Conference report on the ECA GMP & GDP Forum

   

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After the last ECA GMP & GDP Forum had to take place online due to the coronavirus, a face-to-face event was possible again last year. And many took advantage of this opportunity: more than 122 participants from 27 different countries attended the three-day event. The ECA GMP & GDP Forum is a get-together where current and future GMP and GDP aspects are discussed by both industry and authority representatives.

At the beginning of the forum, the head of the ECA Advisory Board, Dr Afshin Hosseiny, gave an overview of the current status of ECA activities. Last year, ECA membership increased by 8% and now stands at around 4300 members from more than 40 countries. The rest of the day was dedicated to current GMP initiatives and trends. Consequently, EMA-speaker Andrei Spinei provided insight into the near future of the European Medicines Agency. Andrei Spinei then showed the EMA's strategic priorities on a slide (Figure 1 on p. 27). Due to the COVID-19 pandemic, GMP inspections are still lagging behind, although a return to on-site inspections is taking place where possible. In 2020 - 2022, the EMA carried out 59 virtual inspections; national authorities carried out as many as 433. Looking back at 2022, Annex 1 was finalized and Annex 21 published in collaboration with PIC/S, and there is a concept paper on the revision of Annex 11. Furthermore, a group was established to revise Chapter 4 of the EU GMP Guidelines and work on Annex 4 and 5 for veterinary medicinal products is progressing on the basis of a concept paper. In addition, two Q&A documents on active pharmaceutical ingredients as starting materials for veterinary medicinal products and one on PMFs were published in 2022.

With regard to Mutual Recognition Agreements (MRA), Andrei Spinei pointed out, among other things, that veterinary medicinal products are now also included in the MRA with the USA and that work is underway on the addition of vaccines and plasma products. In the future, a Pharmaceutical Quality Knowledge Management System (PQKMS) will promote the international exchange where there are the same sites, products, marketing authorizations and marketing authorization holders. Innovations are to be promoted through the interaction of a Quality Innovation Group (QIG, consisting of 3 inspectors) and an Innovation Task Force (ITF). Industry is also to be involved via the QIG.

Figure 1: EMA`s strategic priorities

Spinei primarily named the following as EMA priorities for 2023:

  • continuous manufacturing,
  • decentralized manufacturing and
  • automation/digitalization.

Finally, Andrei Spinei referred to the Organization Management Service (OMS) in the EudraGMDP database, in which companies have had to be registered since the beginning of 2022. The database has also been expanded with regard to veterinary medicinal products. A new EMA platform called IRIS also serves to coordinate GMP inspections. It is planned that pharmacovigilance will also run on this platform.

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In keeping with tradition, Dr Bernd Renger, Bernd Renger Consulting, spoke at the GMPD Forum about the GMP updates for 2023 and gave an outlook for 2024.

Dr Renger cited the planned pharmaceutical reforms, which will change the legal landscape with regard to medicinal products, as an important innovation. Using the 2023/192 draft directive as an example, Dr Renger explained that the Qualified Person will be faced with a number of new changes in terms of availability, responsibilities and qualification. He then briefly addressed the changes in the Annex 1 revision, but referred to two upcoming lectures for more information. He then presented the timelines for the revision of Annex 11. He expects data integrity aspects to be included in the revision, as well as cloud-based topics. He also referred to the corresponding follow- up presentations on this topic, as well as on the topic of ICH Q9 (R1). Based on inspection and audit results (Figure 2), he gave a very good overview of what he considered to be the problems with ICH Q9. He then presented the EMA document on preventing shortages of medicinal products: "Good practices for industry for the prevention of human medicinal products shortage". He summarized his analysis: Do we really need such a document that lists well-known facts but offers no possible solutions? Finally, he addressed the new FDA guidance on diethylene glycol, which was issued as a result of a diethylene glycol contamination in Gambia in 2022 with at least 69 deaths.

