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Clinical Trial Package

A cell therapy is a clinical treatment including an ex vivo cell manipulation step. Such a therapeutical option began more than forty years ago and is now a worldwide reality. Many human cell-based clinical trials have been developed in every medicine’s field mostly to cure diseases where conventional treatments are inadequate. Nowadays each tissue of the human body, including foetal and embryonic ones, can become reliable source for cell therapy.

Cells isolated from a specific source can be used also to cure every other tissue of the body and may be administered  alone, in combination with biomaterials, scaffolds, cytokines and growth factors or can be genetically manipulated (gene therapy).

A cell preparation can be crucial for a treatment such as in bone marrow transplantation or otherwise it may be used as an adjuvant to improve clinical results like in regenerative medicine or to slow down the development of several chronic conditions. Cell effect after treatment can be via the ability to differentiate along several lineages or, as recently highlighted for stem cells, also via the capacity to release anti-inflammatory cytokines, growth factors and proteins, collectively known as paracrine factors, which may modulate the host microenvironment by stimulating endogenous stem cells recruitment, differentiation and angiogenesis, thus acting as real drugs.

Ex vivo cell manipulation protocols are different, depending on cell source, type, target, and disease and Country regulations. Current cell therapy laws classify manipulation types according to potentially associated risks. Cutting, grinding, shaping, centrifugation, soaking in antibiotic or antimicrobial solutions, sterilization, irradiation, cell separation, concentration or purification, filtering, lyophilization, freezing, cryopreservation and vitrification are considered “minimal manipulations”. On the other hand, cell processing like induction to proliferation, non-homologous use (if cells or tissues are not intended to be used for the same essential functions in the recipient as in the donor) and association with scaffolds or medical devices are defined as “extensive” or “substantial” manipulations. These new kind of extensively manipulated cell-based products are termed “medicinal product for advanced cell therapy”.

The choice of raw materials

This is a highly critical step since raw materials, such as culture reagents or plastic wares, become directly in contact with the cells during the process. Moreover other materials, like scaffolds or cell supports, can become an integral part of the medicinal products. Therefore, the choice for such materials should be geared towards products ensuring the highest quality provided by the market at the moment.

First of all, the cell producing facility should attest the quality assurance level of each Company/Institution that intends to choose as supplier. This investigation termed “supplier qualification” is mandatory for a fully GMPs compliance and should be performed not only by examining the accreditations provided by the Company itself but also by on-site inspections. Hence, material’s full batch documentation/certification should be carefully evaluated to attest fulfillment with specific current regulations. For example, cell culture media sterility should be certified by specific analyses validated in compliance with current Pharmacopoeia. In particular, it is required that these products are negative for aerobic, anaerobic bacteria, fungi and endotoxins. Documentation control is a delicate and important step, but not sufficient for entering materials into the process. In fact, each declared critical feature should be cross-checked by internal quality controls in the cell factory.

Only after passing such internal controls, materials are considered adequate for the process and validation can start. An important point to consider for reagent choices to avoid zoonosis risks. A recombinant origin should be preferred for enzymes such as Trypsin used for the rapid detachment of adherent cells, like chondrocytes, from the growth substrate and Collagenase type II utilized to digest cartilage and thus isolate cells. In this case users should control documentation also for recombinant source that must be clearly indicated.

For animal origin products, like fetal bovine serum (FBS) as supplement in culture, high quality is mandatory. FBS should be free of microbial, mycoplasma and viral contaminations. More importantly, it must be stated and certified its origin from Bovine Spongiform Encephalopathy (BSE) free countries such as Australia and New Zealand. The country of processing should be indicated too, if different. The serum producing process should be described giving evidence to exclude any possibility from contamination with tissues that may harbor the BSE agent, such as the brain, spinal cord and distal ileum. If the final product encloses other components like scaffolds or biomaterials they should be appropriately characterized and evaluated for suitability for the intended use.