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11 DESCRIPTION QIVIGY (immune globulin intravenous, human-kthm) is a ready-to-use, sterile, non-pyrogenic liquid solution of human immune globulin (IgG) for intravenous administration.‍‍‍‍‍‍​​​‍​​​​​​ QIVIGY is clear or slightly opalescent, colorless or pale yellow. QIVIGY consists of immune globulin of which IgG represents at least 96% of the total protein. It consists of 9 - 11% protein in 0.20 - 0.28 M glycine. In the solution, the IgG proteins are present by more than 97% (at lot release) and 93% (by expiration date) in monomeric and dimeric forms. Minimum value for osmolality is: 240 mOsmol/Kg. pH of the solution is in the range of 4.0 - 4.5. It contains trace levels of IgA (not more than 50 mg/L). The main component of QIVIGY is IgG (≥ 96%) with a sub-class distribution compatible with native human plasma. QIVIGY contains no carbohydrate stabilizers (e.g., sucrose, maltose) and no preservative. To specifically reduce the anti-A and anti-B titers in the drug product (isoagglutinins A and B), donor plasma is screened for isoagglutinin titer using a validated assay, and plasma units with high agglutination scores are excluded from further processing. All donors of plasma are carefully screened by history and laboratory testing to reduce the risk of transmitting blood-borne pathogens from infected donors. All plasma units used in the manufacture of QIVIGY are tested and approved for manufacture using FDA-licensed serological assays for Hepatitis B surface antigen (HBsAg), Human immunodeficiency virus 1/2 antibodies (anti-HIV-1/2), and Hepatitis C antibodies (anti-HCV). In addition, donations are screened for Hepatitis C virus (HCV), Human immunodeficiency virus 1 (HIV-1), Hepatitis B virus (HBV), Hepatitis A virus (HAV) and Parvovirus B19 (B19V) by NAT. Further testing is performed on the manufacturing pools for HBsAg and antibodies to HIV-1/2; plasma pools are also tested for HCV, HIV-1, HBV, HAV and B19V by NAT with the limit for B19V set to not exceed 10 4 IU B19V DNA per mL plasma. QIVIGY is made from large pools of human plasma by a combination of cold alcohol fractionation, caprylate precipitation and filtration, anion-exchange chromatography, nanofiltration and ultrafiltration/diafiltration (UF/DF). QIVIGY is incubated in the final container at the low pH of 4.0 – 4.5. The product is intended for intravenous administration. The capacity of the manufacturing process to remove and/or inactivate enveloped and non-enveloped viruses has been validated by spiking studies at laboratory scale with a validated model of the manufacturing processes, using the following enveloped and non-enveloped viruses: HIV-1 as the relevant virus for HIV-1 and HIV–2; Bovine Viral Diarrhea virus (BVDV) as a model for HCV; Pseudorabies virus (PRV) as a model for large enveloped DNA viruses (e.g., Herpes viruses and HBV); HAV as relevant non-enveloped virus, Encephalomyocarditis virus (EMCV) as a model for HAV, and Porcine Parvovirus (PPV) as a model for human parvovirus B19. The viral clearance capacity of QIVIGY manufacturing process has been evaluated by summing logarithmic reduction factors from single steps with significant reduction factors more than 1 log, obtaining overall log reduction factors (LRFs) reported in Table 3. The manufacturing process for QIVIGY includes four steps to reduce the risk of virus transmission. Two of these are dedicated virus clearance steps: sodium caprylate incubation to inactivate enveloped viruses and virus filtration to remove, by size exclusion, both enveloped and non-enveloped viruses as small as approximately 20 nanometers. In addition, caprylate precipitation and filtration step and low pH treatment step contributes to the virus reduction capacity. Overall virus reduction was calculated only from steps that were orthogonal in mechanisms of removal/inactivation. In addition, each step was verified to provide robust virus reduction across the production range for key operating parameters. Table 3: Viral Inactivation/Removal Capacity of the QIVIGY Manufacturing Process LRF Enveloped Viruses LRF Non-Enveloped Viruses Step BVDV HIV-1 PsRV HAV PPV EMCV NI: not investigated. NA: Not applicable. 1 st Caprylate (precipitation+depth filtration) 3.35 NI NI > 5.93 2.69 NI 2 nd Caprylate (inactivation) > 5.37 > 4.54 > 6.79 NA NA NA Nanofiltration > 5.26 2.27 NI Due to the low pH condition at which nanofiltration was performed, PsRV was immediately inactivated and it was not possible to properly evaluate virus removal by nanofiltration. > 4.85 > 6.19 > 4.28 Inactivation by Low pH 2.45 6.17 6.65 NI NI 3.43 Overall Viral Reduction > 16.43 > 12.98 > 13.44 > 10.78 > 8.88 > 7.71 Concerning vCJD risk, donor exclusion criteria are in accordance with the relevant FDA Guidance for Industry (Recommendations to Reduce the Possible Risk of Transmission of Creutzfeldt-Jakob Disease and Variant Creutzfeldt-Jakob Disease (vCJD) by Blood and Blood Components, current edition).