Possible ATMP-specific adaptations to the GMP requirements

As a starting point Recital 17 of the ATMP Regulation requires that the ATMPs manufacture should comply with the GMP principles, as set out in Commission Directive 2003/94/EC of 8 October 2003 laying down the principles and guidelines of GMP in respect of medicinal products for human use and investigational medicinal products for human use. Yet, it allows for adaptations where necessary, to reflect the specific nature of ATMPs. Furthermore, Recital 17 requires that guidelines specific to ATMPs should be drawn up by the European Commission, so as to properly reflect the particular nature of their manufacturing process. Yet, regulators have encountered challenges with creation of GMP standards for ATMPs and some developers of ATMPs have faced significant difficulty in some Member States in obtaining approval for manufacture of specific products because of unrealistic expectations of product qualification by their national competent authorities. ⁶²⁴

For instance, the study by Pearce at al. mentions a classification problem with bone marrow-derived mesenchymal stromal cells that are commonly produced for therapeutic use across the EU. Some Member States do not classify them at all as medicines, whereas in those Member States where they are classified as ATMPs, most authorities accept release criteria on the basis of sterility,

622 Pearce, et al., supra note 540, 296.

623 Ibid.

624 Op.cit., 294.

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parameter immunophenotype as definition and above 80 percent viability. It was reported that one national competent authority had required chromosomal stability assays on all mesenchymal stromal cell cultures, which in practice renders the trial unsustainable.⁶²⁵

To address the need for ATMP-specific adaptations to GMP requirements, the European Commission recently arranged targeted stakeholder consultations on GPM requirements for ATMPs.⁶²⁶ These consultations cover so-called “commercial ATMPs”

(i.e., licenced products) as well as so-called “investigational ATMPs” (i.e., ATMPs used in clinical trials). ATMPs produced under hospital exemption were however left out of this consultation under the first consultation document. Stakeholders involved in the development, manufacture and/or commercialisation of ATMPS were invited to share their perspectives on the GMP requirements that should apply to ATMPs.⁶²⁷ The consultation document proposed some adaptations to GMP requirements applicable to ATMPs. The majority of respondents supported the approach in the first consultation document (whilst the second consultation is currently ongoing). In particular, SMEs and academia found it well-adapted to the specific characteristics of ATMPs, and useful and beneficial for the development of the field. Some of the proposed adaptations were also expected to reduce manufacturing expenses. Some respondents perceived that the flexibilities proposed for ATMPs would improve EU competitiveness in the global setting.⁶²⁸ Yet 20 percent of the respondents (mostly representing the industry sector) had a negative view of the development of a self-standing guideline. Some industry sector representatives were concerned that this guideline would create double standards depending on whether ATMPs are manufactured by industry or academia/hospitals.

Now the second consultation document clarifies that the risk-based approach is equally applicable to all type of operators.⁶²⁹ According to the European Commission, a substantial number of respondents objected to the principle that the guideline would not apply to the hospital exemption. Whilst the second consultation document has been amended in this respect and it does not exclude manufacturing under hospital exemption. Clarification regarding the scope of the guidelines and links with general GMP rules was also requested.

625 Op.cit., 295

626 European Commission. Consultation Document. Good Manufacturing Practice for Advanced Therapy

Medical Products, (v.1). Available at:

http://ec.europa.eu/health/files/advtherapies/2015_pc/publ_cons_doc_2015.pdf. Accessed 21 June 2016.

The second consultation is still ongoing: European Commission. Consultation Document. Good Manufacturing Practice for Advanced Therapy Medical Products (v.2). Available at http://ec.europa.eu/health/files/advtherapies/2016_06_pc/2016_06_draft_guideline.pdf. Accessed 26 July 2016.

627 European Commission. Summary of responses to the targetted stakeholder consultation on the development of good manufacturing practice for advanced therapy medical products pursuant to Article

5 of Regulation 1394/2007. Available at:

http://ec.europa.eu/health/files/advtherapies/2015_11_pc_gmp_atmp/2015_11_pc_gmp_atmp_summary.

pdf. Accessed 21 June 2016.

628 Op. cit., 3.

629European Commission. Consultation Document. Good Manufacturing Practice for Advanced Therapy Medical Products (v.2), 6.

