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 *
CFDA FDA 5 % albumin 20 % albumin 25 % albumin
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 % albumin solutions ) ≤10 % ( for 20 % albumin solutions )
≤2 ≤2 0.005 0.08 0.1
* 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 ).
temperatures below 0 ° C . The resulting solution of Fraction V or precipitate C contains purified albumin . It undergoes ultrafiltration and , finally , pasteurisation at 60 ° C for 10 hours in the final container after filling , which inactivates residual viruses that were potentially present in the starting material .
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 solutions since 1944 , and the use of N-acetyl-DLtryptophan to protect
The main goal is to produce preparations with high purity that contain albumin that is as close to the native plasma protein as possible 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
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