caa a22 4500 477126308 CHVBK 20180405111650.0 cr unu---uuuuu 170330e19970701xx s 000 0 eng 10.1023/A:1012199816852 doi (NATIONALLICENCE)springer-10.1023/A:1012199816852 Development of a Freeze-Dried Albumin-Free Formulation of Recombinant Factor VIII SQ [Elektronische Daten] [Thomas Österberg, Angelica Fatouros, Marianne Mikaelsson] Purpose. To develop a stable freeze-dried formulation of recombinant factor VIII-SQ (r-VIII SQ) without the addition of albumin. Methods. Different formulations were evaluated for their protective effect during sterile filtration, freeze-thawing, freeze-drying, reconstitution and long term storage. Factor VIII activity (VIII:C), visual inspection, clarity, solubility, moisture content and soluble aggregates and/or fragments were assayed. Results. A combination of non-crystallising excipients (L-histidine and sucrose), a non-ionic surfactant (polysorbate 80) and a crystalline bulking agent (sodium chloride) was found to preserve the factor VIII activity during formulation, freeze-drying and storage. Calcium chloride was included to prevent dissociation of the heavy and light chains of r-VIII SQ. Sodium chloride was chosen as the primary bulking agent since the concentration of sodium chloride necessary for dissolution of r-VIII SQ in the buffer will inhibit the crystallization of many potential cake formers. It was found that L-histidine, besides functioning as a buffer, also protected r-VIII SQ during freeze-drying and storage. A pH close to 7 was found to be optimal. Some potential macromolecular stabilisers, PEG 4000, Haes®-steril and Haemaccel®, were evaluated but they did not improve the recovery of VII:C. The freeze-dried formulation was stable for at least two years at 7°C and for at least one year at 25°C. The reconstituted solution was stable for at least 100 hours at 25°C. Conclusions. The albumin-free formulation resulted in consistently high recovery of VII:C, very low aggregate formation and good storage stability. The stability of the reconstituted solution makes the formulation suitable for continuous administration via infusion pump. The formulation strategy described here may also be useful for other proteins which require a high ionic strength. Plenum Publishing Corporation, 1997 freeze-dried nationallicence protein stability nationallicence factor VIII nationallicence formulation nationallicence surface adsorption nationallicence Österberg Thomas Department of Pharmaceutical Technology, Pharmacia & Upjohn AB, S-112 87, Stockholm, Sweden aut Fatouros Angelica Department of Pharmaceutical Technology, Pharmacia & Upjohn AB, S-112 87, Stockholm, Sweden aut Mikaelsson Marianne Pharmaceutical and Analytical R&D, Astra Pain Control AB, S-151 85, Södertälje, Sweden aut Pharmaceutical Research Kluwer Academic Publishers-Plenum Publishers 14/7(1997-07-01), 892-898 0724-8741 14:7<892 1997 14 11095 https://doi.org/10.1023/A:1012199816852 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1023/A:1012199816852 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Österberg Thomas Department of Pharmaceutical Technology, Pharmacia & Upjohn AB, S-112 87, Stockholm, Sweden aut NATIONALLICENCE 700 1- Fatouros Angelica Department of Pharmaceutical Technology, Pharmacia & Upjohn AB, S-112 87, Stockholm, Sweden aut NATIONALLICENCE 700 1- Mikaelsson Marianne Pharmaceutical and Analytical R&D, Astra Pain Control AB, S-151 85, Södertälje, Sweden aut NATIONALLICENCE 773 0- Pharmaceutical Research Kluwer Academic Publishers-Plenum Publishers 14/7(1997-07-01), 892-898 0724-8741 14:7<892 1997 14 11095 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer