of active substances and/or finished products should be extended until the end of 2021 without the need for further action from the holder of the certificate. “But at the end of next year the National Institute of Pharmacy and Nutrition (OGYÉI) of Hungary will carry out inspections at sites where inspections have been postponed for the period of the pandemic”, – explained the Head of the Hungarian Inspectorate Dr. Ferenc Lukács. During the pandemic, the Hungarian regulator carried out only emergency inspections of new manufacturing sites and warehouses, remote inspections were started to be conducted, but only for companies with valid GMP certificates.

On April 15, Bosnia and Herzegovina issued the Instruction for Conducting Inspections in Emergency Situations, which establishes the work of inspectors from home under certain regulations: the inspector must

• Review all documentation submitted by a legal entity which is in possession of the Agency;
• Assess if an indirect (remote) inspection can be initiated based on the existing documentation, risk assessment and your experience and, if applicable, initiate it;
• Ask for the statement from the director of a legal entity on handling of medicinal products or medical devices in accordance with positive regulations;
• Issue an opinion on the fulfilment of the conditions upon request.

If the inspector will identify the need to conduct a shortened direct (on-the-spot) inspection at the applicant’s location, prior to going on the spot, it is necessary to:

• Ask for the submission of documentation by e-mail demonstrating implemented quality system and any other documentation required, including the evidence for them necessary for the conduction of inspections;
• Prepare a draft of the record on the basis of documentation submitted in order to stay at the site for which the request has been submitted as short as possible;
• Carry out a direct, on the spot inspection;
• Initiate administrative measures, if applicable;
• Issue an opinion on the fulfilment of the conditions.

“In total, the Agency for Medicinal Products and Medical Devices of Bosnia and Herzegovina has conducted 20 remote inspections during the pandemic,” said Indira Fazlagic, Head of Inspectorate from the Agency for Medicinal Products and Medical Devices of Bosnia and Herzegovina. However, the Inspectorate often faced translation problems in its work – not all documents were available even in English.

HALMED also extended the validity of issued GMP certificates until the end of 2021. At the same time, the automatic extension does not cover changes in the scope of the GMP certificate (e.g. new buildings, new medicinal products), and if the outcome of the distant assessment does not permit the granting of the GMP certificate, a clock-stop will be triggered until an on-site inspection is possible. With regard to foreign manufacturers, HALMED, based on the risk assessment in the pandemic, began conducting remote inspections to confirm GMP status of the manufacturer. For new manufacturing sites, remote inspections are performed by HALMED only in exceptional cases. The procedure of remote inspection is similar to the procedure of the Russian state GMP-Inspectorate: opening meeting, documentation review, final meeting at the end of which, in case of identified non-conformities, received in a written form by the manufacturing site, the manufacturer prepares a CAPA-plan, which is being examined by the inspectors that then prepare an inspection report, and in case of a positive decision – issue GMP-certificate.  

Since June, on-site inspections have been resumed, but with different levels of regional recovery from the pandemic, HALMED continues to conduct remote inspections as well.

The remote inspection process was developed and implemented in June-July when the Guidance related to GMP/GDP, PMF (Plasma master file) distant assessments and AEMPS SOP were released. The last document includes several important points:

• Type of inspection, site and medicines manufactured. GMP compliance
• Planification, preparation and evaluation of the RI/DA: communication system, data integrity and security, video, quality control systems sharing (HPLC, etc.).

3 main set of measures, aimed at ensuring that the supply is uninterrupted

1. SFDA regulates the export of pharmaceuticals products as precautionary measure to ensure they are available in the Kingdom of Saudi Arabia;
2. SFDA facilitates the importation of raw and packaging materials for local manufacturers;
3. SFDA improved communications with the suppliers of API and raw materials.

According to the SFDA’s Executive Director of Inspection Support Muhammed Ali Dahhas, SFDA has concentrated on inspections of local manufacturers, a risk-based approach was introduced for registration of foreign manufacturing sites during the pandemic, and approach has several criteria and factors that help to determine the risk level and decide on the inspection format:

1. Availability of pharmaceutical product in Saudi Arabia
2. Company registered in PIC/S membered authorities
3. Type and category of the product
4. Type of the company: what does it manufacture.

SFDA requested from foreign manufacturing sites valid GMP certificate from local and other international authorities, conducted the assessment of Site Master File (SMF), studied the list of all the products, that were manufactured on the site and supplied to Saudi Arabia, the most recent inspection report from the local authority, its evaluation, which confirms the implementation of Corrective and Preventative Actions (CAPA).

Korean GMP rules are harmonized with PIC/S GMP guidelines.

