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Quality by design (QbD) for lyophilization is about building a robust process that proactively flags critical points and ensures consistent delivery of the best quality product, by minimizing risk and maximizing understanding of the process itself. Regulatory bodies such as the FDA require details of the lyophilization cycle for product registration but a well-designed cycle also has economic benefits since the best quality cycles are the most efficient in terms of energy usage, time and other resources.
QbD terminology and what it means for freeze dried products
Part of standard QbD terminology is the term “Critical Quality Attributes (CQAs)”, which relates to the essential parameters of a product which may be used to describe quality itself. For freeze dried pharmaceuticals, CQAs may include: the appearance of the final product; its behavior under reconstitution; preservation of biological activity and/or chemical structure; the stability profile at defined temperatures and timepoints, and the sterility of the dried product.
Figure 1: An example of how the design space might be constructed for the primary drying conditions for a freeze-dried product
Once a product’s CQAs have been identified, the next step is to define its quantifiable features such as residual moisture content, specific surface area and activity, which will then typically form part of the [quality] target product profile (or [Q]TPP), which – by a combination of modelling and real lyophilization runs – can be linked to variables that affect the quality of the process. By controlling input variables risks can be mitigated.
Core Variables for Risk Mitigation:
Selecting excipients for the formulation
The choice and balance of excipients in a formulation has a significant bearing on its freeze drying process parameters. It has been demonstrated that essential parameters of the active ingredient(s) be investigated prior to starting freeze-drying cycle development, such as solubility in the chosen solvent(s), pH-stability profile, and any chemical incompatibilities identified.
The freeze drying process is significantly affected by aspects of the specific equipment used, such as shelf cooling rate and the trapping rate limit of the condenser. One difficulty in this regard often comes from the fact that the details of the manufacturing equipment are not known during the early stages of product R&D. If they are, the limitations and tolerances of the freeze-dryer(s) can be incorporated into the process, but if not additional robustness will need to be built into the freeze-drying cycle.
Scientific methods of determining the critical temperatures of a formulation make it possible to design a high quality cycle. The key technologies are freeze drying microscopy (FDM), and thermo-analytical methods such as differential thermal analysis (DTA), electrical impedance analysis (Zsinϕ) and differential scanning calorimetry (DSC).
Integrating QbD into Freeze Drying Development
Figure 2 shows an example of a possible “QbD roadmap” for freeze-dried pharmaceutical products.
Starting at the top left of the roadmap one can set the desired parameters and important outputs, and working clockwise, using a combination of mathematical modelling, candidate formulation assessment and real-life freeze-drying, it is possible to design in quality at each stage of a product’s design and development. If the process is successful with regard to the various risks, and the company’s (or end user’s) appetite for each of these risks, the process can be transferred to production.
Biopharma Technology’s Services
Over the past 15 years Biopharma Technology has worked with over 1000 products and uses state of the art analytical equipment to characterize material before and after freeze drying. Biopharma Technology is at the forefront of QbD in the area of freeze-drying and can help you in introducing this approach to your development needs.
If you wish to find out more and consider some of our services, please contact the Commercial Director Dr Laura Ciccolini:
Phone: +44 (0)1962 841 092
Reference: L. Mockus et al (2011) Quality by design in formulation and process development for a freeze-dried small molecule parenteral product: a case study, Pharm. Dev. Tech. 16(6) 549-576