Submission of Comments On
25 September 2016
Submission of comments on
“Good Manufacturing Practice for Advanced Therapy Medicinal Products”
Comments from:
Dr Aurélie Mahalatchimy and Prof Andrew Webster on behalf of the REGenableMED consortium
Please find below comments on ‘Good Manufacturing Practice for Advanced Therapy Medicinal Products’ by the REGenableMED consortium.
REGenableMED - REGenableMED is a United Kingdom Economic and Social Research Council (ESRC)-funded project (N°ES/L002779/1: ). It brings together research team builds on work by social science experts based in Birmingham, Edinburgh, Sussex and York in the UK. It is coordinated by Pr Andrew Webster, Science and Technology Studies Unit at the University of York, UK. The project aims to examine the dynamics of innovation within the field of regenerative medicine. Using a mixed-methods social science approach, the project will undertake a detailed analysis of the interplay between business models, measures of clinical utility, patterns of regulatory oversight and clinical workflows within healthcare settings. The results of the research will inform strategies aimed at facilitating the responsible development of effective and useful regenerative medicine products and services.
All work packages of the project consider what we call the ‘institutional readiness’, i. e. the capacity and willingness of key pre-existing organisations and inter-organisational structures to adopt, respond to and utilise novel technologies, such as advanced therapy medicinal products as part of regenerative medicine. One work package led by Prof Alex Faulkner, Centre for Global Health Policy, School of Global Studies, University of Sussex, the UK is dealing with the role of a range of intermediary agencies, patient groups and health insurance companies, in determining what can be called 'healthcare readiness' for the field, that is, how the field aligns with and can be embedded in existing practice and how far changes need to be made. As part of this work a regular survey of regulatory tools (including relevant linked public consultations) that influence the pathways through which the field develops is performed. The draft response has been prepared by Dr Aurélie Mahalatchimy (academic lawyer). A discussion between persons interested was then organised and the attached answer circulated to all project participants before submission.
The REGenableMED consortium is grateful to the European Commission to have been given the opportunity to contribute to this consultation.
COMMENTS
General comments
The current version of these Guidelines is much clearer and detailed that the previous one. Improvements are clearly noticeable.
Specific comments
Introduction
The clarification on the scope of the guideline regarding authorised and investigational ATMPs is very welcome.
It appears necessary to link these guidelines with the relevant legislations.
To this end, the following paragraph should be added before line 128:
In accordance with Eudralex Volume 4, medicinal products compliance with GMP is required by Directive 2004/23/EC. As Medicinal products, ATMPs have to comply with GMP requirements.
However, it should be noted that Regulation (EC) no 1394/2007 highlights the specificity of ATMPS and its article 5 provides for the development of Guidelines on Good Manufacturing Practice specific to ATMPs. That is why these guidelines have been adopted.
Risk based approach
Examples given on risks associated with the manufacturing process are welcome. However, they do not seem to rely on the risk-based approach as provided by the EMA Guideline on the risk-based approach according to Annex I, part IV of Directive 2001/83/EC applied to Advanced Therapy Medicinal Products (EMA/CAT/CPWP/686637/2011).
It should be clarified and explicitly stated whether the proposed risk approach relies on ICH Q9 Quality Risk Management. If so, the wording “risk- based approach” should be avoided since this could lead to a potential confusion with the current EMA Guideline on the risk-based approach (i.e, as noted above, according to Annex I, part IV of Directive 2001/83/EC) applied to Advanced Therapy Medicinal Products.
Line 202: to strengthen this important point, it would be worth adding a short statement after the sentence ending ‘…at risk’ which reads: ‘ It is vital to understand how these risks may interact and so create unforeseen difficulties for both developer and patient’.
Line 221 –‘shoud’ needs to be corrected to ‘should’
Line 245 should read ‘possible’ not ‘posible’
After Line 254 add an additional short paragraph (reflecting emerging manufacturing/business models that will affect GMP) that reads:’ Testing of quality assurance measures in place where ATMPs are produced and delivered to the clinic via a distributed manufacturing process.’
ATMPs not subject to substantial manipulation
Line 279: In accordance with Regulation (EC) no 1394/2007, ATMPs that are not substantially manipulated but that are for non-homologous use should comply with GMP. This should be stated clearly before the flexibilities provided in lines 279-283.
Lines 287- 290: The JACIE accreditation system is not for medicinal products and consequently not for ATMPs. However, JACIE standards should be taken into account for licensing and inspections of premises of non-substantially manipulated ATMPs as long as “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 Guidelines need not being validated again (for the same type of manufacturing operation).” Thus, although the JACIE accreditation system cannot be requested for ATMPs, a possible flexibility is that JACIE standards could be taken into account for licensing and inspections of “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 Guidelines need not being validated again (for the same type of manufacturing operation).”
Key personnel
Lines 430- 434: It is welcome that flexibilities are accepted for small organisations where the same person could be responsible for QC and production.
Retention of documents
As explained in the paragraph on traceability according to article 15 of Regulation (EC) no 1394/2007, information on raw materials and all substances coming into contact with the cells or tissues should be kept for a minimum of 30 years. It notably includes batch number (lines 903 and 908). Consequently, lines 865-870 regarding batch documentation to be kept for 1 or 5 years are in contradiction with Regulation (EC) no 1394/2007.
Starting and raw materials
Lines 982-986: It should be added that where tissues and cells are imported, their quality and safety should be verified in accordance with Commission Directive (EU) 2015/566 of 8 April 2015 implementing Directive 2004/23/EC as regards the procedures for verifying the equivalent standards of quality and safety of imported tissues and cells.
Lines 935-936: the reference to the European Pharmacopeia is welcome.
Additional considerations for xenogeneic cells and tissues
Lines 1043- 1068: Additional considerations for xenogeneic cells and tissues are welcome. Reference should be made to Guideline on xenogeneic cell-based medicinal products (EMEA/CHMP/CPWP/83508/2009).
It should be specified whether the use of cells and tissues obtained from genetically modified animals poses additional risks. The REGenableMED Consortium would welcome some consideration to be given to the use of cells and tissues obtained from genetically modified animals.
Process validation
Lines 1581- 1622: Examples of pragmatic approaches that take into account the limited availability of the cells/tissues which is typical for most ATMPs are welcome.
Reconstitution activities
Lines 2083- 2101: Examples of reconstitution activities are welcome.
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