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In vitro evaluation of B-domain deleted recombinant factor VIII (ReFacto) stability during simulated continuous
E Neidhardt1, R Koval, E Burke
1Wyeth BioPharma, Drug Product Development, Andover, MA 01810, USA. eneidhardt@wyeth.com
Summary
Continuous infusion of factor VIII (FVIII) is effective for severe bleeding. ReFacto, a recombinant FVIII, shows stability in PVC bags and infusion pumps, with minimal binding issues for safe delivery.
Area of Science:
- Pharmacology
- Biochemistry
- Materials Science
Background:
- Continuous infusion (CI) of factor VIII (FVIII) offers pharmacokinetic and economic advantages over bolus infusions for managing severe hemorrhage and during major surgery.
- Successful CI of FVIII requires understanding product stability under prolonged exposure to delivery devices at ambient temperatures and low concentrations.
- Recombinant human B-domain deleted FVIII (ReFacto) is a potential candidate for CI, necessitating stability and compatibility assessments.
Purpose of the Study:
- To assess the stability and delivery compatibility of ReFacto under conditions relevant to continuous infusion.
- To identify optimal conditions for ReFacto administration via large volume parenteral polyvinyl chloride (PVC) bags and ambulatory infusion pumps.
- To evaluate potential adsorptive losses of ReFacto to delivery system components.
Main Methods:
- Stability studies of ReFacto in PVC reservoirs at varying concentrations (3, 8, and 62 IU mL(-1)).
- Assessment of ReFacto stability and binding in ambulatory infusion pumps (CADD pumps).
- Investigation of factors influencing ReFacto binding to administration sets, including ionic strength, residence time, and protein concentration.
Main Results:
- ReFacto demonstrated stability for 36 hours in PVC reservoirs at 3 and 8 IU mL(-1) and for 72 hours when undiluted (62 IU mL(-1)) in CADD infusion pumps.
- No significant binding of ReFacto to PVC reservoirs was observed over time.
- Appreciable binding of ReFacto to administration sets occurred under specific conditions, influenced by ionic strength, residence time, and protein concentration.
Conclusions:
- ReFacto can be successfully delivered via CI using PVC bags without stabilizers or as an undiluted preparation via ambulatory infusion pumps.
- While ReFacto exhibits favorable stability and minimal binding to PVC, careful consideration of administration set material and conditions is necessary to mitigate adsorptive losses.
- The recovery and stability profile of ReFacto under tested CI conditions appear promising compared to full-length recombinant FVIII products.