Quartz Crystal Microbalance as a Predictive Tool for Drug-Material of Construction Interactions in Intravenous Protein Drug Administration.

As a growing number of protein drug products are developed, formulation characterization is becoming important. An IgG drug product is tested at concentrations from 0.0001-0.1 mg/mL for adsorption behavior to polymer surfaces polyvinyl chloride (PVC) and polypropylene (PP) upon dilution in normal saline (NS) using quartz crystal microbalance with dissipation (QCM-D). The studies mimicked IgG antibody interaction during IV administration with polymeric surfaces within syringes, lines, and bags. Drug product was characterized with excipients, with focus on surfactant. Drug solutions were run over polymer-coated sensors to measure the adsorption behavior of the formulation with emphasis on the behavior of each of the formulation's components. Over 60 sensorgram data sets were correlated with assayed protein solution concentrations in mock NS-diluted infusions of drug product in the equivalent concentrations to QCM experiments to build a preliminary predictive model for determining fraction of drug and surfactant adsorbed and lost at the hydrophobic surface during administration. These results create a method for reliably and predictively estimating drug product adsorption behavior and protein drug dose loss on polymers at different protein drug concentrations.

An Industry Perspective on Compatibility Assessment of Closed System Drug-Transfer Devices for Biologics.

The Formulation Workstream of the BioPhorum Development Group (BPDG), an industry-wide consortium, has identified the increased use of closed system drug-transfer devices (CSTDs) with biologics, without an associated compatibility assessment, to be of significant concern. The use of CSTDs has increased significantly in recent years due to the recommendations by NIOSH and USP that they be used during preparation and administration of hazardous drugs. While CSTDs are valuable in the healthcare setting to reduce occupational exposure to hazardous compounds, these devices may present particular risks that must be adequately assessed prior to use to ensure their compatibility with specific types of drug products, such as biologic drugs, which may be sensitive. The responsibility of ensuring quality of biologic products through preparation and administration to the patient lies with the drug product sponsor. Due to the significant number of marketed CSTD systems, and the large variety of components offered for each system, a strategic, risk-based approach to assessing compatibility is recommended herein. In addition to traditional material compatibility, assessment of CSTD compatibility with biologics should consider additional parameters to address specific CSTD-related risks. The BPDG Formulation Workstream has proposed a systematic risk-based evaluation approach as well as a mitigation strategy for establishing suitability of CSTDs for use.

Preparation and evaluation of sustained release infliximab microspheres.

A sustained release microsphere system for an antibody (infliximab, molecular weight: 140 Kd) was formulated with PLGA 50:50 co-polymer using two methods of preparation: phase separation technique and double emulsion technique. Microspheres were made in triplicate using each technique and varying drug-to-polymer ratios. Drug-to-polymer ratio was maintained at 1:5, 1:10, or 1:20. In vitro release profile of infliximab was studied in phosphate-buffered saline solution at 37 °C. The release profile and encapsulation efficiency was compared between the two methods of preparation. The releases data was modeled by the sum of squares method to isolate the dominant release mechanism. The physical attributes of the microspheres prepared were characterized. The biochemical characteristics of infliximab before and after encapsulation were also evaluated by several analytical techniques such as size exclusion chromatography, isoelectric focusing, and sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Biological activity of infliximab was also evaluated before and after encapsulation. The phase separation technique showed much higher entrapment efficiency than the double emulsion technique. Microspheres prepared using the double emulsion technique showed a longer release profile (∼5 days) compared to microspheres prepared using the phase separation technique (∼72 h). Physical and biochemical properties of infliximab did not change significantly after encapsulation into microspheres with either methods of preparation. Microspheres prepared using phase separation showed some loss in bioactivity. Based on this research it can be concluded that the microspheres can present an alternative delivery method for infliximab. LAY ABSTRACT: A sustained release microsphere system for an antibody (infliximab, molecular weight: 140 Kd) was formulated using polymers. This antibody is currently in the market for rheumatoid arthritis among various indications. Microspheres were made in triplicate using two techniques and varying drug-to-polymer ratios. Drug-to-polymer ratio was maintained at 1:5, 1:10, or 1:20. The release of drug from microsphere was studied. Biochemical properties of microspheres were also studied before and after encapsulation in microspheres. Various analytical techniques were used to study the biochemical properties of infliximab to ensure that it would be efficacious and safe after encapsulation. Sustained release of drug was observed from the microspheres. Infliximab showed no change in biochemical properties and also showed bioactivity. Based on this research it can be concluded that the microspheres can present an alternative delivery method for infliximab that is safe and efficacious and my result in cost savings for patients.