Freeze-drying and quality evaluation of protein drugs.
Gamma interferon from genetic recombination (IFN) has been found to have an optimal pH at about 7. An increase in IFN concentration may cause a decrease in solution clarity. A proper selection of isotonizing agent, as well as the addition of sugars, is effective in improving the clarity. The amount of IFN adsorbed on filter membranes varies with the membrane materials: cellulose acetate adsorbs much IFN, 2-fluorovinylidene is the next, followed by polysulfon, and polycarbonate adsorbs it least of all materials tested. Stainless steel adsorbs little IFN, and the level can be lowered even more by electropolishing. Silicone coating can decrease the amount adsorbed to about 1 microgram per vial of 10 ml. The effect of pressure given to the IFN solution during filtration is negligible. Transfer of IFN solution through pipings of conventional shape may result in partial deactivation by bubbling. At around pH 7, a lower pH of IFN solution causes a higher moisture level of the freeze-dried product. Moisture levels up to 3% have no effect on IFN stability. Upon reconstitution of freeze-dried IFN by vigorous shaking with distilled water, filtration of the solution may become difficult because polymers might have been formed during vigorous shaking. The addition of L-cysteine, maltose, and human serum albumin, has been found to be as effective in preventing such unfavorable reactions. Fatty acids in human serum albumin, which is effective in stabilizing IFN, has been found to participate in preventing denaturation of human serum albumin upon freezing and freeze-drying; however, the denaturation prevention mechanisms are not clear yet.
Inazu
K
K
Production Department, Shionogi & Co., Ltd., Hyogo, Japan.
Shima
K
K
D002626:Chemistry, Pharmaceutical; D004355:Drug Stability; D005227:Fatty Acids; D005612:Freeze Drying / Q000379:methods* / Q000592:standards; D005615:Freezing; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007371:Interferon-gamma / Q000302:isolation & purification; D008855:Microscopy, Electron, Scanning; D011489:Protein Denaturation; D011506:Proteins / Q000302:isolation & purification* / Q000592:standards; D011786:Quality Control; D011994:Recombinant Proteins; D012709:Serum Albumin / Q000302:isolation & purification; D014867:Water / Q000032:analysis
D005227:Fatty Acids; D011506:Proteins; D011994:Recombinant Proteins; D012709:Serum Albumin; D014867:Water; D007371:Interferon-gamma