Regenerative medicine and cellular therapies have the potential to impact many different areas of unmet medical need. There are many human diseases which have either inadequate or no treatment options. One of the main focuses of cellular therapy is the use of stem cells to treat diseases such as osteoarthritis or Critical Limb Ischemia – these products are defined as Advanced Therapeutic Medicinal Products (ATMPs).
Cellular therapy is not a technology of the future, it is having an impact now, with thousands of on-going clinical trials using stem cells as the preferred treatment option. For cellular therapies two distinct categories exist- autologous and allogeneic. Autologous is using the sick patients owns cells and modifying or expanding them and then injecting these cells back into the patient i.e. one patient treatment. Allogeneic is whereby healthy donor cells are used to manufacture the treatment product and injected into the sick patient and/or patients i.e a multi-recipient dose which allows for a more conventional ‘off the shelf product’. A cellular Therapy clinical trial is a complex multidisciplinary endeavour, requiring coordination between scientists, clinicians, and the GMP manufacturing site. There are many stages in a cellular therapy clinical trial which are all inextricably linked; donor recruitment, screening & tissue/ cellular procurement, manufacturing at the GMP manufacturing site, product characterisation & batch release, and distribution back to the clinical site for administration to the clinical trial subject. Each element must be well-defined and rigorously controlled in order to ensure that the cellular product is consistently safe and efficacious, prior to injecting into the patient.
One of the biggest challenges is the provision of an authorised manufacturing facility for the supply of these cellular products. Authorisation from the national regulatory body must be obtained in order to manufacture such products. The manufacturing of cellular products is unique in that it is not a conventional pharmaceutical product but it is a biological product which is manufactured from a living tissue source (starting material). Although it is nonconventional in a pharmaceutical context, the manufacturing of these still require the same level of rigor and overall GMP regulatory requirements. As the starting material is of a human source, this can lead to variability in the manufacturing of the product and batch to batch variation, although the same release criteria must be applied to each batch.
The sustainability of these manufacturing facilities is another key challenge, where many of these were set up as translational facilities within a University setting. While the traditional pharmaceutical industry is driven primarily by profit and fulfilling shareholder needs, the ATMP facilities are largely funded through governmental funding at local and international levels and this may include funding from the University or Institution, where manufacturing facility is located. These facilities are largely focused on patient benefit and act as translational facilities from the bench to the bedside. The focus is not profit driven for the majority of such ATMP facilities and so the challenge of maintaining and running these pharmaceutical facilities is significant. The same level of rigor and compliance to GMP as in a conventional pharmaceutical facility is required in these smaller non-profit operations.
Another key challenge for manufacturing these products, is the availability of competent stem cell experts, who play a critical role at key decisions points in the process. The manufacturing process requires these highly qualified and trained personnel to produce these cells, and these operators are also required to perform routine/typical cleanroom tasks such as cleaning and environmental monitoring. It follows that there is the added challenge of retaining these people who perform significant scientific processes but yet have to perform the routine day-to-day cleanroom activities. One such ATMP facility is the Centre for Cell Manufacturing Ireland (CCMI) at the National University of Ireland Galway (NUIG), which is a custom-built licensed facility designed to manufacture Advanced Therapeutic Medicinal Products such as stem cells for use in human clinical trials. CCMI has facilitated the pathway from the bench to bedside with a focus on GMP manufacture, product characterisation, stability of the IMP and distribution to the trial site, for patient treatment. CCMI received Irish Regulatory Approval in August 2013 to manufacture human Mesenchmyal Stem Cells (hMSCs) for clinical use. CCMI is the first and only approved facility on the Island of Ireland that can manufacture (expand) these hMSCs for clinical use.
CCMI is currently manufacturing hMSCs for a clinical trial for Critical Limb Ischemia, for which the regulatory body in Ireland, the Health Products and Regulatory Authority (HPRA) gave approval for in 2014. This trial will treat at least nine patients, which will require the manufacture of nine human mesenchymal cell batches by CCMI over the period 2015 to early 2017. There are three further clinical trials in the pipeline for CCMI in 2016/2017;
1. ADIPOA-2: Autologous Adipose Derived Stem Cells (ASCs) for the treatment of osteoarthritis 2. Nephstrom: Allogeneic hMSCs for the treatment of diabetic kidney disease
3. Visicort: hMSC in Corneal transplant.