Manufacturing Quality

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 virus inactivation procedures

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

  1. FDA approved plasma centers

    FDA approves and audits each center for compliance
  2. Donor screening

    Health history, self exclusion
    Only qualified donors allowed to donate
  3. Donor deferral

    Registered donors put on National Donor Deferral Registry (NDDR)
  4. Individual donation testing

    Test for antibodies for HIV 1–2, HCV and presence of HBsAg
  5. Mini-pool testing

    NAT for HIV, HBV, HCV, HAV and Parvovirus B19
  6. 60 day plasma inventory hold

    All plasma donations are frozen and put on inventory hold for 60 days. 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
  7. Fraction­ation pool testing

    NAT for HIV, HBV, HCV, HAV, and Parvovirus B19
  8. Cold ethanol fraction­ation

    All processing performed to GMP, cold ethanol fractionation contributes to virus inactivation
  9. Specific validated virus clearance steps

    Solvent/detergent, virus filtration and low pH incubation are three orthogonal virus clearance steps
  10. QA for whole process and product

    QA 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.

Solvent/detergent treatment

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 2 weeks. 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.

Important Safety Information for Gammaplex 10%

Gammaplex 10% (immune globulin intravenous [human], 10% liquid) is indicated for replacement therapy in primary humoral immunodeficiency (PI) in adults. This includes, but is not limited to, the humoral immune defect in common variable immunodeficiency, X-linked agammaglobulinemia, congenital agammaglobulinemia, Wiskott-Aldrich syndrome, and severe combined immunodeficiencies.

Gammaplex 10% is also indicated for the treatment of chronic immune thrombocytopenic purpura (ITP) in adults.

Thrombosis may occur with immune globulin products, including Gammaplex 10%. Risk factors may include: advanced age, prolonged immobilization, hypercoagulable conditions, history of venous or arterial thrombosis, use of estrogens, indwelling central vascular catheters, hyperviscosity and cardiovascular risk factors. Thrombosis may occur in the absence of known risk factors.

Renal dysfunction, acute renal failure, osmotic nephrosis, and death may occur in predisposed patients who receive immune globulin intravenous (IGIV) products, including Gammaplex 10%.

Patients predisposed to renal dysfunction include those with any degree of pre-existing renal insufficiency, diabetes mellitus, age greater than 65, volume depletion, sepsis, paraproteinemia, or patients receiving known nephrotoxic drugs. Renal dysfunction and acute renal failure occur more commonly in patients receiving IGIV products containing sucrose. Gammaplex 10% does not contain sucrose.

For patients at risk of thrombosis, renal dysfunction or acute renal failure, administer Gammaplex 10% at the minimum dose and infusion rate practicable. Ensure adequate hydration in patients before administration. Monitor for signs and symptoms of thrombosis and assess blood viscosity in patients at risk for hyperviscosity.

Gammaplex 10% is contraindicated in patients who have had a history of anaphylactic or severe systemic reactions to human immune globulin and IgA deficient patients with antibodies to IgA and a history of hypersensitivity.

In patients at risk of developing acute renal failure, monitor renal function, including blood urea nitrogen (BUN), serum creatinine and urine output. Hyperproteinemia, increased serum viscosity, and hyponatremia may occur in patients receiving IGIV therapy.

Aseptic meningitis syndrome (AMS) may occur infrequently with IGIV treatment. AMS usually begins within several hours to 2 days following IGIV treatment. Discontinuation of IGIV treatment has resulted in remission of AMS within several days without sequelae. AMS may occur more frequently in association with high doses (2 g/kg) and/or rapid infusion of IGIV.

Hemolysis and hemolytic anemia can develop subsequent to IGIV treatments. Patient risk factors that may be associated with development of hemolysis include high dose (>2 g/kg), non-O blood group, and underlying inflammatory state. Noncardiogenic pulmonary edema may occur in patients following IGIV treatment (i.e. transfusion-related acute lung injury [TRALI]). Monitor patients for pulmonary adverse reactions. If TRALI is suspected, test product and patient’s serum for anti-neutrophil antibodies.

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%.

The most common adverse reactions in adult subjects receiving Gammaplex 10% in the PI clinical trial were headache, migraine, and pyrexia. There were no serious product-related adverse reactions observed in adult clinical trial subjects with PI. The safety of Gammaplex 10% has not been established in patients with ITP. However, the safety profile for Gammaplex 5% has been studied in subjects with ITP, and it is anticipated that the safety profile for both formulations are comparable for ITP patients. The most common adverse reactions in adult subjects receiving Gammaplex 5% in the chronic ITP clinical trial were headache, vomiting, nausea, pyrexia, arthralgia, and dehydration. Serious adverse reactions observed in clinical trial subjects with ITP were headache, vomiting and dehydration.

Please see Full Prescribing Information for complete prescribing details.

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit http://www.fda.gov/medwatch, or call 1-800-FDA-1088.

You may also call BPL at 1-844-4BPLUSA or email medinfo@bpl-us.com.