Manufacturing of plasma-derived C1-inhibitor concentrate for treatment of patients with hereditary angioedema

Abstract

Background: Replacement therapy with plasma-derived C1-inhibitor (C1-INH) has been used for decades to treat patients with hereditary angioedema (HAE) with C1-INH deficiency. Objective: This article reviewed the rationale for using C1-INH replacement therapy in patients with HAE and the process of manufacturing plasma-derived C1-INH. Methods: The manufacture of C1-INH is an involved and carefully monitored process that includes screening and selection of prospective donors, the collection of source plasma, and purification with dedicated pathogen reduction steps. Donor eligibility is determined by restrictive criteria established and monitored by regulatory agencies as well as voluntary standards implemented by plasma collection centers that exceed government regulations. Individual and pooled donations are tested for transfusion-transmissible infections, including hepatitis B virus, hepatitis C virus, human immunodeficiency virus, parvovirus B19, and hepatitis A virus, by using enzyme-linked immunosorbent assays or nucleic acid amplification technologies. Frozen plasma that is cleared for manufacturing undergoes controlled thawing and centrifugation, and the resulting supernatant (i.e., cryoprecipitate-depleted plasma) is used to manufacture several plasma-derived therapies, including C1-INH. In addition to chromatography steps, the manufacturing process consists of dedicated and effective pathogen reduction steps, including pasteurization, hydrophobic interaction chromatography or polyethylene glycol precipitation, and virus filtration. Manufacturers continuously monitor the safety profile of C1-INH products by robust pharmacovigilance processes that enable systematic collection and evaluation of all suspected adverse drug reaction reports as well as evaluation of safety information from all other sources. Results and Conclusion: These procedures used in donor screening, donation and manufacturing pool testing, manufacturing, and pharmacovigilance ensure that plasma-derived C1-INH products have the safety, quality, identity, potency, and purity that is necessary to provide the intended therapeutic effect.

Treatment of Hereditary Angioedema

“…Abbreviations: CPK, creatine phosphokinase; pdC1INH, purified nanofiltered plasma-derived human C1 esterase inhibitor concentrate; rhC1INH, recombinant human C1 esterase inhibitor a The risk of transmission of infections has been reduced by the selection of donors, testing of plasma donations for possible viral contaminants, the methods introduced in manufacturing to inactivate and/or remove viruses and other adventitious agents that might be present in the serum mixture, and regular pharmacovigilance [112]. No cases have been reported to date with currently marketed pdC1INH products [1,37].…”

Mast cells and complement system: Ancient interactions between components of innate immunity

“…Individuals with malfunction of C1‐INH may experience angioedema attacks. C1‐INH functionally suppresses autoactivation of factor XII and inhibits the conversion of prekallikrein to kallikrein 23 . C1‐INH is capable of inhibiting activation of C1r and C1s, and the cleavage of two important components of complement system C2 and C4 24 .…”

“…C1‐INH is capable of inhibiting activation of C1r and C1s, and the cleavage of two important components of complement system C2 and C4 24 . Moreover, C1‐INH has a regulatory role in the coagulation system through inhibition of factor XI 23 . One of the soluble complement inhibitor molecules which acts at the level of C3 convertases is C4b‐binding protein (C4BP) 25 .…”

Bradykinin System: A Therapeutic Goal for COVID-19

“…Berinert and Cinryze are concentrated C1-INH collected from healthy blood donors. The mechanism of action of these molecules is the regulation of kallikrein and factor XII activity and the reduction of bradykinin production (29). Bork et al showed that the mean time of angioedema reversal in 18 HAE patients was 42.2 minutes (22).…”