Understanding Design Space
Quality by design (QbD) assures in vitro product performance which implies an assurance of in vivo product performance. As part of the QbD approach, a systematic methodology to development is applied beginning with predefined objectives and emphasizes product and process understanding. This is supported by scientific knowledge and quality risk management to establish a design space with defined sets of operating variables needed to maintain batch consistency. These are represented graphically as multi-dimensional points in relation to equipment limitation and critical product attributes (Fig 1A). It is common for an inner area of the design space to be designated as the nominal manufacturing conditions (operating space). Operation within the design space will result in a product meeting a predefined quality. Having a larger design space or parameters in which to work increases the probability of executing a successful cycle, even in the face of potential problems occurring, including unplanned process excursions.
The illustration depicted above is a simplistic view on how equipment design and the use of complementary technology such ControLyo® Nucleation Technology can expand your design space. The equipment design addresses the equipment capability curve to the top left by allowing higher sublimation rate and minimizing choked flow. Controlled freezing using controlled ice nucleation technology reduces the product resistance which allows a higher sublimation rate, lower product temperature due to sublimative cooling and so expands the top right curve.
The key to managing product quality is to understand what process parameters are required to reproducibly manufacture the product consistently, whether it is in development environment, technical transfer or commercial manufacturing. Use of scalable technologies across all the different equipment capacities provides the most reliable data for comparison as users develop, scale up and transfer their products and processes, from one scale to the next and even from one facility to another.
As stated in the FDA Guidance for Industry Q8 (R2) Pharmaceutical Development document: “The information and knowledge gained from pharmaceutical development studies and manufacturing experience provide scientific understanding to support the establishment of the design space, specifications, and manufacturing controls”. Data to support process and product understanding is not limited to development process only; it expands throughout technical transfer and to commercial manufacturing. This is of significant importance because variation of product temperature, for example, could create a different product long term stability profile. If users cannot demonstrate the consistency of their products manufactured during the scale up of lyophilization, the process demonstrates lack of understanding and quality.