Inactivation and Elimination of Viruses during the Fractionation
of an Intravenous Immunoglobulin Preparation:
Liquid Heat Treatment and Polyethylene Glycol Fractionation

Uemura, Yahiro; Uriyu, Katsuhiro; Hirao, Yutaka; Takechi, Kazuo; Ishikawa, Hideyuki; Nakajima, Tsunetaka; Kagitani, Yoshio; Yokoyama, Kazumasa; Funakoshi, Satoshi; Nishida, Masayuki; Yabushita, Sadao; Furuta, Koichi; Hamamoto, Yoshisuke; Tochikura, Tatsurokuro; Yamamoto, Naoki

doi:10.1159/000460954

Cited by 10 publications

(13 citation statements)

References 15 publications

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“…By optimizing the parameters of each separate step polymer formation can be minimized over the whole process. The formation of aggregates should be avoided but also the integration of polymer removal steps is a possible strategy to produce aggregate free IVIG preparations [19–21]. Another possibility is to destroy the ACA through low pH treatment as discussed above.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2010

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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.

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Section: Discussionmentioning

confidence: 99%

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

et al. 2010

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“…After investigation, it was discovered that immunoglobulin was not denatured by heat treatment for 10 h, when 30% sorbitol was added to it and the pH adjusted to be weakly acidic [18]. When immunoglobulin was heated under such conditions, after intentionally contaminating it with vi ruses, the viruses, including HIV, which were added to it were inactivated under the detection limit within 1 h.…”

Section: Prevention Of Nanb Hepatitismentioning

confidence: 99%

“…The optimum concentration of sorbitol was de termined to be 33%. Three lots of intravenous immunoglo bulin preparation were manufactured utilizing this treat ment [18]. There were no differences in yield, IgG subclass distribution, or in physicochemical and biological proper ties between lots manufactured by the new method and the nonheated preparations.…”

Section: Prevention Of Nanb Hepatitismentioning

confidence: 99%

Immunoglobulin Preparation: Safe from Virus Transmission?

Uemura¹,

Yokoyama²,

Nishida³

et al. 1989

Vox Sanguinis

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The incidence of non-A, non-B hepatitis associated with the administration of immunoglobulin preparations, especially intravenous preparations, which had been considered to be free from virus transmission, is reported. Research efforts to improve the safety of intravenous immunoglobulin preparations which could be administered in a large volume must be continued. Adding sorbitol under weakly acidic conditions, heat treatment of IgG at 60°C for 10 h is possible. Intravenous immunoglobulin preparation manufactured by polyethylene glycol fractionation followed by the heat treatment is not only intact, but also much closer to the ideal intravenous immunoglobulin preparation in the safety and stability.

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“…However, non-lipid coated viruses, such as hepatitis A (HAV) and parvovirus may remain, although the risk of such viruses causing significant disease seems to be small [12]. Pasteurization of albumin and Factor 8 is a well accepted method for eliminating a wide range of viruses, including HIV and HCV, Technical difficulties relating to stabilizing the immunoglobulin during the pasteurization process have now been overcome [ 13], enabling us to carry oul the first trial in the UK ofa pasteurized immunoglobulin for intravenous use.…”

Section: Introductionmentioning

confidence: 99%

A prospective controlled crossover trial of a new heat-treated intravenous immunoglobulin

Zuhrie¹,

Webster²,

Davies³

et al. 1995

Clinical and Experimental Immunology

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SUMMARY Twenty‐one patients with primary immunoglobulin deficiency were enrolled in a crossover study to test the efficacy and safety of Alphaglobin in comparison with the licensed preparations Sandoglobulin and Gamimune. There was no statistical difference in these parameters between Alphaglobin and Sandoglobulin/Gamimune. The level of total serum IgG and specific IgG to pneumococcal polysaccharides was similar in individual patients when they were receiving Alphaglobin or one of the other products. Transient increases in serum alanine transferase occurred in five patients on Sandoglobulin/Gamimune and two patients on Alphaglobin. Some patients showed a rise in total serum IgM afterwards, indicating a response to infection. However, serum hepatitis C virus (HCV) RNA was not found during the alanine transferase (ALT) rises, and IgM antibody to hepatitis A virus (HAV) was negative afterwards. We conclude that Alphaglobin is a safe, well tolerated and clinically efficacious treatment for patients with primary antibody deficiency.

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Inactivation and Elimination of Viruses during the Fractionation of an Intravenous Immunoglobulin Preparation: Liquid Heat Treatment and Polyethylene Glycol Fractionation

Cited by 10 publications

References 15 publications

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

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

Immunoglobulin Preparation: Safe from Virus Transmission?

A prospective controlled crossover trial of a new heat-treated intravenous immunoglobulin

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