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Pre-formulation Research

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Creative Biolabs can provide pre-formulation research through our CreDA™ developability assessment platform to address several important aspects of the formulation, including concentration, solubility, viscosity, and accelerated stability, for the drug candidate selection.

Therapy biologics, especially monoclonal antibodies, often require single doses of several mg/kg, with intravenous injection or infusion being the preferred administration routes. Most diseases, which are treated with antibody-based pharmaceuticals, are chronic and require continuous therapy. With regard to patient convenience and healthcare costs, it would be of great benefit if these drugs could be self-administered through subcutaneous/intramuscular injection by the patient, which would reduce the frequency of medical interventions by a physician or at a hospital. Thus, the availability of highly concentrated antibody solutions (above 100 mg/mL) that can be administered by the intramuscular/subcutaneous injection routes is essential. And the development of corresponding formulations is becoming a major focus during the developability assessment campaign.

Pre-formulation research of the drug candidates Fig.1 Pre-formulation research of the drug candidates.

Concentration/solubility

Concentration experiments are performed by formulating the protein in the desired buffer and concentrating the samples stepwise using ultrafiltration devices. During the process, the aggregation level and the appearance of precipitate or phase separation are monitored by visual inspection and by assessing the sample turbidity with visible spectroscopy or other dedicated devices. The solubility of a candidate is determined at a protein concentration of typically 100 mg/mL in a pH range between 4.0 and 8.0. The solution is incubated for several days, and solubility assessed by measuring turbidity and UV absorption.

Viscosity

Drug candidates with high viscosity are undesirable since they may be difficult to operate with a syringe, requiring a larger needle gauge, ultimately increasing the discomfort of the patient. Thus, a lower viscosity value is required for biologics to ensure the injectability. Generally, protein viscosity is mainly determined in a capillary rheometer at high concentrations (e.g. 150 mg/mL). If only restricted quantities of the candidate at low concentrations (1~10 mg/mL) are available, the viscosity could be determined by measuring colloidal stability through dynamic light scattering (DLS), due to the fact that DLS results at low concentration and rheometry at high concentrations were found to be well correlated.

Accelerated stability

In the pre-formulation assessment, the stability of the candidates is tested under thermal and mechanical stress, and for long time periods. Candidate solutions at high protein concentrations under different pH values, with and without excipients like sucrose and arginine, are prepared. To assess the thermal stability, the samples are incubated at 25°C and 40°C for several weeks. Mechanical stress is applied by freeze-thawing or by shaking the solutions. For long-term stability evaluation, data generated from samples stored for several weeks are taken into account for assessment and selection of the lead candidate. The determination of aggregation, heterogeneity, and chemical modifications after stress conditions uses methods such as size exclusion chromatography (SEC), capillary zone electrophoresis (CZE), dynamic light scattering (DLS), and turbidity measurements.

Creative Biolabs is experienced in pre-formulation assessment, and if you are interested in this service, please contact us for more information and a detailed quote.




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