Biopharma Technology explains how to build quality in the lyophilisation processes
QbD is an FDA and EMA backed approach to ensure drug quality remains consistently high through ‘statistical, analytical and risk-management methodology in drug design, development and manufacturing’.
Lyophilisation (freeze drying) is a multi-stage process with different risks present at each stage. Using QbD methodology in product and process R&D results, generates robust processes and consistent quality but also safeguards a large amount of data is subsequently available for quality assurance and regulatory submissions.
QbD family for freeze drying
CQAs (critical quality attributes) define the most important characteristics of the final product to ensure it is within acceptable quality levels. CQAs can be chemical, physical, biological, microbiological or any other type so long as they can be defined, measured, and continually monitored.
In freeze drying, the CQAs might typically include:
- the appearance of the final product
- residual moisture left in the dried product
- behaviour under reconstitution
- preservation of biological activity
- stability; and
- sterility of packaged product
The QTPP (Quality Target Product Profile) defines the overall product in terms of its necessary characteristics. QTPPs are product and context specific and therefore may depend on where and how the product is to be used, the container type, product type, and other variables. QTPPs for freeze drying might include porosity, storage conditions, and stability length.
A range of tolerance for each CQA must be established, and with it an understanding of where and how the risk of failures presents in the process. In order to ensure the product’s CQAs are maintained at each stage of the process, Critical Process Parameters (CPPs) translate the product’s requirements into process variables. In freeze drying, variables that must be controlled to mitigate risk include the choice of excipients; temperature and pressure conditions at different stages of freezing and drying; the thermal profile of the formulation; and production conditions.
Selecting your excipients
The choice and balance of excipients in a formulation has a significant bearing on its freeze drying process parameters. Various additives offer protection for different processing stresses and formulation development aims to create a balance that results in the best possible final product. However, the exact constitution of a formulation is what defines the subsequent process parameters and for this reason, formulation and cycle development should ideally be conducted together.
Know your equipment
The efficiency of your freeze drier can be maximised by following the manufacturer’s specifications when setting up shelf spacing, choosing vial fill depth and deciding on the product load.
Equipment limitations can be determined by carrying out ice slab tests. These can be used to determine the trapping rate and the choke flow of your machine, in other words, the maximum rate of vapour that can be efficiently extracted.
Another point to consider is the temperature gradient through the drier. Temperature may vary by height or across a shelf. Shelf mapping will locate any pockets of difference that may impact drying.
Establish the critical temperatures
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), differential thermal analysis (DTA) and impedance analysis.
FDM involves the visual examination of the behaviour of a small sample of the product as it freezes. An expert operator can pinpoint the temperature of the critical events. FDM is used to determine the eutectic melt temperature and the collapse temperature.
DTA allows the determination of significant endothermic and exothermic changes such as crystallisation, eutectic melt, and glass transition events.
Impedance analysis detects changes in molecular mobility that thermal techniques may not pick up. This allows determination of events such as glass transition in more complex amorphous products, or changes in the frozen material that do not have an associated exothermic or endothermic signature.
Building a design space
A design space is a multidimensional combination and interaction of input variables and process parameters that have been demonstrated to provide assurance of product quality. A successful and detailed study into all the product and process variables makes it possible to establish a design space that provides repeatable, consistent and provable results.