Anticomplementary activity of IVIG concentrates - important assay parameters and impact of IgG polymers

Abstract

Background and Objectives A high concentration of large size polymers in intravenous immunoglobulin preparations was always correlated with high anticomplementary activity (ACA). In former days, high ACA was also linked to adverse reactions in patients. The goal of this study was to scrutinize critical parameters of the ACA assay and the influence of different polymer variants of IgG on the complement consumption. Materials and MethodsCritical reagents as the complement and the preparation of erythrocytes were investigated. The influence of molecular integrity of IgG on the ACA was tested by subjecting IgG solutions ranging from pH 4AE5 to 7AE0 to heat treatment at 60°C.Results The different complement batches had a significant impact on the test result of the ACA assay. It was demonstrated that polymers, provoked by heat treatment at pH values above 5AE5, consumed complement almost completely whereas a polymer content up to 12% formed under acidic conditions did not lead to an increase in ACA.Conclusion It was shown that suitable complement batches have to be identified in a screening procedure. Furthermore, it could be demonstrated that IgG polymers formed in the neutral pH range during heat treatment were potential ACA inducing compounds. Manufacturing the IVIG preparations under acidic conditions may help to avoid the formation of those ACA active polymers. Thus, intensive analysis of ACA during process development and validation is recommended.

Therapeutic plasma proteins – application of proteomics in process optimization, validation, and analysis of the final product

“…com/news/home/20100924005668/en/Update-Withdrawal Product-Recall---octagams-octagams5). These events can be caused by trace impurities in the preparation or by unpredicted changes to the Ig molecule that can occur during the production process [59,60,63]. These unexpected side reactions occurred recently, and no analytical data were published yet in order to give a hint about possible impurities that caused these serious accidents.…”

“…Triton X100 and tri n-butylphosphate) [58]. Buchacher et al [59] have demonstrated that the anticomplementary activity of IVIG concentrates is caused by a high concentration of large polymers in some products. They also demonstrated that conditions under which polymers are formed (e.g.…”

Naturally Occurring Antibodies/Autoantibodies in Polyclonal Immunoglobulin Concentrates

“…18 The effect was termed 'anti-complement activty' (ACA) and later the absence of such activity became a release criterion for IVIG. 38 The method how to get a 'close to native' immunoglobulin G concentrate suitable for intravenous application is an example of serendipity in research. Barandun and Isliker were doing in vitro experiments with pepsin treatment of "standard" IgG concentrate.…”

Валидация Методики Определения Антикомплементарной Активности Лекарственных Препаратов Иммуноглобулинов Человека

“…Àíòèêîìïëåìåíòàðíàÿ àêòèâíîñòü (ÀÊÀ) èíôóçèîííûõ ïðåïàðàòîâ Ig ÷åëîâåêà ÿâëÿåòñÿ îäíèì èç êëþ-÷åâûõ ïîêàçàòåëåé ñïåöèôè÷åñêîé áåçîïàñíîñòè èììóíîãëîáóëèíîòåðàïèè. ÀÊÀ îáóñëîâëåíà ïðèñóòñòâèåì â íèõ àãðåãèðîâàííûõ è/èëè ïîâðåaeäåííûõ ïðè ôðàêöèîíèðîâàíèè ìîëåêóë Ig, íà Fc-ó÷àñòêå êîòîðûõ ïðîèñõîäèò ñïîíòàííàÿ àêòèâàöèÿ êîìïëåìåíòà â îòñóòñòâèå êîìïëåêñîâ àíòèãåí -àíòèòåëî [1,2]. Ñîãëàñíî ðåêîìåíäàöèÿì ýêñïåðòîâ ÂÎÇ, âñå ñåðèè èíôóçèîííûõ ïðåïàðàòîâ Ig ÷åëîâåêà ïîäëåaeàò îáÿçàòåëüíîìó èñïûòàíèþ íà ÀÊÀ.…”

“…Ñîãëàñíî ðåêîìåíäàöèÿì ýêñïåðòîâ ÂÎÇ, âñå ñåðèè èíôóçèîííûõ ïðåïàðàòîâ Ig ÷åëîâåêà ïîäëåaeàò îáÿçàòåëüíîìó èñïûòàíèþ íà ÀÊÀ. Ìåòîäèêà îïðåäåëåíèÿ ÀÊÀ ñîïðÿaeåíà ñ ðÿäîì êðèòè÷åñêèõ ïàðàìåòðîâ [1], ñâÿçàííûõ ñ èñïîëüçîâàíèåì áèîëîãè÷åñêèõ ðåàãåíòîâ, òàêèõ êàê êîìïëåìåíò ìîðñêèõ ñâèíîê, ýðèòðîöèòû áàðàíà è ãåìîëèòè÷åñêàÿ ñûâîðîòêà, âàðèàáåëüíîñòü êîòîðûõ îáóñëàâëèâàåò íåîáõîäèìîñòü èñïîëüçîâàíèÿ ñòàíäàðòíîãî îáðàçöà (ÑÎ), ïîëîaeèòåëüíûé è îòðèöàòåëüíûé êîíòðîëè êîòîðîãî ïîäòâåðaeäàþò äîñòîâåðíîñòü ïîëó÷àåìûõ ðåçóëüòàòîâ â ðàçëè÷íûõ äèàïàçîíàõ çíà÷åíèé ÀÊÀ. Îïòèìèçèðîâàííàÿ ìåòîäèêà îïðåäåëåíèÿ ÀÊÀ [3,4] ïðåäóñìàòðèâàåò èñïîëüçîâàíèå aeåëàòèí-ñîëåâîãî ðàñòâîðà, êàê àëüòåðíàòèâàaeåëàòèí-áàðáèòàëîâîãî áóôåðíîãî ðàñòâîðà, ïðåäóñìîòðåííîãî ñòàíäàðòèçîâàííîé ìåòîäèêîé Åâðîïåéñêîé ôàðìàêîïåè (ÅÔ) [5].…”