Drug product development includes bulk drug product formulation, development of the final dosage form and process and fill-finish. The outputs generated during preformulation characterization—solubility and stability parameters and the target pH range—inform the formulation boundaries within which the optimal drug product composition will be determined. The drug product formulation is optimized in a series of experiments, typically using the Design of Experiment (DOE) approach, although discrete studies may also be conducted as appropriate, and the resulting samples are assessed under accelerated stress conditions to select the most stable formulations with sufficient solubility. Pace Life Sciences Boston, MA development site assesses liquid and lyophilized formulations to enable informed decision-making and prevent loss of time if one of the strategies proves unsuccessful.
Pace develops the final drug product formulation and the process in parallel and in an iterative manner. Once both are established, the team characterizes the processes for manufacture of the bulk formulation and of the final dosage form for scale up and robustness, and transfers these to the manufacturing facility. Lastly, the manufactured materials are tested for release under GMP and placed on long-term GMP stability to support clinical trials and commercialization. Analytical methods, which are optimized and validated at the stage-appropriate time, support the formulation development and GMP testing activities.
The vehicles used are typically fairly simple, and the components are summarized in the following table.
Vehicle components typically evaluated
pH control for solubility and stability
Ionic strength modifier
Isotonicity and stability of the drug substance
Prevent aggregation and increase solubility
Stability and improved appearance of lyophilized product
Antioxidants, cryoprotectants, etc. to improve stability in solution and/or lyophilized product
Accelerated stability testing is used to differentiate prototype formulations with respect to stability and thus help define the optimal formulation composition. The manufacturing process may involve long-term storage of the bulk final formulation at either -20°C or -80°C; therefore, Pace Life Sciences assesses frozen and freeze/thaw stability of prototype formulations as part of the formulation optimization. This testing also provides an opportunity to evaluate storage container compatibility and photostability.
Lyophilization Process Development
Solution stability is a common issue, so final dosage forms are frequently lyophilized products. Lyophilization improves the stability, may enable storage at ambient conditions and simplifies preparation of the administrable dosage form. Development of the lyophilization process requires a thorough characterization of the drug substance and lyophilates and is performed in an iterative manner in parallel with formulation development.
Pace Life Sciences Boston, MA development site designs lyophilization cycles based on the thermal properties of the drug substance, the stability data and the formulation composition. The formulation composition impacts the development of the lyophilization cycle in that different materials require different temperatures, sublimation rates, and processing steps and duration. As reconstitution of the drug product is a key evaluation parameter, the speed and reproducibility of reconstitution will be assessed throughout process development. Various reconstitution media may be evaluated. Lyophilization process development also includes the selection of the appropriate container/closure system. Pace conducts compatibility studies with the selected container/closure system(s) on selection of final formulation and process parameters.
Pace optimizes the lyophilization process using the DOE approach, based on the observations of the preliminary lyophilization runs and the formulation optimization results. Variables that affect the process, and thus the quality and stability of the resultant lyophilate, are the temperature and duration of the steps in the lyophilization cycle, as well as the temperature of the sample solution. The vehicle may be re-evaluated. Typical factors that are investigated during the process optimization stage are solution temperature and treatment prior to lyophilization, time and temperature of lyophilization cycle steps, and the impact of moisture content on product stability. The ideal range for moisture content must be determined and maintained during storage to prevent degradation, particularly for formulations without stabilizers. Based on these results, Pace optimizes the freezing, annealing, primary drying and secondary drying process parameters and establishes operational parameters for technology transfer to the manufacturing facility.