Figure 2: Inspection and audit results reg. ICH Q9

Dr Rainer Gnibl, a GMP inspector (Government of Upper Bavaria), then addressed the ICH Q9 revision. He began his presentation with a look at the sub-chapters "Formalities" (5.1.) and "Decision-making" (5.2). In his opinion, the formalism in quality risk management (QRM) should also be reflected in decisionmaking (high-level formalism vs. low-level formalism). With regard to drug shortages, Dr Gnibl then used a slide (Figure 3) to show how complex and therefore vulnerable supply chains are nowadays. Starting from QRM, Dr Gnibl sees knowledge management, deviation systems (OOS, complaints...), change management and the maintenance system as links to GMP. The data life cycle should also be organized in a risk-based manner. Finally, Dr Gnibl emphasized the necessity of integrating QRM into the pharmaceutical quality system.

Figure 3: Supply chain and drug shortage

Dr Peer Schmidt from Abbvie, in turn, spoke on the topic of the "ICH Q9 revision" from an industry perspective. He pointed out the change in the risk management process in the new version, in which risk identification became hazard identification. Dr Schmidt used the example of a hippopotamus to illustrate the difference between hazard and risk (Figure 4). Dr Schmidt sees the linking of hazard databases with critical quality attributes as an aid here. Dr Schmidt named subjectivity as the second topic of the revision of ICH Q9. In order to prevent this as far as possible in risk management, he recommended

  • trained personnel with regard to subjectivity,
  • cross-functional teams,
  • "anonymous" contributions and
  • clear, quantitative evaluation systems.

Figure 4: Difference between hazard and risk

On the third point of change in the ICH Q9 guideline, formality, Dr Schmidt recommended clear specifications in the quality system with regard to high-level formalism and low-level formalism, as already mentioned by Dr Gnibl (see above). As well as a clear definition of the factors that control the degree of formalism. Dr Schmidt sees the key to risk-based decision-making (fourth change point of the ICH Q9 revision) in the clear description in the quality system, also with regard to structuring. Dr Schmidt and Dr Gnibl's views also coincide here. In order to be able to control the fifth change point of the ICH Q9 revision (supply bottlenecks), Dr Schmidt recommends a detailed examination of the supply chains and plans to combat the bottlenecks. The sixth reason for change in the ICH Q9 guideline concerns the "Risk Review". Dr Schmidt also recommended making specifications in the quality system regarding the various risk reviews.

What's next for Annex 11? Ib Alstrup, lead GMP inspector for the revision of Annex 11, presented the draft concept for revision. A draft of the new Annex 11 is expected in December 2024, according to Alstrup. The final version should then be published in mid/late 2026. The group working on the Annex revision also includes members from Canada, Australia and the USA via the PIC/S. The concept paper was commented on by 39 organizations with 567 comments. Ib Alstrup is awaiting the finalization of an OECD document on "Cloud Computing". On "Artificial Intelligence/Automated Learning", Alstrup recommended a two-page question paper by the Danish authority where he is employed. According to Alstrup, both documents could also be considered in the revision of Annex 11.

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Dr Wolfgang Schumacher from SPC then explained the industry perspective on the revision of Annex 11. He began his presentation with an overview of the guidelines published in the last 24 months relating to computer systems. What does the industry expect from the revision of Annex 11? According to Dr Schumacher, the industry expects that validation should be easier and faster; and clear instructions on what validation should look like. Dr. Schumacher then used a 5-star system to characterize the guidelines on computerized systems available on the market and gave his assessment of their sensible inclusion in the revision of Annex 11. In his opinion, the draft OECD document on GLP and cloud computing (which Ib Alstrup also mentioned) and an EMA guideline on computerized systems and electronic data in clinical trials are helpful for the Annex 11 revision. Dr Schumacher sees the concept paper as a good start and made the following recommendations for the working group revising Annex 11:

Review all recent guides available on the market (GMP, GLP, GCP, GDP, medical devices, ISO),

  • no "reinventing the wheel" - simply take the best from each guideline,
  • Change of perspective - put yourself in the shoes of a "Subject Matter Expert" (SME) and
  • also consider future technologies.

