Quality by Design (QbD) in process development and manufacturing
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A sound manufacturing process is key to ensure that the commercial product consistently delivers the intended performance of the pharmaceutical product.  ICH [Q8(R2)] defines Quality by Design (QbD) as a systematic approach to product and process development that begins with predefined objectives, enhances product and process understanding and process control and is based on sound science and quality risk management.

 

Essential to achieve these objectives is experimentation, typically comprising of the following phases:

  • - the screening phase explores the effects of a large number of variables with the objective of identifying a smaller number of parameters to study further in characterization or optimization experiments
  • - the characterization phase focuses on understanding the system by estimating interactions as well as linear effects (i.e. how the variables interact with each other, and how to measure the effects of the variables individually)
  • - the optimization phase where a predictive model is developed for the system which can be used to find important operating conditions (design space)

Crystallics utilizes small scale parallel crystallization equipment, such as the Crystal16® and Crystalline®, in the experimental part of the QbD framework. Crystal16® is used to determine metastable zone widths and to assess the solubility profiles of the API and impurities.  This analysis provides valuable information on the use of various solvents, for instance, for cake wash, vessel wash, purification and crystallization.

 

Crystalline®, with its optical cameras, allows for real-time crystallization observations and simulation of cooling and/or by anti-solvent addition crystallization or salt formation under various conditions. The material obtained from those experiments is characterized for the nature of the solid form (XRPD, DSC, TGMS, FTIR), purity (HPLC), particle size distribution (Malvern), creating the data for the subsequent statistical analysis. Once the important crystallization variables have been determined, MultiMax® is used for confirmation experiments and for a better understanding of the particle size distribution evolution.

 

The advantage of having a systematic approach at small scale, to understand the crystallization process is obvious for cost and time reasons.