Virus inactivation during production of intravenous immunoglobulin

Kempf, Christoph; Jentsch, P; Poirier, Bertrand; Barré-Sinoussi, F; Morgenthaler, J.‐J.; Morell, Anatol G.; Germann, D

doi:10.1046/j.1537-2995.1991.31591263197.x

Cited by 41 publications

(20 citation statements)

References 24 publications

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“…The production of IGSC 20 % follows the same manufacturing processes as IGI, 10 % solution (marketed under the Baxalta, now part of Shire trade-name GAMMAGARD LIQUID® in the US and Kiovig® in the EU) except for ultra/diafiltration and final formulation at 20 % ( w / v ) protein concentration. The manufacturing process of IGSC 20 % includes three dedicated virus inactivation and reduction steps: solvent/detergent (S/D) treatment [15], nanofiltration (35 nm) [15, 16], and low pH incubation with elevated temperature [17, 18]. Similar to IGI, 10 %, IGSC 20 % contains glycine as stabilizer to minimize IgG dimerization.…”

Section: Methodsmentioning

confidence: 99%

Efficacy, Safety, and Pharmacokinetics of a Novel Human Immune Globulin Subcutaneous, 20 % in Patients with Primary Immunodeficiency Diseases in North America

et al. 2016

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Patients with primary immunodeficiency disease (PIDD) typically require life-long intravenous (IV) or subcutaneous (SC) immunoglobulin (Ig) replacement therapy to prevent recurrent infections. The efficacy, safety, and pharmacokinetics of a highly concentrated (20 %) Ig preparation for SC administration (IGSC 20 %) were evaluated in a prospective trial in patients with PIDD. A total of 74 patients (aged 3–83 years) received 4327 IGSC 20 % infusions over a median of 380.5 days. The rate of validated serious bacterial infections was 0.012 event/patient-year (p < 0.0001 compared with the historical control), and the annualized rate of infection was 2.41 events/patient. Median IgG trough levels were >14.5 g/l. The median maximum infusion rate was 60 ml/h/site (range 4.4–180), resulting in a median infusion duration of 0.95 h. A volume ≥30 ml was infused per site in 74.8 % of IGSC 20 % infusions. Most (84.9 %) infusions were administered using ≤2 infusion sites; for 99.8 % of infusions, there was no need to interrupt/stop administration or reduce the infusion rate. No related serious adverse event (AE) occurred during IGSC 20 % treatment; related non-serious AEs occurred at a rate of 0.036 event/infusion. The incidence of related local AEs was 0.015 event/infusion and of related systemic AEs was 0.021 event/infusion; most were mild in severity, none severe. Increased infusion rates or volumes were not associated with higher AE rates. The investigated IGSC 20 % treatment was shown to be effective and safe, enabling higher infusion rates and volumes per site compared to conventional SC treatments, resulting in fewer infusion sites and shorter infusion durations.Electronic supplementary materialThe online version of this article (doi:10.1007/s10875-016-0327-9) contains supplementary material, which is available to authorized users.

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Section: Methodsmentioning

confidence: 99%

Efficacy, Safety, and Pharmacokinetics of a Novel Human Immune Globulin Subcutaneous, 20 % in Patients with Primary Immunodeficiency Diseases in North America

et al. 2016

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“…During the entire study period the series of liver function tests as well as the monitoring of clinical signs of liver dysfunction provided clear-cut evidence that none of the five batches of IVIG used did transmit NANBH. The isolated elevation of potent virus inactivation step [15]. During the last few years, HIV safety was carefully studied and assigned to a combination of a partition effect and inactivation during the fractionation process.…”

Section: Discussionmentioning

confidence: 99%

“…In laboratory experiments in volving spiking with HIV, the various fractionation steps during manufacturing of IVIG were shown to reduce the quantity of HIV by at least 7 logs [12]. The freezing-thawing of the intermediate products in the presence of ethanol as well as the combination of a low pH with a small amount of pepsin inactivates HIV [12][13][14][15]. Today, there exist no exper imental studies which demonstrate inactivation of NANBH viruses or hepatitis C virus.…”

