Round table discussion on GMP for ATMPs in Vienna
One day before this year's ECA ATMP Conference in Vienna, the ATMP Interest Group of the ECA organized a round table discussion with representatives from authorities, industry and academia to provide a platform for the exchange of experiences on the GMP guidelines specific to Advanced Therapy Medicinal Products which came into force in May 2018. In line with the ECA's guiding principle, the round table discussion was intended to support the pharmaceutical industry, academia and regulators in order to promote the move towards a harmonised set of GMP and regulatory guidelines by providing information and interpretation of new guidances.
The participants of the round table discussion were asked in advance to select important and interesting topics and questions from their daily work and to present them in the context of the event and thus put them up for discussion. In this article, we would like to report on some of these topics as well as the individual aspects of the discussion.
History of the ECA ATMP Interest Group
When the Regulation (EC) No 1394/2007 - the overall legal framework on ATMPs in Europe - entered into force in 2007, concomitantly, the ECA began evaluating the interest in ATMPs in courses and additional activities on cell based products. However, the initial interest in such events was limited at the time. The main reason for this may have been that many companies were still in the early phase of development. Nevertheless, to keep their members informed about the ongoing developments, the ECA continued to include ATMP topics in their newsletters and organized courses on GMP for ATMP every two years.
Meanwhile, due to promising results and increasing investments in the development of ATMP, a growing number of institutions and companies have reached the phase of clinical testing and GMP compliant manufacturing, as well as marketing authorisation. This development has resulted in a rising interest of ECA members on the topic of ATMP.
With the European Commission draft Guideline on GMP for ATMP, which was discussed intensely during the ECA ATMP workshop in April 2017, GMP requirements came to be more under scrutiny. During this event, the ECA requested feedback of the participants on whether an ECA Working Group on ATMP would be of interest. Several participants expressed their interest. Within the European Qualified Person Association, the QPs involved in ATMPs started an initiative to discuss the subject at the same time (especially within the IMP Working Group).
To coordinate the increasing interests, ECA decided to establish a joint ATMP Interest Group. The group is directed by an interest group board consisting of nine members from industry and academia and accompanied by two authority representatives. The board had its kick-off meeting in June 2018 where the first actions and activities where planned and a business plan was set up. The group decided to focus in its first working period on the GMP guidelines for ATMPs and to foster discussion between the regulators on one side and industry and academia on the other. In order to achieve this goal, the round table discussion was organised in Vienna, which we report on in this article.
26/27 October 2021
Live Online Training: Bioassays and Bioanalytics
Classical versus specific GMP for ATMPS
At the ECA ATMP conference in 2018 in Berlin, many speakers and participants were already dissatisfied with the decision of the European Commission to publish the GMP guidelines for ATMPs as a standalone document instead of integrating them in the existing GMP guidelines. A year later in Vienna, this attitude was again confirmed. The great concern of all those involved is that the classic GMP regulations (Eudralex Volume 4 Part I for medicinal products and Part II for active substances) and the GMP regulations specific to ATMPs (Part IV) will diverge over time, since the specific ATMP guidelines will hardly be able to trace every change to a chapter or annex from Part I or II. In particular, the forthcoming revision of Annex 1 on the manufacture of sterile medicinal products could lead to first major deviations. This poses a particular challenge for GMP inspectors, who frequently inspect both classical sterile plants and AMTP manufacturers. But ATMP manufacturers are sometimes uncertain how to interpret the new GMP guidelines for ATMPs, as well. Since the new guidelines strongly emphasise the use of a risk based approach and are therefore less detailed in some provisions compared to Part I, they often can be interpreted in multiple ways. In contrast to that, the chapters and annexes of Part I especially have grown over time and are formulated much more straightforward and unambiguously. This is the reason why Part I is still often used as the basis for ATMP inspections although it does not actually apply. A further challenge is that currently, ATMPs are predominantly developed and produced by small companies or academic institutions that are not much experienced in dealing with the general GMP rules and often have limited personnel and material resources. This might be the reason why authority representatives of the discussion round reported that inspection findings are often not ATMP specific but rather linked to overall quality management issues (e.g. change control, handling of deviations or CAPA management). Unfortunately, especially the sections on basic GMP requirements of Part IV offer only reduced guidance compared to Part I. In the context of limited resources, Yolanda van Kooij from the Dutch Health and Youth Care Inspectorate (HYCI) reported on an interesting initiative of the Dutch hospital pharmacists who have joined forces to carry out audits for supplier qualification.
Finally the panel discussed the requirements for equipment and facilities with respect to cross contamination. Currently, it seems that only a limited number of ATMP manufacturers operate dedicated ATMP production sites whereas a large number of facilities are multi-product sites where not only different kinds of ATMPs are produced but also other types of medicines. The uncertainty as to how the new regulations on cross-contamination and concurrent manufacture of different batches or products should be interpreted also became evident in the discussions of the ECA ATMP conference in the following days. One important question with respect to concurrent manufacture of ATMPs seems to be how close closed production systems really are.
Dr Christoph Mück from the Austrian Agency for Health and Food Safety (AGES) shared his experiences on the assessment of marketing authorization applications (MAA) of ATMPs. He emphasized that the definition of critical quality attributes and suitable specifications as well as the presentation of adequate related data are fundamental for the evaluation of quality and comparability of a product and that applicants should pay special attention to these issues.
