How to Make Albumin Clear Again
Abstruse
Br J Anaesth 2000; 85: 887–95
Albumin has a long history of clinical use in colloid replacement therapy dating back over fifty yr. Information technology is currently used in greater volume than any other biopharmaceutical solution that is bachelor, and worldwide manufacturing is of the society of 100s of tonnes annually. However, every bit with many therapies, the clinical use of albumin has oftentimes had its critics. Some of these6 have concluded that albumin therapy may deport an increased take chances of death, relative to crystalloid solutions, in some disquisitional care situations.
When assessing the place for albumin in critical care therapy, the nature of the production existence infused should be considered. Less pure preparations, such as plasma protein fraction, have been replaced past purer preparations with lower associated adverse reactions. Many of the earlier studies of albumin utilise were conducted in the 1970s and 1980s. Since that fourth dimension, human albumin solution has been refined past developments and improvements to manufacturing processes, and then that mod albumin is far removed from the solutions infused in earlier decades.
Albumin solution for therapy should be as near as possible to the native protein institute in the plasma, given the need for purification and viral assurance. This review outlines primal changes in the production of albumin for clinical use, focusing in item on the substantial improvements in purity and tolerability that accept been accomplished in the last xx year. It also provides an upwardly‐to‐date profile of a continually improving product.
Properties and clinical use of albumin
Albumin is a highly water‐soluble protein (molecular weight 66 000 Da) with considerable structural stability. It is an of import component of plasma, making upwards 60% of the total protein. At normal physiological concentrations of plasma proteins, albumin contributes eighty% of the colloidal osmotic (oncotic) pressure of the plasma, and its function as a carrier for hormones, enzymes, fatty acids, metallic ions and medicinal products is much reported.32
Human albumin has been used as a therapeutic amanuensis for over l twelvemonth. Its key indication is the restoration and maintenance of circulating claret book in situations such as trauma, surgery and blood loss, burns management and plasma exchange.26 The platonic product for this purpose would be monomeric albumin of very loftier purity, free from contamination with other plasma proteins, endotoxins, metal ions, albumin aggregates and prekallikrein activator (PKA), as such impurities appear to influence the tolerability of albumin infusion.xi
Feel with albumin products of the older generation suggests that high endotoxin concentrations may be implicated in delirious reactions, while high concentrations of PKA can crusade hypotension.2 Aluminium concentrations demand to exist kept very low to avoid accumulation in neonates and patients with impaired renal function.23 Contamination with trace proteins may consequence in undesirable aggregation when albumin is being pasteurized.xviii The goal for manufacturers in contempo decades has therefore been to minimize or eliminate such impurities.
Virus safety
The prophylactic record of albumin products with respect to virus transmission over the by 50 twelvemonth has been excellent. Pasteurization at 60°C for 10 h was introduced in the 1940s1314 and has been shown to inactivate a range of lipid‐enveloped and non‐enveloped viruses,27 including hepatitis A, B and C and HIV. The inclusion of stabilizers ensures that the albumin solution is not denatured on heating. Pasteurization in the final container after filling removes the potential for late contagion.
Methods of preparation
Albumin is now predominantly derived from human plasma, although both fourth dimension‐expired blood and, in some countries, placental material have been used as sources in the past. The rise in the employ of packed red cells rather than whole blood transfusions means that the amount of albumin derived from time‐expired blood has declined markedly, while the employ of placental fabric was abandoned considering of difficulties in ensuring donor traceability, particularly in terms of viral status.
Albumin products fall into two categories. The plasma poly peptide fraction (PPF)15 is broadly similar to human albumin solution (HAS) and is derived (Fig.1) by a higher‐yielding procedure just has a lower minimum albumin purity (>85% for PPF vs ≥95% for HAS). Its primary disadvantage is the presence of hypotensive contaminants, specially PKA.xx30 Consequently, and with greater supplies of plasma becoming available, PPF has fallen in popularity and is no longer listed in the British Pharmacopoeia. Some PPF products are all the same available exterior the Britain.
The traditional method for the purification of albumin for therapeutic apply has been common cold ethanol fractionation, as described past Cohn and colleagues in 19467 and its afterward variants. Since then, some pharmaceutical providers take chosen to supplement this process with additional purification stepsane while others have moved towards an culling, predominantly chromatographic separation method.xl A schematic representation of the different processes is shown in Fig.ane.
Cold ethanol fractionation
Albumin has some unique properties that allow relatively simple and effective purification past atmospheric precipitation methods. It has the highest solubility and the lowest isoelectric point (the pH at which it bears no internet charge) of the major plasma proteins. Adjustments to pH, temperature, ionic strength, ethanol concentration and protein concentration therefore let the separation of albumin from the other plasma proteins. Seventeen disulphide bonds forth the unmarried polypeptide chain confer considerable structural stability, and so that nether conditions in which other valuable plasma proteins would be totally denatured, albumin is recovered relatively undamaged.