Section: Discussionmentioning

confidence: 99%

“…Today, there exist no exper imental studies which demonstrate inactivation of NANBH viruses or hepatitis C virus. Thus, evidence that these or other manufacturing procedures really destroy causative agents of NANBH is based on analogy with the effect on similar model viruses [15]. The possibility has to be consid ered that NANBH safety is mainly mediated by neutraliz ing antibodies present in the donor pool that render small numbers of viruses noninfectious.…”

Section: Discussionmentioning

confidence: 99%

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Safety of Intravenous Immunoglobulin Preparations: A Prospective Multicenter Study to Exclude the Risk of Non-A, Non-B Hepatitis

Imbach¹,

Perret²,

Babington³

et al. 1991

Vox Sanguinis

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The risk of non-A, non-B hepatitis transmission by an intravenous immunoglobulin (IVIG) preparation was assessed in a prospective multicenter trial in 68 patients with primary immunodeficiency disorders (40 children or adolescents and 28 adults). During the 4-week prestudy evaluation period the clinical examinations and liver function tests including alanine aminotransferase, aspartate aminotransferase, yglutamyl transpeptidase, alkaline phosphatase, and bilirubin were normal in all patients. The treatment consisted of three infusions of 200 mg IVIG (pH 4; pepsin procedure) per kilogram body weight at 2-week intervals. During the observation period of 24 weeks following the first infusion of the study IVIG, the patients were monitored at regular time intervals. No clinical and laboratory signs of hepatitis or liver dysfunction were noticed. All patients completed the study. In 5 patients, one isolated alanine aminotransferase value and in another patient one γ-glutamyl transpeptidase value were moderately elevated, but always below 2.5 times the upper limit of the reference range. Similar isolated and transient elevations were observed for aspartate aminotransferase and alkaline phosphatase. It was concluded that the IVIG preparation did not transmit non-A, non-B hepatitis or other viral liver diseases.

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“…Given the sensitivity of HIV-1 to inactivation by a wide variety of treatments [60][61][62][63][64], this concern is probably unwarranted but it has clearly lowered the priority of KV, as long as inherently safer methods (e.g. recombinant envelope protein) were considered likely to yield efficacy.…”

Section: The Rationalementioning

confidence: 99%

Inactivated- or Killed-Virus HIV/AIDS Vaccines

Sheppard¹

2005

CDTID

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Inactivated or "killed" virus (KV) is a "classical" approach that has produced safe and effective human and veterinary vaccines but has received relatively little attention in the effort to develop an HIV/AIDS vaccine. Initially, KV and rgp120 subunit vaccines were the two most obvious approaches but, unfortunately, rgp120 has not been efficacious and the KV approach has been limited by a variety of scientific, technical, and sociological factors. For example, when responses to cellular antigens, present on SIV grown in human cells, proved to be largely responsible for efficacy, the KV approach was widely discounted. Similarly, when lab-adapted HIV-1 appeared to lose envelope glycoprotein during preparation (not the case for primary isolates), this was viewed as a fundamental barrier to the KV concept. Also, a preference for "safer", genetically-engineered vaccines, and emphasis on cellular immunity, have left KV low on the priority list for funding agencies and investigators. The recent suggestion that "native" trimeric gp120 displays conserved conformational neutralization epitopes, along with the failure of rgp120, and difficulties in raising strong cellular responses with DNA or vectored vaccines, has restored some interest in the KV concept. In the past 15 years, several groups have initiated pre-clinical development of KV candidates for SIV or HIV and promising, albeit limited, information has been produced. In this chapter we discuss the rationale (including pros and cons) for producing and testing killed-HIV vaccines, the prospects for success, the nature and scope of research needed to test the KV concept, what has been learned to date, and what remains undone.

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Virus inactivation during production of intravenous immunoglobulin

Cited by 41 publications

References 24 publications

Efficacy, Safety, and Pharmacokinetics of a Novel Human Immune Globulin Subcutaneous, 20 % in Patients with Primary Immunodeficiency Diseases in North America

Efficacy, Safety, and Pharmacokinetics of a Novel Human Immune Globulin Subcutaneous, 20 % in Patients with Primary Immunodeficiency Diseases in North America

Safety of Intravenous Immunoglobulin Preparations: A Prospective Multicenter Study to Exclude the Risk of Non-A, Non-B Hepatitis

Inactivated- or Killed-Virus HIV/AIDS Vaccines

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