The quality assurance process employed by BPL ensures that Gammaplex 10% is produced to consistently high levels of quality and safety.
- Manufactured from a Food and Drug Administration (FDA) licensed plasma source
- Manufactured by BPL to Good Manufacturing Practice (GMP) standards
- Produced using a manufacturing process based on cold ethanol fractionation followed by ion exchange chromatography
- Manufactured using specific solvent/detergent, virus filtration and low pH incubation viral clearance steps
Rigorous plasma screening process
BPL draws its plasma from collection centers based in the U.S. that are licensed by the U.S. FDA. The quality assurance process employed by BPL to maximize the quality and safety of Gammaplex 10% is shown in the figure below.
BPL Quality Assurance process
FDA approved plasma centersFDA approves and audits each center for compliance
Donor screeningHealth history, self exclusion
Only qualified donors allowed to donate
Donor deferralRegistered donors who test “reactive” for certain viral agents are added to the National Donor Deferral Registry (NDDR) and are permanently prohibited from donating
Individual donation testingTest for antibodies for HIV 1–2, HCV and presence of HBsAg
Mini-pool testingNAT for HIV, HBV, HCV, HAV and Parvovirus B19
Plasma inventory holdAll plasma donations are frozen and put on inventory hold in compliance with FDA guidance. If a donor later sero-converts, earlier plasma donations that have been held frozen can be excluded from manufacture and the donor listed on the NDDR
Fractionation pool testingNAT for HIV, HBV, HCV, HAV, and Parvovirus B19
Cold ethanol fractionationAll processing performed to GMP, cold ethanol fractionation contributes to virus inactivation
Specific validated virus clearance stepsSolvent/detergent, virus filtration and low pH incubation are three orthogonal virus clearance steps
QA for whole process and productQA oversight of whole process, BPL audited by FDA
Virus reduction/elimination: The 3-step process
The manufacturing process for Gammaplex 10% is based on cold ethanol fractionation with additional ion exchange chromatography purification steps. The cold ethanol fractionation process has been validated for virus clearance and shows removal of enveloped and non-enveloped viruses. In addition, a series of dedicated virus clearance steps have been introduced for viruses of concern, such as HBV, HCV and HIV.1
A number of methods are available for improving the viral safety of plasma derivatives, several of which are relevant to Gammaplex 10%. In particular, BPL has incorporated and validated several specific and well-proven virus reduction steps using solvent/detergent treatment, virus filtration and low pH/elevated temperature incubation in the manufacture of Gammaplex 10%. Full validation and robustness testing has been completed for each step.
The procedure was designed to inactivate enveloped viruses such as HBV, HCV and HIV, which are the viruses of principal concern in plasma products. The solvent/detergent procedure will also inactivate more recently described enveloped viruses, such as Hepatitis C virus and West Nile virus. The non-ionic detergent and the solvent components have the capacity to dissolve viral lipid envelopes and are particularly effective in combination. However, they do not inactivate non-enveloped viruses. The solvent/detergent procedure has been in widespread use in the plasma products industry for over 20 years and has become a well-established and proven method of enveloped virus inactivation.2
20 nm virus filtration
The second specific virus reduction step in the Gammaplex 10% process is virus filtration. This involves passing the immune globulin solution through a filter with a pore size of just 20 nm; the immune globulin molecules can pass through the filter, but any virus of approximately 20 nm or larger is trapped. Virus filtration has many advantages as a removal procedure:
- It is a validated process
- Removal is based on size and it is therefore effective against enveloped and non‑enveloped viruses
- It is a relatively gentle method and allows high levels of protein recovery
Terminal low pH/elevated temperature incubation
An additional feature of the Gammaplex 10% production process is the inactivation of viruses during the terminal low pH incubation. The filled product in its final closed container is incubated at 30°C (86°F) for 7–14 days. Under these conditions the low pH formulation and temperature contribute to effective inactivation of lipid-enveloped viruses and some non-enveloped viruses.
Gammaplex 10% is made from human plasma and may contain infectious agents, e.g. viruses and, theoretically, the Creutzfeldt-Jakob disease agent. No cases of transmission of viral diseases or CJD have been associated with the use of Gammaplex 10%.
References: 1. Roberts PL, et al. Development of an intravenous immunoglobulin with improved safety and functional activity. Biologicals. 2015. 2. Horowitz B, Prince AM, Hamman J, et al. Viral safety of solvent/detergent-treated blood products. Blood Coagul Fibrinolysis. 1994;5(Suppl 3):S21-S28.