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From a regulatory perspective the proposed GMP guidelines on ATMPs appear quite casuistic. However, it seems to be unavoidable as further clarity and practical exampes have been requested by the developers of ATMPs to standardise risk proportionate approaches to GMP and clinical trials. In short, the following general observations can be made based on the first consultation:

i. the proposed, more flexible risk-based approach was strongly supported, but a need for additional guidance regarding the application of this approach was expressed (as presented below second consultation document provides now further clarifications in this respect);

ii. some of the respondents (mostly from academia) supported the proposed opportunity to recognize to the quality systems established under the parent directive of EUCTDs (Directive 2004/23/EC)⁶³⁰ and/or the JACIE accreditation system⁶³¹ (the second consultation document now provides further clarification regarding ATMPs that are not that are not subject to substantial manipulation);

iii. regarding the premises, academia gave strong support to the possibility of accepting the use of a clean room with a background of C or D grade for early phases of clinical trials for TEPs and CTMPs (but there was no consensus on whether this flexibility should extend beyond the early phases of clinical trials and whether GTMPs should be also covered). Furthermore, a very large number of respondents from all sectors noted that this possibility should also be extended to the manufacture of ATMPs in closed systems or when isolators are used and that flexibility for the use of semi-closed systems should also be considered. Criticism was directed towards the requirements for dedicated production facilities (manufacture can take a long time and it may not be economically possible to have dedicated facilities);

iv. the requirements adapted for raw materials were widely supported among respondents from all sectors. In particular, the principle that ATMP manufacturers should not be required to audit blood and tissue establishments authorised and supervised in accordance with Directives 2002/98/EC and 2004/23/EC was supported; ⁶³²

v. most proposed requirements regarding production were considered well-adapted, but a number of adaptations were suggested (e.g., some respondents from all sectors objected to the principle that simultaneous manufacture of various viral gene therapy vectors in the same area is not acceptable, as well the principle of cleaning validation between the manufacturing of different batches for cell-based products). The need for additional guidance regarding the possibility of re-processing in exceptional cases, where the treatment of patients requires the re-administration of autologous materials, was also expressed;

630 Under Article 16 of Directive 2004/23/EC tissue establishments shall take all necessary measures to ensure that the quality system includes at least the following documentation standard operating procedures: guidelines, training and reference manuals, reporting forms, donor records and information on the final destination of tissues or cells.

631 JACIE. Accreditation. Available at: http://www.jacie.org/applicants/why. JACIE is a joint accrediation committee of European Sociaty for Blood and Marrow Transplantation and International Society for Cellular Therapy. Accessed 21 June 2016.

632 Additional adaptations were suggested such as the use of raw materials that are covered by a marketing authorisation (e.g., cytokines). As for the sterilisation of starting materials, many found that the preference for heat over other sterilisation methods should be reconsidered.

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vi. respondents from all sectors generally agreed that a pragmatic approach is required to process validation;

vii. the approach adopted on qualified person oversight and release regarding products from third countries has been generally considered useful. Many also requested that the guideline should require that the professional qualifications/experience of the qualified person should be specifically adapted to the characteristics of ATMPs;

viii. most respondents supported the approach adopted on sampling and testing. (However, additional flexibilities and more detail have been requested and second consultation documents provides some clarifications in this respect as presented below);

ix. it was also noted that in small organisations (hospitals, in particular), teams are multi-skilled and trained in both quality control and production activities. While recognising the importance of securing the independence of the quality control from the production activities, need for accommodation of constraints on small organisations was expressed;

x. the approach to reconstitution suggested in the consultation document was widely supported across all sectors⁶³³; and

xi. it was noted that the GMP obligations should be adapted to ATMP manufacture by means of automated devices/systems (the second consultation document provides clarifications in this respect).⁶³⁴

All in all, these proposed adaptations in ATMP-specific GMP Guidelines were widely welcomed in the first public consultation and represent a leap forward to a more flexible risk-based approach to the manufacture of ATMPs. To provide further clarification of how the risk-based approach should be applied to ATMPs DG SANTE launched a new public consultation and issued a new consultation document on 28 June 2016 that has been elaborated based on the issues raised in the first consultation.⁶³⁵ In particular, this new consultaltion document provides further examples and suggest guidance regarding risk-based approach to GMP manufacture of ATMPs.