At that place are two cold ethanol fractionation processes in common use; these are compared in particular elsewhere.28 Many American suppliers have retained the original Cohn process.seven The Kistler and Nitschmann process, which uses fewer protein precipitation steps and hence less ethanol, is more cost‐effective,19 and has been favoured by some European fractionators (Fig.ane). The valuable coagulation factors are removed as cryoprecipitate on initial thawing of the plasma earlier cold ethanol fractionation. With either method, an initial low ethanol precipitation stage removes the fibrinogen from the source plasma. Subsequently, by raising the ethanol concentration to 25% at pH 6.nine for the Cohn method or 19% at pH 5.85 for the Kistler and Nitschmann method, the immunoglobulins are precipitated while the albumin remains in solution. Albumin is then isolated from the bulk of the other plasma contaminants (mainly α and β globulins), which are precipitated by the further addition of ethanol to a final ethanol concentration of xl%. This is carried out in ii stages in the Cohn process but as a single step in the Kistler and Nitschmann method. In a terminal stride, the albumin is itself precipitated near its isoelectric point. The precipitate paste (fraction 5) can be held frozen before farther processing.
Chromatographic purification
An alternative to cold ethanol fractionation is the chromatographic purification of plasma to produce albumin. This method was first described in the early on 1980s.3eight40 Afterwards description, the plasma is buffer‐exchanged by either column gel filtration or diafiltration to allow subsequent ion exchange chromatography. At that place follows one or more column chromatographic purification steps, then farther gel filtration chromatography or buffer exchange.
The appeal of chromatographic processing of plasma over cold ethanol fractionation in principle is its ease of automation, the relatively inexpensive establish required, and the ease of sanitizing and maintaining a Skillful Manufacturing Practice environment. The process is potentially less damaging to the protein than ethanol precipitation, and the concentration of assemblage resulting from processing is minimized. The yield of albumin is also generally college by chromatographic methods (80–85% yield at >98% purity) than by common cold ethanol atmospheric precipitation (typically lx–70% yield and a 95% pure product).
Despite these potential advantages, chromatographic albumin purification has not been widely adopted until relatively recently considering of the limited availability of the very large chromatographic equipment required to meet demand for the product.
Other methods
A combined method, whereby chromatographic purification steps supplement the cold ethanol fractionation process, has been adopted by a number of manufacturers. Single or multiple column steps can improve product purity by assuasive convenient buffer exchange and depleting trace poly peptide contaminants. Several other strategies for the purification of albumin have been evaluated over the by fifty yr but none has been adopted on a large scale. These are discussed more fully elsewhere.28
Pharmacopoeial standards for albumin products
Man albumin is produced at two concentrations. The 4–v% albumin solution is an isotonic solution specially suitable for fluid replacement in hypovolaemia. The xx–25% albumin is a hypotonic only hyperoncotic solution for the treatment of fluid loss where electrolyte or fluid load is contraindicated. The highly concentrated protein solution provides colloidal pressure while minimizing the additional salts and fluid volume that are infused. These depression‐common salt, high‐concentration albumin products are also used to treat patients with poor renal function, to avoid electrolyte disturbances, and in the treatment of neonates. Electrolyte balance can be maintained more than accurately by tailoring the use of advisable crystalloids with the 20% albumin solution.
An examination of the changes to the pharmacopoeial requirements for albumin products over the past decade provides an interesting insight into alterations in processing methodologies and the resulting product improvements. Thus, a review of the requirements of the British Pharmacopoeia (BP) dated 1988, 1993 and 1999 and the European Pharmacopoeia (EP) 1997 (Tabular array1) shows the move abroad from allowing placental sources, and the introduction of maximal permitted concentrations for PKA and aluminium. Improvements in analytical technology are reflected in the use of HPLC (high‐operation liquid chromatography) rather than soft gel chromatography for the measurement of aggregates. Screening of plasma pools for hepatitis C was introduced once the causative agent had been identified. Finally, the defined appearance of albumin solutions has been broadened to permit greenish coloration, as anion exchange‐purified albumin generally has a green colour25 resulting from the conversion of bound bilirubin to biliverdin by oxidation during the pasteurization stride.
Developments in albumin fractionation
Whatsoever review of developments in albumin processing is hampered by the paucity of information; the detailed methods business organisation confidential industrial processes. For this reason, nosotros will apply the evolution of the albumin purification process at Bio Products Laboratory (BPL; a UK fractionator, which is part of the National Blood Service in England) to illustrate the general changes that take occurred in the industry over the by 20 yr. The albumin produced by BPL has long been of the standard required by the British Pharmacopoiea for human albumin solution, fifty-fifty though until the mid 1980s it was termed 'plasma poly peptide fraction'.21
The Kistler and Nitschmann variant of ethanol fractionation19 was introduced past BPL in 1964 and has remained the basis for production ever since, even though the scale has increased from a few tens of litres to over 6000 litres of plasma per batch. In the early days, the excess h2o and ethanol present in the albumin subsequently cold ethanol fractionation were removed either by freeze‐drying or, from the early 1980s, by thin‐layer evaporative methods.43 However, since 1987 this step has been carried out by the utilise of diafiltration technology, which is far less probable to result in poly peptide denaturation than the previous methods.
