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Stabilisers are included to ensure that albumin is not denatured or precipitated upon heating ; without them , high levels of polymers and aggregates would be present in the final container .
Sodium caprylate has been used as a stabiliser for albumin solution since 1944 , and the use of N-acetyl-DL-tryptophan to protect albumin during pasteurisation was first described in 1958 .
Albumin consists of three cylinder-like domains , each with a hydrophobic inner space that can bind hydrophobic molecules such as the stabilisers . Although the mechanism of stabilisation has not been fully elucidated , they may function by minimising irreversible reactions following thermal unfolding .
Chromatography Albumin is commercially purified by some manufacturers using chromatography . Chromatography was first used to purify albumin in the 1980s and a wide variety of techniques have been reported , including ion exchange , hydrophobic / reverse phase , group-specific affinity , or bio-specific affinity . To combine the benefits of both ethanol fractionation and chromatography , some manufacturers integrate the two processes .
Pharmacopoeial standards The increasing stringency of UK and European Pharmacopoeial standards and US Food and Drug Administration guidelines reflect the continual improvements to albumin production . Only 25 years ago , British Pharmacopoeial standards stated that albumin purity should be at least 85 %, with a maximum 10 % of aggregates . Maximum levels of PKA and aluminium were not specified .
Current European standards state that therapeutic human albumin solutions must be at least 96 % pure and contain no more than 5 % aggregates . In addition , requirements for maximum levels of aluminium , PKA and potassium have been introduced : albumin preparations must now contain ≤200μg / l aluminium , ≤35IU / ml PKA and potassium ≤12.5mmol / l for a 25 % albumin solution or ≤10mmol / l for a 20 % albumin solution .
Current regulations in the US are similar – albumin preparations must be > 96 % pure , with
PKA levels required to be ≤35.7IU / ml , aluminium ≤200μg / l and potassium ≤2mmol / l .
The 2020 edition of the Chinese Pharmacopoeia ’ s standard on human albumin stipulates that the purity of albumin preparations should be no less than 96 % of the total protein , and the content of aggregates should be no more than 5.0 % ( see Table 1 ). Modern human albumin products usually exceed the specified standards .
Virus safety The virus safety record of human albumin products over the past 60 years is excellent , and the European authorities state that there have been no reports of virus transmissions with albumin manufactured by established processes that meet European Pharmacopoeial standards . 3 Virus safety is achieved through a three-pillar strategy , based on :
• Careful donor selection and testing of donations
• Release of plasma pools for fractionation only when confirmed as non-reactive for defined contaminating infectious viruses , and
• Inactivation / removal of viruses during the manufacturing process .
First , plasma donations are tested for serology for certain blood-borne viruses and by nucleic acid amplification techniques , such as polymerase chain reaction . In addition , plasma pools are only released for further processing once non-reactivity has been confirmed against serological virus 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
TABLE 1
Current requirements for albumin solutions from the European Pharmacopoeia , CFDA , and FDA , and mean values for albumin manufacture
Current regulatory requirements Mean values for 20 batches of albumin manufactured *
European
CFDA
FDA
5 % albumin
20 % albumin
25 % albumin
Pharmacopoeia
Purity (%) ≥96 ≥96 ≥96 97.94 97.75 97.45
Aggregates (%) ≤5 ≤5 – 3.00 # 4.25 # 3.61 #
PKA ( IU / ml ) ≤35 ≤35 ≤35.7 < 5 < 5 < 5
Aluminium ( μg / l ) ≤200 ≤200 ≤200 < 20 < 20 4.55
Potassium ( mmol / l )
≤12.5 ( for 25 %
≤2
≤2
0.005
0.08
0.1
albumin solutions ) ≤10 % ( for 20 % albumin solutions )
* Mean value for either Bern or Marburg products . † Company-specific limits set by FDA ; # Area of the peak due to polymers and aggregates is ≤10 % of the total area of the chromatogram ( corresponding to approximately 5 % polymers and aggregates ).
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