As for investigational ATMPs, it emphasises that the safety of the product needs to be ensured from the first stages of development. Yet, it also notes that due to a gradual increase in the knowledge of the product additional flexibilities may be possible in early phases of clinical trials. Manufacturing procedures and control methods are expected to become more specified during the more advanced phases of the clinical trial.⁶³⁶ It also emphasises that it is important to ensure that data obtained from the early phases of

633 Reconstitution covers activities required after batch release and prior to the administration of the ATMP to the patient, and which cannot be considered as a manufacturing step.

634 European Commission. Summary of responses to the targetted stakeholder consultation on the development of good manufacturing practice for advanced therapy medical products pursuant to Article 5 of Regulation, 5.

635 European Commission. Consultation Document. Good Manufacturing Practice for Advanced Therapy Medical Products (v.2), supra note 626.

636 Op.cit., 7.

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clinical trial can be usedin later phases of development.⁶³⁷ It encourages developers to seek early advice from the competent authorities in connection with the implementation of the risk-based approach for IMP ATMPs (especially regarding early phases of clinical trials). The draft GMP Guidelines provide examples of possible adaptations that are acceptable in case of IMP ATMPs as follows:

 For first-in-man clinical trials, production may take place in an open environment in a critical clean area of grade A in a background clean area of grade C. It is however required that there are appropriate controls of microbiological contamination, separation of processing procedures, and validated cleaning and disinfection. Also, risk-analysis study should be conducted to demonstrate that the implemented control measures are adequate to ensure aseptic manufacturing.⁶³⁸

 In early clinical trial phases I/II when the manufacturing activity is very low, annual calibration, inspection or checking can be limited to the facility, cabinets, incubators, isolators, freezers, air sampler and particle counters, unless a lower frequency is justified due to periodicity of use. Yet, the rest of equipment could be tested less frequently based on a risk analysis and the production activity. The suitability for use of all equipment should be verified before it is used.⁶³⁹

 The level of formality and detail for the documentation should be adapted to the stage of development. ⁶⁴⁰

 During early phase I/II clinical trials specifications can be based on wider acceptance criteria taking due account of the current understanding of the risks.⁶⁴¹

 Also some additional flexibilities regarding qualification of premises and equipment, process validation, and validation of analytical methods.⁶⁴²

As for licensed ATMPs, marketing authorisation is the starting point for the application of the risk-based approach in GMP manufacture of ATMPs. Hence, any specific limitations shoud be agreed as part of the marketing authorisation. The specific characteristics of the product or manufacturing process can be taken into consideration to justify deviation from standard expectations when providing the description of the manufacturing process and process controls in the marketing authorisation application.

In addition, regarding aspects that are not specifically covered by the marketing authorisation, it is mandatory for the manufacturer to document the reasons for the approach implemented when the risk-based approach is applied, and to justify that all of the measures applied are adequate to ensure the quality of the product.⁶⁴³

637 Ibid. According to the second Consultation Document, a too immature quality system risks to compromise the use of the study in the context of a marketing authorisation application. Furthermore, a weak quality system may compromise the approval of the clinical trial if the safety of trial subjects is at risk.

638 Op.cit., 11.

639 Ibid.

640 Ibid.

641 Ibid.

642 Op.cit., 11, 44-49.

643 Op.cit., 8.

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When it comes to risk-based approach to ensuring the quality of the raw materials, it is required that the manufacturer has a good knowledge of the role of the raw material in the manufacturing process.⁶⁴⁴ Especially, understanding on specific properties of the raw material are vital for the manufacturing process and final quality of the product.

Also the level of risk of the raw material due to the inherent properties thereof must be taken into consideration (e.g,. basic media v. growth factors), or the use thereof in the manufacturing process (higher risk if the raw material is in direct contact with the starting materials). Finally, it must be assessed whether the control strategy (i.e.

qualification of suppliers) is sufficient to eliminate the risks or to reduce them to an acceptable level.

