Batches of intravenous immunoglobulin associated with adverse reactions in recipients contain atypically high anti‐Rh D activity

Background and Objectives The presence of anti‐Rh D in intravenous immunoglobulin (IVIG) products has been claimed to be associated with adverse reactions in recipients. There is currently no regulatory specification to control the level of anti‐D in IVIG products and it is unclear what this should be. Two reports of haemolysis occurring in recipients of IVIG manufactured from US plasma provided a rare opportunity to investigate whether high anti‐D levels could have induced the haemolysis. Materials and Methods We developed a direct microtitre plate haemagglutination method suitable for screening IVIG products and starting plasma pools for haemagglutinating activity. Results Of 101 batches of IVIG tested, six were found to contain specific anti‐D. Four of these batches had anti‐D titres ranging from 64 to 256 (including the two batches each associated with a report of haemolysis) and could be linked, in each case, to a starting plasma pool also positive for anti‐D. Conclusions Our results show that IVIG products can contain appreciable anti‐D levels. To avoid potential problems in recipients, we propose an anti‐D titre of 8 as the maximum permissible limit of anti‐D in IVIG products for batch acceptance and release. The availability of a reference preparation is essential for control of this proposed requirement.