Minutes from the GAiT QC workshop, Sheffield, 5th October 2017
Contents
[1] Delegates
[2] Context
[3] Meeting Objectives
[4] A process for prioritising potential QC tests
[5] Identification of QC mandatory and informative tests
[6] Compatibility of GAiT QC standards with regulatory requirements.
[7] Summary of actions
[1] Delegates
Glyn Stacey (chair), NIBSC (GS)
Alok Srivastava, CMC Vellore
Amit Chandra, Yposkesi
Annelise Bennaceur, APHP/INSERM
Chihiro Akazawa, TMD
Harald Stachelscheid, BIH
Jack Price, NIBSC
Jihwan Song, KHiB
Jo Mountford, SNBTS
Lygia Pereira, USP
Marc Turner (GAiT board chair), SNBTS
Mathide Girard, YPOSKESI
Michael Sheldon, RUCDR
Naoki Aoyama, AMED
Natalie Ward, CGT
Ngaire Elwood, MCRI
Patrick Bedford, CCRM
Shaji Ramachandran, CMC Vellore
Ricardo Baptista, CGT
Scott Noggle, NYSCF
Shin Kawamata, FBRI
Stephen Lin, CIRM
Stephen Sullivan, GAiT (SJS)
Tenneille Ludwig, WiCell (TL)
Tadaaki Hanatani, CIRA
Tamara Malygina, OPTEC
Theodoros Latsis, APHP/INSERM
[2] Context
The Global Alliance for iPSC Therapies (GAiT) exists to facilitate the translation of scientific advances in iPSC generation and differentiation technology to develop and deliver cellular therapeutics to the clinic. A key issue in the application of iPSC-related therapies, in both the autologous and allogeneic setting, will be ability to generate a given therapeutic product using different clinical-grade iPSC lines as a starting material. In order to facilitate mutual recognition of clinical-grade cell lines, it will be important to demonstrate comparability across a number of parameters:
- Permissiveness of donor consent (e.g. for global dissemination, commercial use, genetic analysis etc.)
- Donor selection criteria (e.g. classes based on ABO blood group, Human Leukocyte Antigen (HLA), or Killer-cell immunoglobulin-like receptors [KiR])
- Donor screening criteria (health assessment and donor testing)
- Good Tissue Practice (GTP) / Good Manufacturing Practice (GMP) compliance of iPSC manufacture
- Compliance with mandatory Quality Control (QC) release criteria
Delegates agreed that GAiT should prepare an evaluation procedure against which clinical-grade iPSC lines can be assessed in liaison with the human pluripotent stem cell registry (hPSCreg). It was agreed that an early evaluation of the key aspects of putative clinical-grade iPSC lines will avoid wasting time and resources on cells which will ultimately not be suitable for clinical use and commercial development.
Action: GAiT to coordinate development of the clinical grade cell line evaluation procedure.
It was agreed that it would be valuable to assess existing iPSC databases for their ability to document the parameters outlined above either currently or with a small amount of investment.
Action: GAiT to review and assess existing iPSC databases’ suitability for how they capture key parameters and associated criteria.
The GAiT Quality Standards Working Group was asked to define key Quality Control criteria for clinical grade iPSC cell lines.
[3] Meeting Objectives
Key objectives for the meeting agreed with delegates were identified as:
- Identification of key quality control (QC) elements based on a review of the Master Cell Bank (MCB) testing table from the International Stem Cell Banking Initiative (ISCBI)’s 2015 publication which discriminates between mandatory requirements and additional information. Mandatory requirements will assist directly in determining which induced pluripotent cells (iPSCs) are fit for use in the manufacture of cellular therapeutics and which are not (i.e. they should be Critical Quality Attributes [CQAs]). Additional information may be gathered which might be of scientific interest and may potentially be of clinical importance in the future, but it is not critical at this stage.
- Consensus Development on QC methods and standards required for clinical-grade iPSC banking.
- Determination as to which pre-existing methods and standards can be utilised and / or further developed by GAiT.
Delegates agreed that the ISCBI (2015) publication and the GAiT Quality Standards Survey responses constituted a solid basis from which to develop a common set of QC standards based on CQAs for clinical grade iPSCs. Additionally, the group were asked to identify any other iPSC cell banking document that might prove useful.
Action: All delegates to identify any further iPSC cell banking documents
[4] A process for prioritising potential QC tests
It was agreed, that during the process of identifying key QC tests, delegates should discriminate between those that are mandatory (i.e. release criteria) and those that are not (i.e. for information). Typically tests used “for information” are those which may be useful in cell characterisation and may provide useful data for later analysis, but for which it is difficult to set acceptance metrics or interpret the meaning of signals detected at the present time. However, it was felt useful to acquire ‘for information’ data in order to inform further evolution in selecting critical quality attribute. It was agreed that for release tests, only techniques accepted by Regulators should be used. These will need to be validated and could be outsourced to accredited testing laboratories or performed in-house.
[5] Identification of QC mandatory and informative tests
The MCB testing table from the ISCBI (2015) paper was reviewed by all delegates. Preferred test methodologies were identified, agreed, and classified as either a “mandatory test” or a test “for information”. The agreed methodologies and classifications are described in Table 1.
Table 1: Critical Quality Attributes for clinical grade iPSCs
Modified from ISCBI (2015).
Notes:
1There was considerable discussion around the acceptability of karyological data analysis and it was agreed to consider the use of the WiCell criteria
2It was proposed to review the EBiSC viability standard operating procedure (SOP).
