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TABLE 2
Virus safety data for some human albumin preparations
Virus reduction factors [ log10 ]*
Human immuno-
Hepatitis C
Pseudo
Hepatitis A
Parvovirus
deficiency virus
virus 1
rabies virus 2
virus 3
B19 4
Ethanol precipitation > 5.1 > 5.3 > 6.6 > 4.1 > 3.5
Pasteurisation > 6.6 > 8.1 > 7.2 > 6.8 > 4.2
Overall reduction factor > 11.7 > 13.4 > 13.8 > 10.9 > 7.7
* Minimum virus reduction factors demonstrated for each of three different albumin preparations produced at CSL Behring by cold ethanol precipitation . Model viruses used : 1 Bovine viral diarrhoea virus or Sindbis virus ; 2 Herpes virus ( enveloped , double-stranded DNA virus – a non-specific model virus ); 3 Hepatitis A virus or Encephalomyocarditis virus ; 4 Parvovirus B19V or canine parvovirus .
assays that both lipid-enveloped viruses ( for example , HIV , HCV model viruses and West Nile virus ) and non-enveloped viruses ( for example , HAV and B19V ) were effectively inactivated . 5 , 6
Specific steps during the manufacture of albumin are therefore effective in removing / inactivating a wide range of relevant and model viruses exhibiting diverse physicochemical properties very effectively ( Table 2 ).
Tolerability and safety Albumin has an excellent long-term safety record . When assessing the risks and benefits of human albumin preparations , judgements should be based upon experience with modern generation products .
Modern production techniques ensure that concentrations of impurities such as aluminium and PKA are minimised ; some of the adverse reactions observed in the past may be attributable to impurities that are eliminated or minimised in modern preparations . This calls into question the relevance of side effects reported in clinical studies that were performed more than 30 years ago .
Tolerability and pharmacovigilance Modern human albumin products are generally well tolerated , especially considering that they are often administered in large volumes . This is illustrated by the low incidence of spontaneously reported adverse events , and although reporting may underestimate the true incidence of adverse events , this finding nonetheless provides a good indication of the favourable tolerability profile of modern albumin products .
Two large pharmacovigilance studies have examined the incidence of spontaneously reported adverse events associated with administration of albumin . The first study by von Hoegen and Waller examined serious adverse events reported by nine major suppliers of therapeutic albumin worldwide . 7 Nearly 100,000,000 doses of albumin , corresponding to nearly 4,000,000kg , were distributed by suppliers during the study period . A total of 123 serious adverse events ( SAEs ) were reported , corresponding to an incidence of 1.29 SAEs per 1,000,000 doses .
Notably , no deaths were judged to be probably attributable to the administration of albumin . Five deaths per 100,000,000 doses were possibly related to the administration of albumin . The majority ( 75 %) of deaths were considered to be unrelated to albumin , and the study concluded that both non-fatal and fatal adverse reactions in albumin recipients are very rare .
The second pharmacovigilance study was performed by Vincent et al 8 during a period of heightened interest in the safety of albumin following the publication of controversial safety data . Approximately 16,000,000 doses of albumin were distributed by 10 major suppliers worldwide during the study period . A total of 211 serious adverse events were reported , corresponding to an incidence of 5.28 SAEs per 1,000,000 doses .
In agreement with results from the first pharmacovigilance study , no deaths were judged to be probably attributable to the administration of albumin . Although the incidence of SAEs was higher than in the first study , only half of the number of non-fatal SAEs was judged to be probably related to albumin in the second study , as compared to the first . Results of this analysis confirmed those from the first pharmacovigilance study : spontaneously reported SAEs are rare and human albumin has an excellent tolerability profile .
Conclusion The production of human albumin is a continually improving process , with biopharmaceutical companies striving to produce preparations with increased purity that continue to exceed the strict guidelines specified by regulatory bodies worldwide .
Albumin has excellent long-term , and viral , safety , and is well tolerated . Randomised controlled trials have demonstrated a favourable efficacy and safety profile for human albumin , and further studies are underway to define its efficacy , safety and tolerability across a wide variety of clinical settings .
References 1 Cohn EJ et al . Preparation and properties of serum and plasma proteins ; a system for the separation into fractions of the protein and lipoprotein components of biological tissues and fluids . J Am Chem Soc 1946 ; 68:459 – 75 . 2 Kistler P , Nitschmann H . Large scale production of human plasma fractions . Eight years experience with the alcohol
fractionation procedure of Nitschmann , Kistler and Lergier . Vox Sang 1962 ; 7:414 – 24 . 3 European Medicines Agency 2011 . Guideline on the warning on transmissible agents in summary of product characteristics ( SmPCs ) and package leaflets for plasmaderived medicinal products . EMA / CHMP / BWP / 360642 / 2010 rev . 1 . 4 Dichtelmüller HO et al .
Contribution to safety of immunoglobulin and albumin from virus partitioning and inactivation by cold ethanol fractionation : a data collection from Plasma Protein Therapeutics Association member companies . Transfusion 2011 ; 51:1412 – 30 . 5 Hilfenhaus J et al . A strategy for testing established human plasma protein manufacturing procedures for their ability to
inactivate or eliminate human immunodeficiency virus . J Biol Stand 1987 ; 15:251 – 63 . 6 Blümel J et al . Inactivation of parvovirus B19 during pasteurization of human serum albumin . Transfusion 2002 ; 42:1011 – 18 . 7 Von Hoegen I , Waller C . Safety of human albumin based on spontaneously reported serious adverse events . Crit Care Med 2001 ; 29:994 – 6 .
8 Vincent JL , Wilkes MM , Navickis RJ . Safety of human albumin – serious adverse events reported worldwide in 1998 – 2000 . Br J Anaesth 2003 ; 91:625 – 30 .
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