Ministry of Food and Drug Safety of Korea established an inspection plan for local and foreign manufacturer and conducts inspections of foreign manufacturers in order to obtain authorization for import of pharmaceutical products. “In doing so, even before the pandemic, in Korea not only have the forms of inspections changed specifically on sites, but so have desktop inspections – the pandemic prompted to extend this mechanism to foreign manufacturers”, – underscored Deputy director of Pharmaceutical Quality Division Ministry of Food and Drug Safety of Korea, Chung Myung-hoon.

In July 2020 a guideline “Development and implementation of Guidance on Good Practice (GxP) Inspections during emergencies/disasters including the COVID-19 pandemic” was published. This guideline stipulates the requirement for agreements on confidentiality between parties as well as declarations of document authenticity from the inspected party.

“The virtual inspection is a mixture of online interaction with the site and desktop review of documents”, – amplified Deon Poovan, Senior Manager of Inspectorate and Regulatory Compliance Unit at SAHPRA

 Among the tools leveraged by the SAHPRA for virtual inspections – Skype, WhatsApp, Zoom, Microsoft Teams, Internet-cloud systems for document exchange. If required, SAHPRA may perform an onsite inspection. 

In relation to the inspection procedure, SAHPRA follows 3 phases:

1. Opening meeting

• Ensuring that confidentiality agreements are in place
• Discussion of previous CAPAs
• Proposed inspection plan
• Discussion on documents required for inspection plan

2. Desktop inspection / Review

3. Remote inspection

• Connect through virtual communication platform
• Feedback from Phase 2 to the site
• Discussion and provision of additional documents / evidence
• Close out of inspection

Virtual inspections have a number of limitations and require more time. It is very important that the personnel of the local subsidiaries are engaged in virtual inspections of foreign companies. With that being said, a company may not be prepared for a virtual format. It is quite often that during an online inspection there are difficulties related to simultaneous translation and the level of knowledge of English, both from the site representatives’ and inspectors’ side. There are also several challenges with regards to the technical side – in certain countries or on sites, safety standards don’t permit the use of ZOOM or other means of communication.

“Amgen company recommends a consolidated approach, in which documents, requested in advance, are provided to inspectors via BOX. Subsequently, a local inspector is allowed to enter the site (if the permission is obtained), who in the course of 1 to 4 hours inspects the site, and further on, all the communication is done in an online mode”, – shared his perspective Director for Quality and  External Affairs of Amgen (Switzerland), Stephan Roenninger.

Akrikhin’s Quality Director Olga Maklakova shared a successful experience of re-inspection (GMP) of pharmaceutical factory Polfa, which is located in Warsaw. “It was important to rapidly and effectively pivot communications to the use of digital technologies for a virtual demonstration of the manufacturing site’s preparedness for the conformity with GMP requirements. A coherent liaison of the site with authorized representative, which was the focal point between the inspectorate and the manufacturer, was of great significance. Our experience of conducting inspections in such format was one of the first and it became successful”.

Olga Maklakova concurs with an inspector’s view that desktop inspection requires considerably more time and agrees with the aspect pertinent to the importance of quality of document translation.

The experience of conducting inspections of foreign manufacturers was also shared by Matthias Schniberger, Head of Quality and Compliance Division, Roche company, a strategic partner of V All-Russia GMP Conference with international participation. In May 2020 FSI “SID & GP” of the Ministry of Industry and Trade of the Russian Federation conducted a video inspection of a manufacturing site of the company in Basel. It was the first time that such format was implemented in the country. Matthias Schniberger recommended that manufacturers place a special emphasis on the technical side of preparing for online inspections – cameras, IT services, – and to ensure that a mock tour is conducted. Besides, the expert recommended to check local requirements and company rules in relation to disclosure of personal data and video-recording. Company Roche also recommends to do the following in advance:

• Agree with inspector on the premises/processes, that will need to be demonstrated;
• Provide plan of the premises/floors(inspectors can “follow” the plan in parallel with the video-tour);
• Introduce all the relevant personnel;
• Begin to show each premises with the number of a premise and general plan of a premise with all the equipment (process, if applicable);
• Allow time for questions.

Also in the workshop Roche demonstrated video-clips, simulating online inspection of premises, where samples are archived, and laboratories of microbiological control of a pharmaceutical factory.

At the end of the whole day of GMP worshop, inspectors and representatives of drug manufacturers concluded that on-site inspections would resume as soon as circumstances will allow. Remote inspections – have become a necessary measure, which despite their benefits, have drawbacks too:

• requires extra time and effort in order to prepare and conduct GMP-inspections, for both, manufacturers as well as inspectors;
• some subjects are difficult to demonstrate during a virtual tour – for example, suitability of a manufacturing site to the stated processes;
• connectivity-related problems during the tour (for instance, in zones of the first floor);
• significant input of labour/time required during technical preparation and organization of video;
• limited time to discuss potential questions (dependent on the timetable).