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Virus safety data for some human albumin preparations
Virus reduction factors [ log10 ]*
Human immuno-deficiency virus
Hepatitis C virus 1
Pseudo rabies virus 2
Hepatitis A 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 .
markers such as HBsAg , a surface antigen of the hepatitis B virus , and antibodies against human immunodeficiency virus ( HIV ) type 1 and 2 . Non-reactivity must also be demonstrated by nucleic acid amplification techniques for hepatitis A , B and C viruses ( HAV , HBV and HCV , respectively ) and HIV , and titres of parvovirus B19 ( B19V ) must not exceed 104IU / ml according to regulatory guidance .
Steps during the manufacture of albumin , particularly the use of cold ethanol fractionation , effectively remove viruses 4 ; in addition , pasteurisation at 60 ° C for 10 hours effectively inactivates viruses . Pasteurisation was first introduced in the 1940s after studies with volunteers demonstrated that HBV was inactivated by this manufacturing step . Later , it was demonstrated in virus validation studies using cell culture infectivity 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 .
Article modified and reproduced from Lenz K , Kramer L ( eds ) Disorders of Albumin Metabolism in Liver Diseases ; UNI-MED Science , 1st edition 2014 ( ISBN 978-3-8374-1417-2 ) with kind permission
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