Guest Blog: Critical stability and Bioprocess consensus for manufacturing, storage and clinical delivery of cell and tissue products

cryopreservation stem cells (Kevin Dooley

Aby Mathew, Senior Vice President and Chief Technology Officer at BioLife Solutions, spoke at the World Stem Cells and Regenerative Medicine Congress London 2013 and gave us some heads up about the importance of ensuring biopreservation at all levels (upstream and downstream) of the bioprocess for the successful commercialization of cell therapy products. He said: "Biopreservation is vital for clinical reach and product economics". Once again in this talk, the relevance of an a priori solid plan design was highlighted: "Think beyond approval, because that is just the beginning."

A biopreservation strategy across all the steps of the development and commercialization system positively influences the cell yield to COGs ratio. In order to obtain a platform of global leverage and distribution, one must identify the market spheres the product delivery is limited to; the ones the company wants to commit to; and embrace a biopreservation strategy to overcome the product stability constraint potential, once approved (e.g. if the shelf life is 18 hours). System yield, viability and functioning of a cell therapy product irreversibly decrease during the whole bioprocessing, while at the same time system costs accumulate over the different steps. Once the product is packaged and ready for distribution, the best practice perspectives should further consider preservation across the whole process of delivery through collection, transport, processing and storage, not only storage! But what are practically the main goals to aim for?

  1. The optimization of commercialization scale manufacturing by maximizing the source material, the manufacturing process line and the final dose stability across package 1 and 1000 delivered with the same shipment;
  2. The minimization of system costs risks, which lie in process variability and contamination.

Biopreservation methods realistically have to rely on hypothermia (2-8 ⁰C) or cryopreservation (-80 ⁰C or liquid nitrogen). Recent evidence was shown regarding the criticality of time and temperature to overcome the product stability issue for bone marrow and blood units. Hypothermia at 4 ⁰C buffers some of the damage up to 3 days, therefore cryopreservation is the method of choice for a broader market reach. Cryopreservation relevant points include type of cryoprotectant reagent (temperature and concentration at the addition also to be considered); cooling rate down to desired temperature; best storage temperature ( liquid nitrogen versus -80 ⁰C: the former is not good for 3D models but allows years-long storage, whereas in the latter glass vials cannot be used but remains suitable for mid-length storage). Warming temperature and washing/dilution of the product before infusion are also critical and involve final user manipulation, a parameter out of the manufacturer's control: therefore ready-to-use dosages should be commercialized to limit variability ("Make it easier to make it function"). Freeze/thawing also results in a delayed onset of cell death, therefore initial freezing cell concentration and eventual population selection by apoptosis must be taken into account in order to be able to administer truly viable cell infusions that do engraft in vivo and maintain their original therapeutic effects.

Cell natural response to cold is the lowering of their metabolism: full cell restore after thawing includes survival, recovery and only then functional performance. Improvements in the freezing down steps are made at BioLife Solutions: the company has generated a variety of cGMP-grade freezing freezing media, serum-, protein- and animal origin-free, tested for endotoxins and and pH buffered. These cryopreserving reagents aim to provide maximum cell product performance and lot-to-lot consistency while minimizing the error risks that can be induced by home-brews and other operator-related manipulations. Dr Mathew main recommendation to achieve maximum viability and functionality of the end product is to shift from the use of an isotonic to an intracellular-like freezing media. He informed us that over 65% of the speakers at the Congress have used this approach for improved manufacturing, therefore embracing a business strategy that accurately considers biopreservation parameters to ensure product stability sustenance.

By Giulia Detela (UCL)

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