The complex manufacturing processes for ATMPs are often changed significantly during the preclinical and clinical development phases and thus might require compatibility studies that should follow the applicable ICH guidelines. Sufficient demonstration of comparability of material previous to and after manufacturing changes is vital for the MAA assessment. For release assays, bridging studies between old and new/optimized assays might be required. A challenging point that came up during discussion was the lack of suitable data from the early development phases. Often, the relevance of comparability studies for later development phases is not clear to the applicants. This may lead to the question if pre-clinical data are still applicable to a product in advanced stages of development.
Another safety-related topic is impurities that are often more varied in ATMPs than in other biologics. They stem from both, the complex manufacturing processes and from the complex products and their starting materials. Impurities should be thoroughly tackled by the applicant.
A hot topic on specifications is the possibility to administer OOS batches (see below), and how to handle OOS in sterility testing. The group discussed how the risk based approach could be applied in cases of sterility OOS, and whether the concept of sterility requirement might be modified with focus on bioburden.
Import of ATMPs from Third CountriesA focus on commercial products came with the question of retesting ATMPs after importation from third countries. Since ATMPs are excluded from most Mutual Recognition Agreements (MRA) a complete retest upon import is mandatory following the guidelines. Omission of retesting could only be justified by a limited batch size. But what about the other difficulties associated with ATMPs, such as short shelf life of the products? The group discussed that facilitations for the release testing of ATMPs (e.g. microbiological testing of surrogate material from intermediate production stages) has been accepted by the authorities in the past, but these issues have so far mainly been discussed in the context of product release, not so much with respect to importation from third countries. Therefore, the applicants should discuss the requirement with the regulators early on. The "Concept paper on new guidance for importers of medicinal products", EMA/238299/2015, should be considered.
Administration of OOS products
One of the most intensively discussed topics of the day was the possible administration of OOS batches, a specific provision allowed for by the GMP for ATMP guidelines under certain prerequisites. The participants shared their experiences and discussed possible processes as well as responsibilities and obligations. One important point of discussion was whether OOS batches have to be released and therefore certified by a qualified person in order to allow their administration, or whether, on the contrary, they must not be released at all as they do not meet the release specifications. It is clear that the relevant passage in the specific GMP guidelines for ATMPs does not mention the word "release". But what does that mean for the implementation of a possible procedure in the quality management system? How can a risk assessment be performed? How should the process be documented? What is the responsibility of the treating physician? Is there a responsibility of the QP? Which OOS parameters can justify an application at all? The group agreed that ATMPs, due to their complexity and the variability of the starting material of human origin, are generally susceptible to OOS results and that manufacturers should prepare for these cases. As always in the context of GMP, it is mandatory to have a detailed written procedure in place and to thoroughly document the incident once it occurs. Not mentioned in the guidelines is the role of the patient, who is supposed to receive the OOS batch. The group agreed that the affected patient should be informed on the OOS result, but that he or she should not have to make the decision whether or not he or she wants to receive the product. In clinical trials, it might be advisable to discuss the procedure for OOS batches as well as potential risks in advance with the investigators. Such information could also be part of the Investigator's brochure. Further advice on how to deal with OOS batches of authorised ATMPs is provided in a Q&A Paper published by the EMA in April this year.
26-28 October 2021
Live Online Training: Bioassays and Bioanalytics + Stability Testing for Biological/Biotechnological Drug Substances and Drug Products
Training of GMP Inspectors for ATMPsAn interesting presentation that was not directly related to the GMP guidelines for ATMPs was Yolanda van Kooij's explanation on the training system for GMP inspectors in the Netherlands. The Dutch Health and Youth Care Inspectorate (HYCI) shall have specialized inspectors for ATMPs different from those for cells and tissues at its disposal. GMP inspectors for ATMPs in the Netherlands have different professional qualifications and can be both biologists and pharmacists. There is an internal training concept for the qualification of new inspectors, which provides, among other things, for experienced inspectors to be accompanied by newly qualified inspectors. In addition to this internal training, care is taken to ensure that individual inspectors also participate in external events. The inspectors attending external training sessions, workshops or conferences report on these events in the ATMP team and thus act as multipliers. For the preparation of inspections, those assessors who have granted the MAA or CTA and are therefore familiar with the individual products and the requirements for production and quality control are consulted. They can provide information on which aspects are to be particularly taken into account during the inspection. The results of the inspection are finally discussed with the entire ATMP team in order to impart knowledge and harmonise the supervision.
The round table workshop was concluded after very constructive discussions of shared experiences. In this open environment, new ideas arose for further activities that will be implemented in the ATPM Interest Group's next work plan. We will report on those activities in due course.
Interesting discussions also followed the next two days during the official ECA ATMP conference where again representatives from industry, academia and authorities shared their experiences and views on various topics related to ATMPs. You can find a conference report in one of the following articles of this GMP journal.
Dr. Sabine Hauck
... works for Leukocare AG in Germany and is Chair of the ECA ATMP Interest Group.
Dr. Andrea Hauser
... works at the Universitätsklinikum Regensburg in Germany and is Vice Chair of the ECA ATMP Interest Group.
1 EudraLex Volume 4 Good Manufacturing Practice, Part IV: Guidelines on Good Manufacturing Practice specific to Advanced Therapy Medicinal Products
2 “Questions and answers on the use of out-of-specification batches of authorised cell/tissue-based advanced therapy medicinal products”, 24 April 2019, EMA/CAT/224381/2019