As for risk-based approach to be applied in connection with the testing strategy, it is noted that in some cases it may not be possible to perform the release tests on the active substance or the finished product due to technical reasons or when the amount of available product is limited to the clinical dose.⁶⁴⁵ In such cases an adequate control strategy should be designed and explained in the marketing authorisation or clinical trials authorisation application based on the validation of the manufacturing process and the in-process controls.⁶⁴⁶ Following alternative measures have been proposed: (i) testing of intermediates (instead of the finished product) or in-process controls (instead of batch release testing) if the relevance of the results from these tests to the finished product can be demonstrated; or (ii) substituting routine batch testing by process validation.⁶⁴⁷ In addition following adapted approaches have been suggested: (i) it may be justified to waive the on-going stability programme for ATMPs with a very short shelf-life; (ii) the strategy regarding sterility assurance may need to be adapted if the application of the sterility test⁶⁴⁸ to test the final product is not possible due to the scarcity of materials available or it may not be possible to wait for the result of the test before the product is released due to short shelf-life⁶⁴⁹; and (iii) the particulate matter test may be limited to foreign visible particles in case of cells in cell culture suspension that are not clear solutions, if alternative measures⁶⁵⁰ are implemented.

When it comes to cells or tissues that have not bee subject to substantial manipulation, some flexibilies are suggested as such materials are typically associated with lower risks than the manufacturing of ATMPs that require complex substantial

644 Op.cit., 8, 29-31.

645 For instance, it may not be possible to perform the release tests on the combined components of certain combined products due to time restrictions if the product needs to be administered immediately after completion of manufacturing.

646 Op.cit., 8-9.

647Op.cit., 9. It is noted that the process validation is usually not required for investigational medicinal products, it may be very important when routine in-process or release testing is limited or impossible.

648 A sterility test in accordance with the European Pharmacopoeia (Chapter 2.6.27).

649Such adaptation may involve use of alternative methods for preliminary results, combined with sterility testing of media or intermediate product at following relevant points of time. If the results of the sterility test of the product are not available at release, appropriate mitigation measures should be implemented.

650 Op.cit., 9. These alternative measures may inlude controls of input of particles from materials and equipment used during manufacturing, or the verification of the ability of the manufacturing process to produce low particle products with simulated samples without cells.

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manipulations.⁶⁵¹ Yet, processes that are not qualified as “substantial manipulation” are not risk-free, especially if the processing of the cells involves long exposure of the cells or tissues to the environment. Therefore, there is a need for a risk analysis to identify the measures that are necessary to ensure the quality of the product in the manufacturing process. To avoid administrative burden in manufacturing process of ATMPs that do not involve substantial manipulation, premises and equipment that have been duly validated to process cells/tissues for transplantation purposes in accordance with standards that can be deemed comparable to those laid down in these draft GMP Guidelines for the same type of manufacturing operation do not need to be validated again. Yet, premises/equipment used to process cells/tissues under the same surgical procedure (derogation under Article 2(2) of Directive 2004/23) or for research purposes must be validated in accordance with these GMP Guidelines.⁶⁵² Draft GMP Guidelines emphasise the responsibility of the manufacturer to ensure that the manufacturing of ATMPs takes place in aseptic conditions, also when the manufacturing process does not involve substantial manipulation. Yet, some adaptatios regarding clean room facilities are allowed, but subject to risk assessment. ⁶⁵³

The Directorate General for Health and Food Safety, DG SANTE, has also recently (1^st of June 2016) launched a public consultation to seek the views of stakeholders and other interested parties on the document regarding "Risk proportionate approaches in clinical trials" which has been drafted in preparation for the implementation of the Clinical Trials Regulation. ⁶⁵⁴ However, the particularities of ATMPs have not been specifically addressed in this document. Whilst the second consultation document regarding risk-based approach to GMP manufacture of ATMPs specifies that

“the description of the manufacturing process and process controls in the clinical trial authorisation application should also describe, as appropriate, the quality strategy of the manufacturer when the risk-based approach is applied. For aspects that are not specifically covered by the clinical trial authorisation, it is incumbent upon the manufacturer to document the reasons for the approach implemented and to justify that the totality of the measures applied are adequate to ensure the quality of the product.”⁶⁵⁵

Yet, it should also be noted that none of the adaptations in the proposed GMP Guidelines (including the risk-based approach) should be seen as derogation of the marketing authorisation or clinical trial authorisation terms. The manufacturing requirements (e.g., specifications, manufacturing process, controls, etc.) specified in the

651 Op.cit., 9-10.

652 Op.cit., 9-10.

653 Op.cit., 10. More specifically it is stated that “[w]hen manufacturing operations take place in an open

653 Op.cit., 10. More specifically it is stated that “[w]hen manufacturing operations take place in an open

In document Commercialisation of Advanced Therapies : A Study of the EU Regulation on Advanced Therapy Medical Products (sivua 154-161)