Plasma fractionation

The first plasma fractionation process was developed in the 1940s by Cohn and co‐workers to prepare albumin and immunoglobulins. It relies on sequential precipitation steps at negative temperatures, different ethanol concentrations and various pH to segregate bulk plasma proteins. The ‘Cohn procedure’ has been modified over the years but largely remains the core fractionation process in use up to now. The introduction of cryoprecipitation (thawing of plasma at 2–4°C), as the first plasma fractionation step, to isolate a crude factor‐VIII fraction, and the integration of chromatographic steps to extract labile plasma or trace plasma proteins, have eventually shaped the modern fractionation technologies into complex procedures. Viral inactivation and removal treatments are performed to prevent the risks of transmission of enveloped and non‐enveloped viruses. Viral inactivation steps are applied most often on pre‐purified fractions, the downstream steps being used to remove protein contaminants and viral inactivation agents. Depending upon products and protein stability, treatments include incubations with combinations of solvent (TnBP) and detergent (e.g. Tween 80 or Triton X‐100) (S/D), pasteurization (heat‐treatment in the liquid state at 60°C for 10 h in the presence of stabilizers), as well as low pH or caprylic acid treatments (these last two treatments are restricted to immunoglobulins). Nanofiltration, to capture viruses on nm‐membranes, is typically performed on the final purified protein fractions prior to sterile filtration and aseptic filling. Terminal dry‐heat treatment at 80–100°C is used for some coagulation factor preparations. Modern plasma protein products have an unprecedented level of quality and safety when there is careful process control and monitoring together with sensitive test methods to detect potentially harmful contaminants, such as procoagulant impurities. Since the implementation of validated robust viral reduction treatments, plasma products have a high viral safety profile including against emerging agents (WNV, Dengue virus, Chikungunya virus). Experimental spiking studies suggest that several fractionation steps are capable of removing prions causing variant Creutzfeldt‐Jakob disease. Alternative fractionation processes based exclusively on chromatography have been developed at pilot scale and need further validations to demonstrate the quality, safety and consistency of resulting plasma products. A mini‐pool viral inactiva