Polishing improves purity
A chromatographic refining or 'polishing' footstep was as well introduced into the BPL process in 1991 to farther reduce concentrations of contaminant proteins and occasional loftier endotoxin concentrations. Subsequently diafiltration and adjustment to a suitable pH, the albumin solution is applied to a DEAE–Sepharose Fast Flow chromatography column, where impurities are jump and removed. The albumin, which is unretained, is then formulated, filled and pasteurized to produce the product known as Zenalb®, which has been in use for over 8 yr. The addition of this single anion‐substitution chromatographic pace produced marked improvements in the quality of the production. The purity of the albumin increased to ≥99% and the monomer content to >95%. At the same fourth dimension, concentrations of endotoxin and aluminium were consistently lowered, as shown in Fig.2.
Whereas the introduction of a chromatographic polishing stride has resulted in a major improvement in the albumin product, several other process changes, instituted over the past 10 yr, take besides influenced purity and quality. The addition in 1992 of majority pasteurization of the albumin earlier filling (whilst retaining the post‐filling pasteurization pace) has helped to control PKA concentrations during storage. The treatment of the plasma pool with the diatomaceous filter aid Celite, introduced in 1995, promotes the removal of PKA during the early on fractionation process. Also, since 1997, aluminium concentrations have been further reduced by changing the blazon of glass used for the product container, a alter widely adopted by other manufacturers.17
The internet result of these process changes is a chromatographically purified human albumin solution that meets or exceeds the specifications set by regulatory bodies. The albumin remains undamaged during processing, contamination with non‐albumin proteins is reduced to negligible concentrations, and the concentrations of PKA, endotoxin and aluminium are well controlled. This increased purity has enabled the shelf‐life at room temperature storage to be extended. At the aforementioned fourth dimension, the process for this very high purity albumin delivers a high yield within an acceptable processing fourth dimension.
Clinical implications
The clinical importance of these product improvements has been demonstrated in the evaluation of patients undergoing therapeutic plasma exchange. In ane comparison,46 the incidence of production‐related adverse reactions (defined as untoward changes in pulse, blood force per unit area or temperature) was markedly reduced from 1 for every 83 units infused (500 ml, 4.5% albumin) with the former BPL product to 1 for every 374 units infused with Zenalb 4.5. Likewise, in an initial assessment of Celite‐treated albumin,4 reduced numbers of febrile reactions were observed in comparing with the not‐Celite‐treated product (0.34 and 2.5%, respectively).
Albumin solution is generally well tolerated, especially in view of the size of the infusion volume. Adverse reactions have been reported in the scientific literature,xi34 most notably when albumin has been used in plasma commutation. The tolerability of modern human albumin solution is illustrated by the incidence of spontaneously reported adverse reactions. Although such reporting underestimates the true incidence of adverse events, it provides a useful indication of a product's overall safety contour. Spontaneous reports received past the BPL Medical Department from various indirect sources (such as publications) or directly from individuals using Zenalb® suggest that the reported incidence of adverse reactions may be as low every bit ane in 17 200 infusions for four.five% albumin and 1 in 78 200 infusions for 20% albumin. Based on the information received, the agin reactions were assessed by the BPL Medical Section in terms of the seriousness of the reaction and the body system (e.one thousand. cardiac, vascular, respiratory, neurological) affected (Table2). None of the adverse events classified equally serious in Table2 was fatal. This level of incidence compares favourably with the 1 in 6600 incidence of adverse reactions to albumin reported by McClelland in 1990.26
Give-and-take
This review has concentrated on the methods of preparation and their relevance to the clinical use of albumin. Nonetheless, a number of papers have appeared over recent years which are disquisitional of any significant role for albumin in therapeutic strategies, favouring other colloids or crystalloid solutions.244247 Even so, whereas Tjoeng and colleagues42 recommend the utilize of synthetic colloidal supplements equally an alternative to albumin, they practise not talk over the adverse reactions which tin occur to these alternatives, such equally anaphylactoid reactions, issues with disordered coagulation and alterations in blood viscosity,five2637 or their frequency, which may exceed those for albumin.26
Other workers have tried to critically assess the basis for the use of albumin in a diverseness of clinical weather condition, and have classified albumin usage every bit being appropriate, unproven or inappropriate.v94445 Whereas usage for certain clinical conditions has fallen, for others (e.g. meningococcal illness) albumin therapy is still the preferred treatment.31 Other clinicians are unwilling to move away from the utilise of albumin in fluid replacement until the case has been proven by thorough clinical trials.1229 A recent study in cirrhotic patients with spontaneous bacterial peritonitis showed that antibiotic plus albumin had a significant do good on conserving renal function and survival compared with antibiotic alone,39 although whether constructed plasma expanders would have been equally effective was not studied.