Action: Tenneille Ludwig to provide WiCell criteria for karyotypic analysis [Update: This has been recieved].
Action: Jack Price to seek a copy of the EBiSC viability SOP.
It was suggested that the above recommendations should be sent out for broader consultation.
Action: GAiT to arrange a broader consultation on the recommendations.
Having selected the preferred mandatory test methods, further discussion will be needed to resolve the acceptable levels of sensitivity, specificity, robustness and appropriate controls and reference materials where these do not exist already. The NIBSC representative (Jack Price) explained that NIBSC make around 95% of the WHO reference materials used around the world by manufacturers and had begun making standards for cell therapies. He indicated that NIBSC would be happy to discuss GAiT requirements for reference materials to be used for international quality rounds to standardise analytics between laboratories.
Action: GAiT to discuss with NIBSC and other international standards authorities what reference materials already exist and what may need to be developed for standardisation of analytics used for mandatory quality assurance tests.
Update: This work is underway. If you have a reference material you wish considered, please email details to stephen.sullivan@gait.global.
[6] Compatibility of GAiT QC standards with regulatory requirements.
It was agreed that it will be critical that the above proposed QC testing strategy complies with the expectations of international regulators and also that there is clarity on the different GXP standards in play in different jurisdictions. SJS gave a summary of the responses to a questionnaire (developed by GS, Regulatory Working Group Lead Jacqueline Barry and SJS) to which 15 centres had responded which gave an indication of the diversity of level of development across GAiT participants. This survey would be used again in the future to monitor progress.
Action: SJS to analyse and summarise the key elements of the survey as a starting point.
Update: This survey has highlighted the miriad of tests and techniques that are being used by the GAiT community and is being used to inform the development of the clinical grade iPSC database.
For an iPSC cell bank to be considered by a regulatory body as clinical grade, it would have to be made under a GTP or GMP manufacturing licence dependent on the jurisdiction within an appropriate Quality Management System (QMS). A clinical grade line made under a GTP system will need to have sufficient documentation to be acceptable as a starting material to go on to be used make a GMP medicinal product. The terminology used to describe a cell bank varies from the “product” from a cell supply perspective, a starting material for a cell therapy manufacturing process or an intermediate in the manufacturing process.
Manufacturing processes used in different centres vary and it will be important to understand the nature of process diversity in order to better assess comparability of clinical grade iPSC banks. Delegates agreed that all centres planning to provide clinical grade cells should produce and share process maps for the generation of their iPSC lines. A process map for hESC generation is shown in Figure 1 (overleaf). An example for generation and banking of iPSC lines has been produced in the Pluripotent Stem Cell Platform project and was based on a detailed map provided by CiRA. Delegates agreed that manufacturing centres should be invited to provide a similar map of their manufacturing processes.
Action: manufacturing centres to be invited to provide a map of their process.
Figure 1. Example of human pluripotent cell derivation process map
Taken from ISCBI (2015), this process map details derivation of a human embryonic stem cell line.
Delegates also discussed whether it was feasible to bank iPSC lines from research laboratories under clinical grade conditions and qualify them for manufacturing of cell therapies, a process sometime referred to as “re-derivation”. The group endorsed that having a full quality management system which covers all aspects of manufacture is the best option as prescribed under the relevant regulations. However, TL outlined experience at WiCell in the “re-derivation” process under which regulatory approval in the US had been achieved. She indicated that it was a substantial and costly process only to be undertaken if there was no reasonable alternative option such as rederiving a line from the original donor or starting material.
It was noted that regulatory acceptability would be facilitated by a cell line history file and a general outline for such a document has been developed by the ISCBI group. A more detailed structure had been developed by the CGT and may be available.
Action: SJS to request a copy of the exemplar Cell History File from CGT.
Update: This has been procured 20 NOV 2017 and the Regulatory Compliance working group are using it to develop Governance, Regulatory, & Compliance Fields for the clinical grade iPSC database.
The delegates agreed that the GAiT Regulatory working group should be asked to develop a regulatory requirements database against which Table 1 can be reconciled.
Action: GAiT Regulatory Compliance working group to develop a regulatory requirements database.
Update: This work is currently underway.
[7] Summary of actions:
- GAiT to coordinate development of a clinical grade cell line evaluation procedure.
- GAiT to review and assess existing iPSC databases as suitable for documentation of key parameters and criteria.
- All delegates to identify any further iPSC cell banking documents.
- Tenneille Ludwig to provide WiCell criteria for karyotypic analysis.
- Jack Price to seek a copy of the EBiSC viability SOP.
- GAiT to arrange a broader consultation on the recommendations.
- GAiT to discuss with NIBSC and other international standards authorities what reference materials already exist and what may need to be developed for standardisation of analytics used for mandatory quality assurance tests.
- Stephen Sullivan to analyse and summarise the key elements of the survey as a starting point.
- Manufacturing centres to be invited to provide a map of their process.
- Stephen Sullivan to request a copy of the exemplar Cell History File from CGT.
- GAiT Regulatory Group to develop a regulatory requirements database.
- It was agreed that it would be useful to meet again once these actions had been taken and this might take the form of a comparability workshop.
- GAiT to incorporate a comparability workshop into its strategic planning.
We thank the GAiT Quality Standards & Controls working group for their efforts identifying Critical Quality Attributes for clinical grade iPSC lines to be included in the GAiT haplobank network.
An early draft of the Quality Control Guidelines captures all that was discussed in this workshop and provides further rationale and context:
