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S. Pellegrin et al.
the yield by 30-50%. Strategies and more research are needed to improve reticulocyte recovery after filtration, which will lead to a dramatic increase in yield. There are open-ended filter technologies, such as tangential flow fil- tration systems or acoustic resonance cell filtration,65 which could potentially be used but are as yet untested. More experimental approaches include lab-on-a-chip microfluidic label-free reticulocyte-sorting methods.66 All these possibilities need testing and optimizing on a large culture scale which is expensive, therefore, highlighting filtration as a key area of research calling for innovation as well as commercial investment and collaboration.
Oncefiltered,themRBCneedtobestoredwhilstqual- ity control tests are carried out and until they can be transfused into a patient. As reticulocytes, mRBC are more fragile than RBC and more optimal storage condi- tions need to be developed. An alternative approach is to promote maturation of cultured reticulocytes into bona fide erythrocytes, which is another area of active research.
Compliance with Good Manufacturing Practice and quality control
Finally, it should be remembered that the challenge for mRBC production is not only to deliver a manufacturing process that can produce enough mRBC at scale but to develop a process that is GMP-compliant. Often GMP compliance includes the use of clean rooms, highly trained staff specialized in GMP, using closed processes to mini- mize any risk of infection, robust batch manufacturing protocols, as well as specific manufacturing processing and quality release criteria which are not required in stan- dard R&D laboratories. The challenges of GMP compli- ance on large-scale erythroid cultures for a transfusion
Summary
Technologies to revolutionize transfusion options for patients with anemia, in particular for those receiving reg- ular life-long transfusions, are much needed. There is great potential for laboratory-grown mRBC to be used in transfusion practice once production is mastered at scale. In the meantime, these culture systems at smaller scale have proven to be brilliant tools for understanding human erythropoiesis and optimizing culture methodology. The efficient production of mRBC at scale is now essentially a biotechnological challenge that requires multidisciplinary efforts. We have highlighted some of the key areas, breakthroughs and challenges (summarized in Table 2), in which investment together with intensive research into further optimization of culture systems and use of biore- actors at scale are needed to make the clinical use of adult therapeutic doses of mRBC become a reality. Focused research and collaboration between academics, blood banks, commercial entities and new spinouts, especially around the use of RBC-based therapeutics, will no doubt help to drive the development and efficiency of mRBC production under GMP conditions into the clinic.
Disclosures
No conflicts of interest to disclose.
Contributions
SP, CES and AMT wrote the review together and all authors approved the final submitted version.
Funding
SP, CES and the work in AMT’s laboratory is funded in part by a National Institute for Health Research Blood and Transplant Research Unit (IS-BTU-1214-10032) in red blood cell products (University of Bristol) and NHSBT R&D grants(WP15-05; WP15-04). The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care.
product may have an impact on yield, ture times and increase costs, so will ered and planned for from the outset.
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