An iterative design of experiments (DOE) approach has traditionally been used to perform lyophilization cycle development at small and manufacturing scales.
Unfortunately, this is resource-intensive and needs large amounts of material that can make it prohibitively expensive, particularly on a commercial scale. This often prevents the use of screening experiments required to identify the optimal cycle parameters with large volumes.
An alternative to resource-intensive DOEs is using mathematical models to understand and optimize cycle parameters. However, while the availability of models is not new, and a number have been developed for the critical primary drying phase of a lyophilization cycle, their adoption as a viable alternative for scaled experimentation is relatively new in the pharmaceutical industry.
This is why BioPhorum has generated a practical paper titled Application of First Principles Primary Drying Model to Lyophilization Process Design and Transfer: Case Studies from the Industry, to demonstrate for the first time how modelling can be applied in commercial biopharmaceutical production.
The paper acts as a pathway to share the collective knowledge of industry models and accelerate their adoption. Written by BioPhorum’s Lyophilization Workstream, the paper is supported by detailed tabular and graphical data, and includes a spreadsheet tool that presents fresh examples to introduce the process of modeling the primary drying phase.
Reducing the burdens
The model described in the paper provides a greater understanding of a primary drying process and shows how to reduce some of the significant cost and resource burdens associated with multiple commercial-scale trials. The model can enable faster product development, deviation analysis and efficient technology transfer activities.
The paper’s case studies highlight the tangible benefits that companies have already realized. They also demonstrate the robustness and flexibility of the model in predicting the primary drying parameters in completely different settings, such as formulations, equipment, primary containers, etc. The case studies cover:
- The use of a primary drying model to predict and optimize a late-stage lyophilization process
- Using a model to predict cycle parameters during scale-up from lab to commercial scale lyophilizers
- The use of a model to analyze the effect of a pressure deviation on product quality during commercial scale operations and generate design space
- Application of the lyophilization model in assessing the change of process conditions during biologics drug product manufacturing
- Using a model to assess the impact of vial size.
Published in the Journal of Pharmaceutical Sciences, the paper builds on a previous BioPhorum presentation called An Industry Perspective on the Application of Modeling to Lyophilization Process Scale-up and Transfer. This highlighted the benefits of a model-based understanding of the primary drying process in various pharmaceutical settings and at different stages of development, technology transfer and manufacturing. Applying modeling to lyophilization process design requires generating inputs (e.g. vial heat transfer coefficients) that are essential for the model’s accuracy. However, to gain the most benefit, industry should use a standard methodology and principles to generate those inputs. BioPhorum’s paper shows that the systematic presentation of inputs in a commonly accepted format, and its link to actual examples of applying the model, can help readers understand and accept a modeling approach for routine lyophilization process development.