Preformulation Studies and Thermal Assessment

The first step in lyophilization cycle development for a freeze-dried product is essentially understanding of bulk formulation solution thermal properties. The amorphous or crystalline nature of the bulk solution during the freezing stage must be critically characterized in order to define appropriate drying parameters of shelf temperatures, soak and ramps, chamber pressures, and duration of all the phases.

To achieve this, some critical temperatures should be accurately determined: freezing temperature, glass transition temperatures, and the eutectic and collapse temperatures. Based upon these fundamental properties, operational parameters are established during experimental phase and optimized over the development phase.

Kamat Pharmatech houses highly sophisticated instruments such as Differential scanning calorimetry and Freeze-drying microscopy to characterize the thermal properties of the bulk solution destined for lyophilization.

Cycle Design and Optimization

A freeze-drying cycle essentially consists of three distinct phases:

• Freezing of the solution
• Primary drying or sublimation
• Secondary drying

Loading of the filled vials in the chamber, maintenance of vacuum throughout the drying phases, supply of refrigeration during freezing and heat during the drying phases, and completion of the drying cycle by stoppering the dried vials and unloading them out of chamber are some other required actions. For a systematic approach to the development of a suitable freeze-dried product, knowledge of the various stages of the process is necessary.

The target freeze drying process must deliver dry product that is safe, stable, and efficacious. That is, the process must ensure acceptable product quality attributes, such as low residual water content, short reconstitution time, and retention of potency, as well as exhibit pharmaceutical elegance. Since freeze drying is a costly and time intensive process, from an operational point of view, the process should be short, reproducible, and robust. An optimized process that operates within the constraints of the equipment, plant utilities, and appropriate safety margins should be the goal.

With multiple freeze dryers in the laboratories, KAMAT has the capability and experience of developing very efficient and optimum cycles that are operationally viable and cost-effective.

Quality by Design

Complete formulation characterization and robust lyophilization process development that is scalable and site-independent is essential part of the development process. Moreover, QbD principles for freeze-drying process design and development are absolutely essential and several tools must be used to monitor and control the freeze-drying process in real time so that the quality can be built within the process rather than monitoring offline at the end of the process.

The application of quality by design in pharmaceutical product development is now mandated by the US-FDA, ICH and other worldwide regulatory authorities. Inclusion of QbD related considerations are now part of the new question-based review of the chemistry, manufacturing, and controls section of regulatory submissions and when implemented, lead to a successful product development, subsequent prompt regulatory approval, reduce exhaustive validation burden, and significantly reduce post-approval changes. The key elements of QbD viz., target product quality profile, critical quality attributes, risk assessments, design space, control strategy, product lifecycle management, and continual improvement are the necessary elements during the development phase and KAMAT knows how to successfully address these elements in developing the lyophilization process.

Scale-Up to Manufacturing Site

A successful technology transfer ensures the quality of product during the entire life cycle of manufacture and validation, in accordance with current good manufacturing practices, providing predictable and consistent operation of the processes. TT based on the principles of Food and Drug Administration International Conference on Harmonization Q8, Q9, Q10, Q11 guidelines, involves knowledge transfer, science and risk-based approaches, and efficient processes transfer, which ensure a comprehensive and systematic transfer of information and documentation between transferring site and receiving site.

Kamat Pharmatech has extensive experience in successful scale-up and transfer of many injectable products.