A number of adverse events have been reported to be associated with albumin therapy, including allergic (anaphylactoid) reactions, impairment of renal function, hypotensive reactions, cardiac problems and pulmonary oedema.eleven2634 Anaphylactoid reactions to albumin occur relatively infrequently; they are likely to exist due to a combination of subtle factors, including the sensitivity of the individual, the rate of infusion, and product characteristics. Problems with renal part and hypotensive reactions are thought to result from the presence of contaminants. Pulmonary oedema, resulting from the leakage of albumin into the extravascular infinite with its consequent osmotic consequence on fluid accumulation, may be a effect of inappropriate utilise. Rather than adhering to strict dosage regimens for albumin therapy, fluid and haemodynamic variables should be monitored carefully and therapy adjusted accordingly. In one written report of pulmonary oedema occurring in children with nephrotic syndrome, the problem was assigned to also high an albumin dosage or too rapid infusion.34 Indeed, the study of Lucas and colleagues,22 who reported the greatest relative run a risk from albumin therapy, employed an extremely large 'fixed' dose of common salt‐poor albumin: 150 g during the operation and 150 g day–one for the first five postoperative days. Margarson and Soni24 have pointed out the mistake of chasing strict plasma albumin concentrations rather than using the amount of protein required to restore the colloidal osmotic balance. Some practitioners have distinguished, in their acceptance of albumin therapy, between high‐ and depression‐concentration preparations.16 The tragic consequences of the inappropriate dilution of 25% human albumin have also been reported.33
Later the publication of the Cochrane meta‐analysis,6 the use of albumin in the UK vicious markedly.36 Several authors accept raised criticisms of the Cochrane meta‐assay itself, highlighting weaknesses in the performance of the review, failure to discriminate between information derived from patients with markedly different clinical conditions, and the grouping of data from trials with unlike clinical endpoints.10313538 Indeed, Horsey16 commented that at that place were only two explanations for the increased risk: that albumin had been given in excessive amounts or that it had go toxic equally a consequence of commercial processing.
Some workers have suggested that the purity of the albumin preparations used may have influenced the results observed in clinical use, highlighting especially the toxicity of metallic ions, in particular aluminium, which can be present in the products.624 The aim of albumin processing is to provide a rubber product whose properties mirror equally closely as possible those of albumin found in plasma. This review has shown that, far from remaining unchanged over half a century, the process past which albumin is extracted from plasma and purified has undergone continuous improvement. As a event, albumin solutions for clinical apply have been improved markedly, peculiarly in the past 20 twelvemonth. Modernistic processing technology ensures that damaged protein is removed and that concentrations of impurities such as PKA and aluminium are minimized. Such pregnant changes to the industry of human albumin phone call into question the validity of clinical studies performed over 20 yr ago. When making realistic assessments of the risks and benefits of albumin therapy to patients in intensive care, it is important to base such judgements upon experience with modernistic‐generation products.41 Some of the adverse reactions observed in the past may accept been attributable to impurities that have since been eliminated or minimized past improved manufacturing applied science.
It is likewise important to administer an appropriate dose of albumin, at a suitable charge per unit, with conscientious monitoring of the patient's cardiovascular and pulmonary condition. Although mod albumin solutions are closer than always to the native substance, as with all therapeutic interventions in that location are inherent risks. With modern direction techniques, such risks from albumin can be minimized and therapeutic gain accomplished. Albumin is not just a fluid for hypovolaemia—harnessing its carrier functions32 is a positive challenge for the futurity.
Acknowledgements
We thank our colleagues Dr J. E. More, Mrs J. Rott and Dr G. E. Chapman (the developers of the Zenalb process) and Mr M. Willner for their communication.
Conflict of interest
The authors are employed past Bio Products Laboratory (BPL), a unit of the National Blood Authority, a special Wellness Authority within the United kingdom of great britain and northern ireland National Health Service. BPL manufactures a range of plasma‐derived products, including human albumin solutions under the registered trade names Zenalb four.5 and Zenalb 20.
Fig i Schematic catamenia diagram comparing traditional methods for the preparation of plasma protein fraction and human albumin solutionone vii fifteen 19 with modern processes which comprise chromatography (Zenalb® BPL and Albumex CSL) and those which are wholly chromatographic (Bergloff). Details of the processes are given in the references cited beneath each procedure.
Fig 1 Schematic flow diagram comparing traditional methods for the preparation of plasma poly peptide fraction and human albumin solution1 7 15 nineteen with modern processes which incorporate chromatography (Zenalb® BPL and Albumex CSL) and those which are wholly chromatographic (Bergloff). Details of the processes are given in the references cited beneath each process.
Fig 2 (a) Comparisons of previous BPL human albumin solution and the Zenalb® product. Concentrations of 4 common plasma protein impurities measured by radial immunodiffusion for the laboratory‐calibration process. α2‐HS = α2‐HS glycoprotein; α1‐AG = αane‐acrid glycoprotein. (b) Some properties of albumin produced at production/pilot batches for previous BPL human albumin solution and Zenalb®. Monomer content was measured by FPLC (Pharmacia) size exclusion chromatography, aluminium content by atomic assimilation spectrometry and endotoxin concentrations past the Limulus amoebocyte lysate analysis.
Fig 2 (a) Comparisons of previous BPL man albumin solution and the Zenalb® production. Concentrations of iv common plasma protein impurities measured by radial immunodiffusion for the laboratory‐scale process. α2‐HS = α2‐HS glycoprotein; α1‐AG = αone‐acid glycoprotein. (b) Some properties of albumin produced at production/pilot batches for previous BPL human albumin solution and Zenalb®. Monomer content was measured past FPLC (Pharmacia) size exclusion chromatography, aluminium content past atomic absorption spectrometry and endotoxin concentrations by the Limulus amoebocyte lysate analysis.
