Shaping release criteria for embryonic stem cell-based therapeutic products

by Alexey Bersenev on June 4, 2014 · 0 comments

in cell product, embryonic/iPS

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Currently, there is a number of embryonic stem (ES) cell-based products in clinical development. Most of them are developed by companies (ACT, Asterias, ViaCyte, NeoStem…) and, therefore, protected by patents/ IP. Unfortunately, there is no publicly available information about product characterization and release criteria for such products. Recently, I came across a paper, describing ES cell-based product, which was approved by French regulatory agency for firt-in-human trial.

Unlike other cell products (derived from mature-, progenitor- or adult stem cells), ES cell-based products should (or even must) include at least 2 groups of additional assays before release:

  1. Residual undifferentiated ES cells assessment
  2. Genomic stability tests

A lot of assays were proposed for detection of residual undifferentiated ES and iPS cells (we keep a hand on pulse!). But which one will make to clinical cell product manufacturing? Which one is the most sensitive, robust, quick and cheap? So, French group, implemented the following ES cell-specific assays as release criteria for their cardiomyocyte final product:

  • expression of pluripotency markers by qPCR –> Nanog, Sox-2 <0.1%
  • cardiac differentiation marker (i) Isl by qPCR >5% and (ii) SSEA-1 flow cytometry >95%
  • residual feeder cells by flow cytometry SSEA-1+/CD29+
  • cytogenetic tests – karyotype, FISH, CGH (criteria are not indicated).

Genomic stability (cytogenetic) and purity tests were performed multiple times on different stages of GMP production: (1) master cell bank, (2) working cell bank and (3) late production cell bank. Quality control tests and product release criteria can change, based on phase of clinical manufacturing. So, such cytogenetic tests as karyotype, FISH and CGH were methods of choice for safety assessment in this case.

Depending on differentiation protocol, additional tests for ES/iPS cell-based products should be performed and could be asked by regulatory agencies:

  • residual feeder cells detection
  • residual transgene
  • tumorigenicity

If you know or work on clinical manufacturing of ES/iPS cell-based products, please share, suggest and/ or discuss quality control assays and release criteria. I can’t wait publications of the first clinical data from ACT and Asterias in order to look at product characterization and release criteria.

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