Cell therapy tech transfer blog
Despite the no-man’s land between academia and industry is a well-trod area, it is still fraught with pitfalls this is especially the case when it comes to cell therapy tech transfer. While researchers are often frustrated with the overbearing rigour and control that forms the backbone of GMP, the industry too, is baffled by the seemingly laisse-faire approach in research. However, in order to translate research into meaningful therapies, industry and academia must be able to work harmoniously.
With this in mind, and to assist with the cell therapy tech transfer ‘translation’, I’ve compiled a checklist of different areas to consider when performing tech transfer to GMP.
1. Define the Source Material
Issues in cell therapy tech transfer often arise as a result of the product development process starting outside of the industry for which it is intended, e.g. cell lines developed in academia passed to industry without any certificates of origin, or even cell lines that have not been fully characterised. This of course can lead to problems later down the track when Production are trying to make consistent batches for GMP validation purposes and wondering why the process isn’t working properly.
The table below outlines some key questions to answer when selecting your source materials:
|What is the source?||• Has the source material been sufficiently cloned and purified? e.g. vectors/cells not properly cloned can cause heterogenous clonality and lead to variability in the finished product. Re-cloning can be risky and operators could potentially isolate cells with difference sequences or properties from the main desired source material. • Is it from a donor? e.g. if using donors, it is important to consider their health status or if they on any medication that would damage the target tissue.|
|Has the source been sufficiently tested and characterised?||• What is the limit of the source material? Cell lines often have a limited capacity to divide (tried and tested prior to commencing manufacture), after which the active phenotype can be lost, or it could accumulate mutations. On the commercial scale, if a source has a limited usable passage number then it cannot be used beyond that number in GMP production. • Is the material free from undesirable components? Source material intended for clinical use will require different barrages of tests depending on the source type, i.e. to detect any infectious agents, residual animal proteins, or any new viral risks.|
|Are there any legal requirements prior to use?||• Will you need informed consent from the donor? • Is a special licence or permit needed? • Does it require special ethics approval? • What additional documentation is required? Depending on the country of origin, donors may also require payment (e.g. acceptable in the US, but frowned upon in Japan). To save on time and energy, outsourcing to qualified bio-carriers can save on the extra paperwork hassle, especially if intending to import.|
In the UK there is a lot of emphasis placed on getting material that is TSE/BSE free, and companies have been known to source as far as New Zealand.
One company obtained blood from 4 different NZ donors with an aim to purify and expand the CD34+ cell population (hematopoietic stem cells that makes up around 0.03% of peripheral blood).
3 batches from 3 donors were processed in GMP cleanroom conditions and were successful, however one batch failed to generate any CD34+ cells despite 2 additional trials. Further investigation into the original donor revealed they were using methotrexate at the time of the donation (known to be an immune system suppressant and inhibitor of cell division).
2. Define the Product
EMA/CAT/80183/2014 are the “go to” regulatory guidelines for cell therapy product design, BUT, the field is fast moving and the regulations are not always up to date. A good rule of thumb for cell therapy tech transfer is to design products for the international market – if it’s good for one, it’s likely going to be good for another (pending some minor tweaks).
The table below picks out some key questions when defining the product and identifying any potential risks:
|What is the finished product?||• What is the finished dose form and volume? • Can the final product be frozen, or does it have to be delivered fresh? • Will it require any additional processing prior to delivery? • Is it made up of heterologous cells or homologous cells? • What are the complications and risks?|
|What is the intended treatment?||• Has the product been developed with maximum target specificity? • What is the biodistribution? • What are the limitations of treatment? • What is the cost to the patient?|
|Are there any specific safety considerations? any legal requirements prior to use?||• If there is any modification machinery, have they been rendered as safe as possible? e.g. short half-life RNA, non-replicating vectors, self-inactivating components, etc. • What in-process safety checks are required? • What biosafety measures are required for manufacture? e.g. viral vectors GMOs all have their own regulatory requirements.|
A CAR-T therapy uses a viral vector to transform immune cells of a patient (T cells). T cells are incubated with the vector to transform cells, after which vector is washed out of the culture by dilution and/or medium exchange.