Table 1
Comparison of changes in some of the pharmacopoeial requirements for human albumin over the menstruation 1988–1999. Information derived from the relevant year's pharmacopoeia. IEP = immunoelectrophoresis
| Criterion | BP 1988 | BP 1988 | BP 1993 | BP 1999 | EP 1997 |
| Plasma protein fraction | Human albumin solution | Human albumin solution | Man albumin solution | Human being albumin solution | |
| Source material | Plasma/serum | Plasma/serum/placenta | No change | Plasma | No change |
| Albumin purity | ≥85% | ≥95% | No modify | No alter | No change |
| Albumin concentration | iv–v% | 15–25% | No change | No change | No change |
| 4–5% | No modify | 3.v–five% | No change | ||
| Stabilizer | Octanoate | Octanoate | Octanoate | Octanoate and/or N‐acetyl tryptophan | Octanoate and/or N‐acetyl tryptophan |
| Sterility | Passes text | No alter | No change | No change | No change |
| Antimicrobial agent | None | No change | No change | No alter | No change |
| Pasteurization | 10 h at sixty°C | ten h 60 ± 0.5°C | No change | No change | ≥10 h at 60 ± 0.5°C |
| Sterility check thirty–32°C | Incubate ≥fourteen days | No change | No alter | No modify | No change |
| Sterility cheque 20–25°C | Incubate ≥4 weeks | No change | No alter | No change | No alter |
| Appearance | Clear pale xanthous liquid | Almost colourless or bister | No change | Almost colourless, yellow or dark-green | No modify |
| Man identity (using specific antisera) | Precipitation/IEP. Electrophoretic profile distinct from HAS | Precipitation/IEP. Electrophoretic profile distinct from PPF | Precipitation/IEP. Electrophoretic profile distinct from PPF | Precipitation/IEP | Precipitation/IEP |
| pH | 6.vii–7.3 | No alter | No change | No modify | No modify |
| Alkaline phosphatase activity (u g–1) | ≤0.1 | No change | No change | Not required | No alter |
| Haem content:absorbance at 403 nm, one% solution | ≤0.15 | No change | No change | No change | No change |
| Prekallikrein activator | Non divers | No change | No change | ≤35 iu ml–ane | No change |
| Aggregates | Unretained height ≤x% of total nitrogen content run on dextran gel | Unretained summit ≤v% of total nitrogen content run on dextran gel | No alter | Aggregate peak area/2 ≤5% (HPLC ) | No change |
| Potassium (µmol g–i) | ≤fifty | No change | No change | No change | No change |
| Sodium (mmol litre–1) | ≤160 | No alter | No alter | No change | No change |
| Abnormal toxicity | Pass | No change | No change | Not required | No modify |
| Storage in dark | 5 years ii–eight°C, | No alter | No change | No timescales given | No alter |
| three years ≤25°C | No alter | ||||
| Aluminium (µmol litre–ane) | Non defined | No modify | ≤200 if for utilise in premature infants or for dialysis | No alter | No change |
| Indication of suitability for dialysis and in premature infants | Not stated | Not stated | Stated on label | No modify | No change |
| Origin of albumin | Non stated | Stated on label | No alter | No change | Non stated |
| Pyrogenicity | Test in rabbits; dose iii ml kg–ane body weight | Test in rabbits; dose 3 ml kg–i body weight | Exam in rabbits; dose 3 ml kg–one trunk weight | Test in rabbits; dose 10 ml kg–one (5% product), 3 ml kg–1 (20% product) | No alter |
| Benchmark | BP 1988 | BP 1988 | BP 1993 | BP 1999 | EP 1997 |
| Plasma protein fraction | Man albumin solution | Human albumin solution | Human albumin solution | Human albumin solution | |
| Source material | Plasma/serum | Plasma/serum/placenta | No change | Plasma | No modify |
| Albumin purity | ≥85% | ≥95% | No change | No change | No change |
| Albumin concentration | 4–5% | 15–25% | No alter | No change | No change |
| four–v% | No change | 3.v–5% | No change | ||
| Stabilizer | Octanoate | Octanoate | Octanoate | Octanoate and/or N‐acetyl tryptophan | Octanoate and/or Due north‐acetyl tryptophan |
| Sterility | Passes text | No modify | No change | No modify | No change |
| Antimicrobial agent | None | No change | No modify | No change | No change |
| Pasteurization | 10 h at 60°C | x h 60 ± 0.5°C | No change | No alter | ≥10 h at lx ± 0.5°C |
| Sterility check 30–32°C | Incubate ≥xiv days | No change | No alter | No alter | No change |
| Sterility cheque 20–25°C | Incubate ≥4 weeks | No change | No alter | No modify | No change |
| Appearance | Articulate pale yellowish liquid | Near colourless or amber | No change | Virtually colourless, yellow or green | No change |
