| Human albumin(ALB)is an injection prepared from isolated and virus inactivated healthy human plasma.Clinically,it is mainly used for the treatment of shock,cerebral edema and increased intracranial pressure,liver cirrhosis and edema or ascites caused by liver and kidney disease,neonatal hyperbilirubinemia as well as prevention and treatment of hypoproteinemia.Human Albumin,as a blood product,is a human-derived product.Due to its special source,it is a high-risk pharmaceuticals.Therefore,the Biological product batch issuing system is usually adopted,and each batch of products is subject to mandatory review and inspection when it is released from the site or is imported.In recent years,the quality of human albumin has been generally good.However,there are still potential risks.In 2017,the unannounced inspection of a blood product company adopted by Center For Food And Drug Inspection Of NMPA found that the aluminum content in the stability study greatly exceeded the Pharmacopoeia limit(200?g/L).Subsequently,National Institutions for Food and Drug control organized seven provincial institutions to carry out the batch-test of the aluminum content in retained samples.The result shows that the overall average value of the aluminum content in the retained samples was about one times higher than the average value of the lot release.At the end of the shelf life,the content of aluminum from some domestic products exceeds 200?g/L.This phenomenon has aroused widespread concern in the industry.Human Albumin,as an intravenous infusion product,has been widely used in the clinics.An excess aluminum content may cause potential diseases such as osteomalacia and Alzheimer's disease.Therefore,it is particularly vital to study the rising trend of aluminum ions and its mechanism.Currently,the overall situation of aluminum in domestic albumin products requires to be evaluated,and the cause and mechanism of the change in aluminum content is still not clear.Therefore,this study is based on the problems found during the country's supervision and inspection of albumin,using the albumin products launched on the domestic market,to make a comparative study of the manufacturing process and aluminum content from various enterprises.Atomic absorption spectrophotometer,gel chromatography,liquid chromatography-mass spectrometry,ICP-MS,and other analytical methods were applied in the systematically study the aluminum residues for domestic and foreign products to measure the changes in aluminum content during storage and find out the factors that caused the rise of aluminum ions.1 Comparison of aluminum content in human albumin from different enterprises of domestic and foreign sourceTo obtain a comprehensive knowledge of aluminum residues content in Human Albumin and the differences in aluminum concentration of domestic and foreign products,Atomic absorption spectrophotometry was applied to determine the content of aluminum in 153 batches of Human Albumin from 33 companies.The results showed that,Firstly the content of aluminum residues varies widely between companies,it is closely correlated with the manufacturing process parameters of various enterprises.Secondly,the average aluminum residue from domestic enterprises is higher than that of foreign enterprises.Finally,comparing with the ex-factory value,the aluminum residue has increased by different degrees during storage and the growth rate is 10% ~ 1050 %.It is suggested that transferrin is not the main factor for the increasing of aluminum content in Human Albumin during storage.2 Study on influencing factors of aluminum in human albuminThen we analyze the root causes of aluminum ion concentration changes during storage,the effects of multiple factors on aluminum ion changes during simulated sample storage were studied.The results show that during storage,the change of aluminum residue in human albumin is directly related to the type of glass bottle(type I glass bottle has more aluminum release than type II glass bottle).The following factors will indirectly promote the rise of aluminum: the amount of citrate ion residue(the higher amount of citrate ion content,the faster the aluminum increases),the storage temperature(the higher the temperature,the faster the aluminum increases),and the protein concentration(the higher the concentration,the faster the aluminum increases),And the sample comparison study shows that the four kinds of samples stored at the same time,only the glass of human blood albumin storage shows an increase in aluminum ions.3 Study on correlation between transferrin and aluminum content in Human AlbuminSome literature reports that transferrin can bind and transport aluminum,and residual transferrin in the product can promote the increase of aluminum content.To study the correlation between the aluminum content and the residual transferrin during the storage of Human Albumin,in this study,we use protein identification analysis technology to identify the unknown proteins in the product and select the companies that contain transferrin and then quantify it.Through accelerated experiments,the effect of transferrin on the change of aluminum content was investigated.The experimental results indicated that there was no significant correlation between aluminum concentration and transferrin in Human Albumin.Further discussion and investigation are required.4 Study on detection method of human albumin aluminum residueThe current method for determining the residue of aluminum adopted in the current Pharmacopoeia(2015 edition)is Atomic Absorption Spectrophotometry.Chinese Pharmacopoeia Commission plans to add Inductively Coupled Plasma Mass Spectrometry(ICP-MS)to the 2020 Pharmacopoeia,and the method has been publicized on the website.We used both methods to test the aluminum concentration in 35 batches of samples,and results of some batches were slightly different.The pretreatments and the detection principles of the two methods are different.Therefore,we preliminarily established a microwave digestion pretreatment method,which could completely release the aluminum into free ions,making the detection results more accurate.However,factors such as temperature and time in the microwave digestion system determine the degree of sample digestion and directly affect the measurements.Further explorations are required to identify the optimal microwave digestion system.This study comprehensively investigated the increase of aluminum content in Human Albumin during storage,compared and analyzed the aluminum content in domestic and foreign products and analyzed the influencing factors of aluminum content change during storage.Besides,the study determined that the increase of aluminum is related to the type of glass bottle,citrate ion concentration,protein concentration,sample type,and temperature.The main effect of transferrin was excluded.The two detection methods of aluminum residue were compared.The pretreatment method of microwave digestion in ICP-MS method was explored.Moreover,this subject has conducted a comprehensive study on the content of aluminum in human albumin,providing a theoretical basis for the control of aluminum in this product,and promoting the clinical safety of human albumin. |
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