3. Define the Manufacturing Process
Starting materials can be another source of frustration in cell therapy tech transfer as they are not always GMP quality. Cell lines may also be exposed to uncontrolled or non-human materials and consumables (e.g. mouse laminin for coating plates, vectors and viruses, BSA, cell lines). Ideally any manufacturing changes curing cell therapy tech transfer should be made as early as possible in the process to show that proceeding studies are still relevant (i.e. clinical data).
The table below highlights some key GMP considerations:
|Where does GMP start?||• Cells – primary cells and cell lines • CAR-T - GMP starts with leukapheresis • Gene therapy – packaging cells, viral vector seed stock.|
|What are the manufacturing methods?||• Single use disposables, multiuse vessels • Laminar flow hoods, closed systems, isolators, etc. • Cell culture flasks, bioreactors, etc.|
|How manual is the process?||• Short stints in the cleanroom to monitor automated equipment? • 24-hr manufacturing cycle requiring operator input at all stages? • What is the impact on operators?|
|What other areas need to be considered during scale up?||• Do consumables need to be changed? • How much longer will it take?|
|How sensitive is the process?||• Is there a rigorous feeding cycle? • Are there strict environmental conditions? • What in-process checks, and safety tests are required?|
|What starting materials are required?||• Does your product require niche consumables? e.g. custom-made flasks or media. (This can have an impact on the manufacturing schedule if, suddenly a consumable is discontinued or there is a long wait time for additional stock.) • Are the starting materials GMP quality? • What is the potential of exposure to these starting materials? • Could alternatives for animal sources be used? (e.g. human/animal growth factors, matrices, feeder cells, etc.) • Is the number of materials from an animal source actually needed? (Are they viral safety assured? This can be expensive)|
|How much additional equipment is required?||• Are those equipment items complex? (e.g. how long will it take to train operators? Does the cleanroom need modifications?)|
|Do any consumables require special treatment?||• How will you control critical materials? (e.g. fridge/freezer stores).|
4. Define the Testing Requirements
Unlike other pharmaceuticals, biotech products often require very custom testing. There can also be unknown viral risks in new animals that require in-depth sequencing. Testing requirements must be defined as a part of the cell therapy tech transfer process.
The table below outlines some key questions relating to testing:
|What are they key tests?||• Titre for dosing • Potency (tends to increase as product development and clinical trials progress)|
|What custom testing is needed for the type of product?||Tailor your testing program to the type of product, e.g. • Synthetic small molecules - genotoxicity • Biologics and biological molecules - monoclonal antibodies • Stem cells - karyotyping after a certain number of passages • Cell therapies - definition of the type of cells, actives, impurities, etc. • CAR-T therapies – definition of any other B and K cells present in suspension • Viral vectors – capsid genome copies, aggregation status, etc • Genome editing - heterogeneity of modified cells and frequency of modifications|
|What stability parameters do I need?||Stability tests are governed by ICH Q5C The recommendation is to select only relevant tests, e.g. • cell viability (especially if stored frozen) • viral vector aggregation • accelerated conditions (useful for storage condition deviations and freezer failure) • required shipping conditions (in-use conditions and half-life).|
To sum up:
To ensure as much success in the cell therapy tech transfer process as possible, ensure you:
- define the quality of the source material
- design out any foreseeable safety risks
- select the most appropriate manufacturing platform for your process
- check that your materials and consumables are GMP-friendly
- check that your process is operator-friendly
- identify the appropriate testing regimen for the product.
A big thing to note is that even if all the due diligence has been completed from initial research to GMP translation, the therapies themselves can change when they are in the patient environment.
Best thing to do is eliminate all the predictable sources of error in advance so you can address any additional surprises when they arise later down the track!
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