Dr Rainer Gnibl then spoke again about the revision of Annex 1 from the perspective of a GMP inspector. Dr Gnibl considers the Contamination Control System (CCS) to be a central element of the new Annex 1 and sees the CCS as an overview document that is intended to ensure sterility safety. On the subject of requalification, Dr Gnibl showed that there are unchanged limit values (e.g. for particle and microbiological limit values) but also changes (requalification frequencies in areas A/B and C/D). The "Barrier Technologies" chapter can lead to problems with older cleanrooms, according to Dr Gnibl, but an "alternative approach" in the new Annex 1 could provide assistance here. According to Dr Gnibl, transfer processes are now also undergoing some changes. Validation is required. The chapter on production and specific technologies has been extensively expanded in the revision (21 pages). Dr Gnibl showed minimum requirements for an SOP on filter integrity tests (Figure 5). Finally, Dr Gnibl addressed aseptic processing simulation (APS, medial fills). The worst cases of APS are of particular interest to GMP inspectors.

Figure 5: SOP filter integrity test

In the response from Dr Ingrid Walther (Pharma Consulting Walther) from an industry perspective, she emphasized the importance of quality risk management in the revision of Annex 1. The word "risk" appears 124 times in Annex 1, while it only crops up 20 times in the previous version. According to Dr Walther, the focus of the current Annex 1 is on

  • sterility safety
  • control of bioburden
  • the control of pyrogens/endotoxins
  • the control of particle contamination

Dr Walther then focused on the Contamination Control System (CCS). She does not see CCS as a new requirement; for her, the documentation of the system is what is actually new. According to her, the structure of a CCS is already specified in Annex 1 (Figure 6). She particularly referred to an ECA document on CCS with many examples. The first day of the forum ended with a tour of the city and a tapas menu.

Day 2 started with a presentation by Thomas Schmid from CSL Behring. His topic was "Hybrid Inspections". Thomas Schmidt made a very subtle distinction between "Distant Assessments" and "Remote Audits". In both cases, the auditor is not on site. In the first case, the focus is on documentation (via a document-sharing platform or emails). In the second case, virtual tours are often included. Communication takes place with cameras switched on. In hybrid audits, at least one person is on site and the audit is also conducted virtually. However, the transitions between the two types are fluid. What are the advantages of hybrid audits? Less on-site involvement and therefore less travel time for Subject Matter Experts (SMEs). Less impact from geographical risks (political unrest, pandemic situations). But the local presence of a qualified auditor is guaranteed. For Thomas Schmid, the preparation of a hybrid audit is very important. It should be considered:

  • What is done on site, what is done online?
  • Who is on site, who is online?
  • What are the technological framework conditions (document camera...)?
  • What confidentiality agreements are necessary?
  • More detailed audit agenda than for on-site audits
  • Plan buffer times for IT problems
  • Clarify whose turn it is and when?
  • Schedule breaks (5-10 min after 60-90 min)

In any case, it should also be taken into account that communication takes longer for hybrid audits. In principle, they are conducted in a similar way to on-site audits (welcome with coordination of the agenda, wrap-up at the end, etc.). However, the virtual tour is a special feature, as the technical requirements with the camera are sometimes difficult to implement. Attention, special questions, e.g. on sterility safety, can delay the tour considerably. Thomas Schmidt presented the necessary communication rules during hybrid audits on a slide (Figure 7).

Figure 7: Guiding principle for communication during remote session  

Dr Afshin Hosseiny then presented the Compliance Monitor of the MHRA (Medicines and Healthcare products Regulatory Agency) and posed the rhetorical question: could this also be a system for the EU? What is behind the Compliance Monitor (CM)? It is a pilot program to monitor companies that have problems complying with GMP and/or GDP. Part of the program is also a reference to an Inspection Action Group (IAG). The IAG is a group that advises the MHRA head on, for example, inspection results, standards, etc. The aim of the pilot program is to provide support in order to prevent drug shortages. It should also help the MHRA to focus its resources more strongly on patient safety. As an independent overview, the CM is intended to help the companies concerned to rectify their shortcomings.

