(171f) Rapid Process Development - Bridging the Gap from Early Formulation Design to Integrated Continuous Drug Product Manufacture for a Dry Granulation Process

Authors: 
Dinarello, E., Vertex Pharmaceuticals
O'Mahony, M., Vertex Pharmaceuticals
Dale, S., Vertex Pharmaceuticals
Connelly, G., Vertex Pharmaceuticals
The adoption of integrated continuous manufacturing platforms has been pioneered in both academic and industrial environments in recent years.1 The primary drivers for the adaption of integrated continuous drug product manufacture include: reduced processing time, reduced capital and operating costs, minimized scale-up risks, more consistent process control achieved via automation and opportunities for rapid process development.2,3 Where the drug product is an oral solid dosage form, continuous tablet manufacture is made possible by a defined sequence unit operations that operate continuously – e.g. continuous powder feeding, continuous powder blending, continuous granulation, milling, tablet compression and coating. Ensuring the integrated operation of such unit operations is critical to the successful implementation of a continuously manufactured drug product.

Early formulation design and development is often performed on a small scale where discrete unit operations that are either performed in batch mode or inherently continuous in their operation (e.g. tablet compression, roller compaction, etc.) are used to produce the product. Significant effort is required to translate these non-integrated unit operations to integrated continuous unit operations working in concert in order to produce the final product for commercial manufacture.

In this work, we present the necessary workflow highlighting considerations and efforts needed to transfer the knowledge from early formulation design through to a fully integrated continuous dry granulation process, specifically, excipient and API powder through to coated tablets. The continuous dry granulation process is described. The methods used for non-integrated testing of unit operations are outlined. The connection between non-integrated testing and measurement and the selection of appropriate process parameters is discussed. Product control strategy and residence time distribution measurements are highlighted. Early considerations for the generation of a desired manufacturing range in line with critical quality attributes are also discussed. A process workflow is generated that provides a means for rapid process development from early formulation design to Integrated Continuous Drug Product Manufacture for a Dry Granulation Process.

References

1-Moghtadernejad, S. et al. A Training on: Continuous Manufacturing (Direct Compaction) of Solid Dose Pharmaceutical Products. Journal of Pharmaceutical Innovation 13, 155-187, doi:10.1007/s12247-018-9313-5 (2018).

2-Teżyk, M., Milanowski, B., Ernst, A. & Lulek, J. Recent progress in continuous and semi-continuous processing of solid oral dosage forms: a review. Drug Development and Industrial Pharmacy 42, 1195-1214, doi:10.3109/03639045.2015.1122607 (2016).

3-Byrn, S. et al. Achieving Continuous Manufacturing for Final Dosage Formation: Challenges and How to Meet Them May 20–21 2014 Continuous Manufacturing Symposium. J. Pharm. Sci. 104, 792-802, doi:http://dx.doi.org/10.1002/jps.24247 (2015).