| Man identity (using specific antisera) | Atmospheric precipitation/IEP. Electrophoretic profile distinct from HAS | Precipitation/IEP. Electrophoretic profile distinct from PPF | Precipitation/IEP. Electrophoretic profile distinct from PPF | Precipitation/IEP | Atmospheric precipitation/IEP |
| pH | 6.seven–vii.3 | No change | No change | No change | No change |
| Element of group i phosphatase action (u g–1) | ≤0.1 | No modify | No alter | Not required | No change |
| Haem content:absorbance at 403 nm, ane% solution | ≤0.15 | No change | No change | No change | No change |
| Prekallikrein activator | Not defined | No change | No change | ≤35 iu ml–i | No change |
| Aggregates | Unretained elevation ≤10% of full nitrogen content run on dextran gel | Unretained peak ≤5% of total nitrogen content run on dextran gel | No change | Amass height area/two ≤5% (HPLC ) | No alter |
| Potassium (µmol 1000–ane) | ≤fifty | No change | No alter | No alter | No modify |
| Sodium (mmol litre–1) | ≤160 | No modify | No change | No change | No change |
| Abnormal toxicity | Pass | No change | No change | Not required | No alter |
| Storage in dark | 5 years 2–eight°C, | No change | No change | No timescales given | No alter |
| 3 years ≤25°C | No change | ||||
| Aluminium (µmol litre–one) | Not defined | No change | ≤200 if for use in premature infants or for dialysis | No change | No change |
| Indication of suitability for dialysis and in premature infants | Non stated | Not stated | Stated on label | No change | No change |
| Origin of albumin | Not stated | Stated on label | No alter | No change | Not stated |
| Pyrogenicity | Exam in rabbits; dose iii ml kg–ane body weight | Test in rabbits; dose 3 ml kg–1 body weight | Test in rabbits; dose three ml kg–1 torso weight | Test in rabbits; dose ten ml kg–1 (five% product), 3 ml kg–i (xx% product) | No change |
Tabular array 1
Comparison of changes in some of the pharmacopoeial requirements for human being albumin over the period 1988–1999. Data derived from the relevant yr'southward pharmacopoeia. IEP = immunoelectrophoresis
| Benchmark | BP 1988 | BP 1988 | BP 1993 | BP 1999 | EP 1997 |
| Plasma poly peptide fraction | Human being albumin solution | Human albumin solution | Human being albumin solution | Man albumin solution | |
| Source textile | Plasma/serum | Plasma/serum/placenta | No modify | Plasma | No alter |
| Albumin purity | ≥85% | ≥95% | No change | No change | No change |
| Albumin concentration | iv–five% | fifteen–25% | No modify | No change | No change |
| four–5% | No change | three.5–v% | No change | ||
| Stabilizer | Octanoate | Octanoate | Octanoate | Octanoate and/or N‐acetyl tryptophan | Octanoate and/or N‐acetyl tryptophan |
| Sterility | Passes text | No change | No modify | No change | No change |
| Antimicrobial agent | None | No alter | No change | No alter | No change |
| Pasteurization | 10 h at 60°C | x h 60 ± 0.five°C | No change | No alter | ≥10 h at sixty ± 0.5°C |
| Sterility check 30–32°C | Incubate ≥14 days | No change | No change | No change | No alter |
| Sterility check 20–25°C | Incubate ≥4 weeks | No change | No alter | No change | No change |
| Appearance | Clear pale yellow liquid | Almost colourless or bister | No change | Almost colourless, yellow or dark-green | No alter |
| Homo identity (using specific antisera) | Precipitation/IEP. Electrophoretic profile distinct from HAS | Precipitation/IEP. Electrophoretic profile distinct from PPF | Precipitation/IEP. Electrophoretic profile distinct from PPF | Precipitation/IEP | Precipitation/IEP |
| pH | 6.7–7.three | No change | No change | No change | No modify |
| Alkaline phosphatase activity (u g–i) | ≤0.1 | No change | No alter | Not required | No alter |
| Haem content:absorbance at 403 nm, i% solution | ≤0.15 | No change | No change | No change | No alter |
| Prekallikrein activator | Non defined | No change | No change | ≤35 iu ml–1 | No change |
| Aggregates | Unretained superlative ≤10% of full nitrogen content run on dextran gel | Unretained peak ≤v% of total nitrogen content run on dextran gel | No change | Aggregate elevation expanse/2 ≤5% (HPLC ) | No change |
| Potassium (µmol g–ane) | ≤50 | No change | No alter | No alter | No change |
| Sodium (mmol litre–1) | ≤160 | No modify | No change | No change | No change |
| Aberrant toxicity | Pass | No change | No change | Not required | No alter |
| Storage in dark | 5 years two–viii°C, | No change | No change | No timescales given | No change |
| iii years ≤25°C | No change | ||||