Compliance Monitors are consultants selected by the MHRA from a CM register. The requirements for these consultants are relatively high, including at least 5 years' experience as an auditor, completion of the MHRA training program for this role, etc.. A company that is monitored under the program selects a consultant from the CM list. This selected consultant will then work with the firm to develop a compliance plan. This plan is approved by the MHRA, the consultant and the firm. The consultant supervises the implementation. The company pays the consultant for his work. Dr. Hosseiny then presented the advantages of the program on a slide (Figure 8). And what is Dr Hosseiny's answer to the initial question of whether the system would also be suitable for the EU? His answer: If the prerequisites are met, why not?

Figure 8: Benefits from MHRA´s Compliance Monitoring Program

Dr Frank Seibel then presented the FDA's Quality Metrics Initiative. He began by giving an overview of the history of the program. According to the present status, comments from two pilot programs are currently being requested by the FDA. With regard to the program, the FDA's goals include

  • help to make data-related decisions,
  • prioritize inspection resources,
  • identify areas for improvement and
  • identify potential risks to the public.

The metrics program is a basic element of a quality overview. He showed examples of quality metrics that could be of interest to the FDA as an overview on a slide (Figure 9). So what are the benefits for the pharmaceutical industry? Dr Seibel named 5 fields:

  • solving quality problems,
  • effectiveness of inspections,
  • reduced inspection frequency, 
  • faster product authorizations and
  • simplified post-approval change management.

Figure 9: Examples of FDA Quality Metrics

Dr Seibel then contrasted "metrics" with "key performance indicators" (KPIs). All KPIs are metrics, but not all metrics are KPIs. KPIs measure performance in relation to specific goals. On a separate slide, Dr Seibel then shows examples of metrics, KPIs and trending data (Figure 10).

Abbildung 10: Examples for metrics, KPIs and trending data

Finally, Dr Uwe Rettig from CSL Behring discussed how to deal with drug supply bottlenecks from a GMP perspective. How can the impact on the pharmaceutical supply chain be reduced? He chose a somewhat unusual example, namely dry ice, which CSL needs as a vaccine manufacturer. The dry ice is used for the internal transportation of QC samples, for the internal transportation of semi-finished goods and for external transportation processes. These processes are validated. The weekly quantity of dry ice required by CSL is between 1 - 1.5 tons. Due to the uncertain supply of CO2 as a raw material, the dry ice manufacturer no longer wanted to guarantee a reliable supply of dry ice. In addition to the dry ice problem, there were many uncertainties in the supply chain at CSL during the COVID-19 pandemic. He showed this in an overview slide (Figure 11). Dr Rettig listed possible solutions:

  • flexibility in the procurement of materials,
  • transparent and collaborative communication between supplier and customer regarding risks (prioritization of delivery, increase storage capacity),
  • local suppliers and
  • reducing the variety of raw materials.

Abbildung 11: Supply chain and uncertainties

And how did the company react to the potential bottleneck in the supply of dry ice? Dr Rettig named the following countermeasures:

  • establishing different dry ice suppliers,
  • alternative methods using cool boxes for samples,
  • reducing the quantities of dry ice through multiple use and longer use of the dry ice.

Finally, Dr Rettig referred to risk reduction as "daily business" with regard to supply bottlenecks. In addition, a clearly structured process should be in place to deal with any supply bottlenecks. This concluded the second day of the GMP & GDP Forum. The article on the following pages tells you what happened on day three of the forum.

The GMP & GDP Forum takes place every two years. The next forum is planned for June 2025.

 

About the Author
Sven Pommeranz is Operations Director and organises and conducts courses and conferences on behalf of the ECA Academy in the area validation.

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