Degradation products of factor VIII which can lead to increased immunogenicity

The biochemical and immunochemical aspects of the development of inhibitors with a plasma-derived, double-virus inactivated factor VIII (FVIII) concen trate (marketed as Octavi SDPlus in Germany and Bisinact in Belgium) are de scribed. A total of 12 cases of inhibitor formation (predominantly type II) were reported in Germany, 8 in Belgium but none in Portugal. Initially, th e only difference between the non-pasteurised, SD virus-inactivated product Octavi and the pasteurised product Octavi SDPlus appeared to be pasteurisa tion, though subsequently, the quality of source material for the product w as found to differ in different countries. Separation studies revealed the presence of a 40 kDa peptide fragment in some batches. It was subsequently shown that there was a strong correlation between inhibitor development and batches containing the 40 kDa marker, and a relationship between elevated markers of coagulation activation (FPA in particular) and the occurrence of the 40 kDa marker. Further work revealed that analytical methods commonly used for quality control were not suitable to highlight batch-to-batch diff erences. It was concluded that inhibitor potential (neoantigenicity) in Oct avi SDPlus arose due to two effects; degradation of FVIII already present i n source material; and heating of unstable FVIII degradation products. In t his case, inhibitors were not caused by the overall production process, nor by GMP failures. The problem of inhibitor potential can be avoided if appr opriate preventive measures are taken. Further work is needed to prove non- neoantigenicity and to reinforce the scientific findings, and to characteri se pilot batches.