| Aluminium (µmol litre–one) | Non divers | No change | ≤200 if for utilise in premature infants or for dialysis | No change | No alter |
| Indication of suitability for dialysis and in premature infants | Not stated | Non stated | Stated on label | No change | No change |
| Origin of albumin | Not stated | Stated on label | No change | No change | Not stated |
| Pyrogenicity | Test in rabbits; dose 3 ml kg–ane body weight | Examination in rabbits; dose 3 ml kg–1 trunk weight | Examination in rabbits; dose three ml kg–ane body weight | Test in rabbits; dose 10 ml kg–one (v% product), 3 ml kg–ane (twenty% production) | No alter |
| Criterion | BP 1988 | BP 1988 | BP 1993 | BP 1999 | EP 1997 |
| Plasma protein fraction | Human albumin solution | Homo albumin solution | Homo albumin solution | Human albumin solution | |
| Source textile | Plasma/serum | Plasma/serum/placenta | No change | Plasma | No modify |
| Albumin purity | ≥85% | ≥95% | No modify | No change | No modify |
| Albumin concentration | four–5% | xv–25% | No change | No modify | No change |
| 4–5% | No alter | 3.5–5% | No modify | ||
| Stabilizer | Octanoate | Octanoate | Octanoate | Octanoate and/or N‐acetyl tryptophan | Octanoate and/or N‐acetyl tryptophan |
| Sterility | Passes text | No change | No change | No change | No alter |
| Antimicrobial agent | None | No change | No alter | No alter | No change |
| Pasteurization | x h at 60°C | 10 h sixty ± 0.5°C | No modify | No change | ≥10 h at 60 ± 0.v°C |
| Sterility cheque xxx–32°C | Incubate ≥xiv days | No alter | No change | No alter | No modify |
| Sterility check 20–25°C | Incubate ≥iv weeks | No change | No modify | No alter | No change |
| Appearance | Clear stake yellow liquid | Almost colourless or amber | No modify | Almost colourless, xanthous or light-green | No change |
| Human being identity (using specific antisera) | Atmospheric precipitation/IEP. Electrophoretic profile distinct from HAS | Precipitation/IEP. Electrophoretic contour distinct from PPF | Precipitation/IEP. Electrophoretic profile distinct from PPF | Atmospheric precipitation/IEP | Precipitation/IEP |
| pH | half dozen.vii–vii.3 | No change | No change | No modify | No modify |
| Alkaline phosphatase activity (u g–1) | ≤0.1 | No change | No modify | Not required | No alter |
| Haem content:absorbance at 403 nm, 1% solution | ≤0.15 | No modify | No change | No change | No alter |
| Prekallikrein activator | Non defined | No alter | No change | ≤35 iu ml–1 | No alter |
| Aggregates | Unretained peak ≤10% of full nitrogen content run on dextran gel | Unretained peak ≤v% of total nitrogen content run on dextran gel | No alter | Aggregate pinnacle area/two ≤five% (HPLC ) | No change |
| Potassium (µmol one thousand–1) | ≤50 | No change | No modify | No change | No modify |
| Sodium (mmol litre–i) | ≤160 | No modify | No change | No change | No change |
| Aberrant toxicity | Pass | No change | No change | Non required | No change |
| Storage in dark | 5 years two–viii°C, | No change | No change | No timescales given | No modify |
| 3 years ≤25°C | No change | ||||
| Aluminium (µmol litre–1) | Not defined | No change | ≤200 if for apply in premature infants or for dialysis | No change | No change |
| Indication of suitability for dialysis and in premature infants | Not stated | Not stated | Stated on label | No alter | No alter |
| Origin of albumin | Not stated | Stated on characterization | No change | No change | Non stated |
| Pyrogenicity | Exam in rabbits; dose 3 ml kg–1 torso weight | Examination in rabbits; dose 3 ml kg–1 body weight | Test in rabbits; dose three ml kg–ane body weight | Test in rabbits; dose ten ml kg–one (v% production), 3 ml kg–1 (20% product) | No alter |
Table 2
Summary of spontaneous adverse reaction reports for human albumin solution (HAS) received past the BPL Medical Department (1993–1997). *Serious adverse reactions include fatal or life‐threatening reactions, or crusade persistent or significant disability/incapacity, or result in or prolong hospitalization, or lead to congenital anomalies or birth defects. **One infusion estimated as 500 ml of 4.5% HAS or 100 ml of 20% HAS
| Severity of adverse reactions | Body organization | Homo albumin solution 4.5% | Human albumin solution xx% | ||
| No. of symptoms | No. of patients | No. of symptoms | No. of patients | ||
| Non‐serious* | Cardiac | ix | 8 | 0 | 0 |
| Dermatological | 2 | ii | i | 1 | |
| Gastrointestinal | 2 | ii | 0 | 0 | |
| General | 23 | xi | 1 | i | |
| Musculoskeletal | 1 | one | 0 | 0 | |
| Neurological | 4 | 3 | 0 | 0 | |
| Respiratory | 3 | 3 | 0 | 0 | |
| Vascular | 8 | 8 | 0 | 0 | |
| Subtotal | 52 | 17 | ii | 1 | |
| Serious* | Cardiac | 0 | 0 | 4 | 2 |
| Dermatological | one | 1 | 0 | 0 | |
| Gastrointestinal | 3 | ii | 0 | 0 | |
| General | ten | iv | 1 | 1 | |
| Neurological | 2 | 1 | 1 | 1 | |
| Respiratory | 0 | 0 | 7 | 4 | |
| Vascular | 2 | 2 | 2 | one | |
| Subtotal | xviii | 5 | 15 | iv | |
| Grand total | seventy | 22 | 17 | 5 | |
| Total book of albumin issued (litres) | 602 000 | 133 000 | |||
| Approximate number of infusions** | i 204 000 | 1 330 000 | |||
| Total number of reported agin reactions | 70 | 17 | |||
| Incidence of agin reactions per infusion | 1:17 200 | 1:78 200 | |||
| Severity of adverse reactions | Trunk system | Human being albumin solution 4.v% | Human albumin solution 20% | ||
| No. of symptoms | No. of patients | No. of symptoms | No. of patients | ||
| Non‐serious* | Cardiac | nine | 8 | 0 | 0 |
| Dermatological | 2 | 2 | one | 1 | |
| Gastrointestinal | 2 | 2 | 0 | 0 | |
| General | 23 | 11 | i | 1 | |
| Musculoskeletal | one | 1 | 0 | 0 | |
| Neurological | 4 | iii | 0 | 0 | |
| Respiratory | 3 | 3 | 0 | 0 | |
| Vascular | 8 | 8 | 0 | 0 | |
| Subtotal | 52 | 17 | 2 | 1 | |
| Serious* | Cardiac | 0 | 0 | 4 | 2 |
| Dermatological | 1 | 1 | 0 | 0 | |
| Gastrointestinal | 3 | 2 | 0 | 0 | |
| General | ten | 4 | 1 | 1 | |
| Neurological | 2 | 1 | one | ane | |
| Respiratory | 0 | 0 | vii | 4 | |
| Vascular | ii | two | two | one | |
| Subtotal | 18 | five | 15 | 4 | |
| Grand total | seventy | 22 | 17 | v | |
| Total volume of albumin issued (litres) | 602 000 | 133 000 | |||
| Approximate number of infusions** | one 204 000 | one 330 000 | |||
| Total number of reported agin reactions | 70 | 17 | |||
| Incidence of adverse reactions per infusion | 1:17 200 | 1:78 200 | |||
Table 2
Summary of spontaneous agin reaction reports for human albumin solution (HAS) received by the BPL Medical Department (1993–1997). *Serious agin reactions include fatal or life‐threatening reactions, or cause persistent or significant disability/incapacity, or result in or prolong hospitalization, or lead to built anomalies or nascence defects. **One infusion estimated as 500 ml of iv.five% HAS or 100 ml of 20% HAS
| Severity of adverse reactions | Body arrangement | Human albumin solution 4.5% | Human being albumin solution 20% | ||
| No. of symptoms | No. of patients | No. of symptoms | No. of patients | ||
| Non‐serious* | Cardiac | 9 | eight | 0 | 0 |
| Dermatological | 2 | 2 | 1 | i | |
| Gastrointestinal | two | two | 0 | 0 | |
| General | 23 | 11 | one | ane | |
| Musculoskeletal | 1 | 1 | 0 | 0 | |
| Neurological | 4 | 3 | 0 | 0 | |
| Respiratory | three | 3 | 0 | 0 | |
| Vascular | 8 | 8 | 0 | 0 | |
| Subtotal | 52 | 17 | ii | ane | |
| Serious* | Cardiac | 0 | 0 | 4 | two |
| Dermatological | 1 | i | 0 | 0 | |
| Gastrointestinal | 3 | 2 | 0 | 0 | |
| General | x | 4 | 1 | 1 | |
| Neurological | two | 1 | 1 | 1 | |
| Respiratory | 0 | 0 | 7 | iv | |
| Vascular | 2 | 2 | two | 1 | |
| Subtotal | 18 | 5 | 15 | four | |
| Grand total | 70 | 22 | 17 | five | |
| Total volume of albumin issued (litres) | 602 000 | 133 000 | |||
| Guess number of infusions** | 1 204 000 | one 330 000 | |||
| Total number of reported adverse reactions | 70 | 17 | |||
| Incidence of adverse reactions per infusion | 1:17 200 | 1:78 200 | |||
| Severity of adverse reactions | Body system | Homo albumin solution four.5% | Homo albumin solution twenty% | ||
| No. of symptoms | No. of patients | No. of symptoms | No. of patients | ||
| Non‐serious* | Cardiac | 9 | 8 | 0 | 0 |
| Dermatological | 2 | ii | 1 | 1 | |
| Gastrointestinal | 2 | ii | 0 | 0 | |
| General | 23 | 11 | i | ane | |
| Musculoskeletal | 1 | i | 0 | 0 | |
| Neurological | 4 | 3 | 0 | 0 | |
| Respiratory | 3 | 3 | 0 | 0 | |
| Vascular | 8 | 8 | 0 | 0 | |
| Subtotal | 52 | 17 | two | 1 | |
| Serious* | Cardiac | 0 | 0 | 4 | 2 |
| Dermatological | ane | 1 | 0 | 0 | |
| Gastrointestinal | 3 | two | 0 | 0 | |
| General | ten | 4 | 1 | ane | |
| Neurological | 2 | ane | i | one | |
| Respiratory | 0 | 0 | 7 | iv | |
| Vascular | ii | 2 | two | 1 | |
| Subtotal | 18 | 5 | 15 | 4 | |
| M total | 70 | 22 | 17 | five | |
| Total volume of albumin issued (litres) | 602 000 | 133 000 | |||
| Gauge number of infusions** | one 204 000 | 1 330 000 | |||
| Total number of reported adverse reactions | 70 | 17 | |||
| Incidence of agin reactions per infusion | 1:17 200 | ane:78 200 | |||
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