Articles & News
by biopharma-admin in BTL News
Quality by Design (QbD) is a systematic approach to ensure that the quality of the product is built into production processes from the outset, rather than being tested once development has commenced.
This requires gaining an understanding of the product and each unit operation involved: the requirements of the product and the effect of any changes to it, the various process steps involved and the robustness within these steps, as well as robustness of the end product.
Within this scenario a broader knowledge of the processes is necessary, and key points related to achieving and maintaining product quality must be identified. Once this information is available it can be used to investigate how these critical product quality attributes are derived and the specification range that is acceptable.
An area with significant interest for QbD is that of cytotoxic compounds, with particular growth in combination therapies and biologic medication. The increase in incidence of cancers and an ageing population is leading to a high demand of services by companies that have expertise in cytotoxics.
QbD in Freeze Drying of Cytotoxics: Defining Objectives
The goal of freeze drying is to produce a stable product with good levels of activity and quick reconstitution. Therefore stability, dissolution and activity of the product immediately after processing and over time will be three of the most important goals to define. However a number of other “Quality Attributes” may also be important, including location and mobility of residual moisture and batch / unit process costs.
Cytotoxic products are very concentrated and highly toxic and therefore need to be well quantified. It is especially important to ensure product uniformity as even small variations can have significant effects (for example in concentration / toxicity) and must be avoided.
Each of the relevant parameters must be identified and tolerances must be defined that are stringent enough to produce the best possible product, while remaining practically achievable.
Designing in Quality from the Start
Freeze drying formulations are, in general, complex mixes of excipients that benefit the active ingredient or the product as a whole. However, the exact constitution of a formulation is what defines the subsequent process parameters: for example, the lower the critical temperatures of a product, the slower, longer and more expensive freeze drying will be. For this reason formulation and cycle development should ideally be conducted together.
Identification of Formulation Parameters
Many of the parameters for cycle development can be determined mechanistically: for example, freeze drying microscopy enables the determination of freezing and collapse temperatures, DTA/Impedance analysis identifies frozen-state mobilities, and there are various PAT techniques in-process monitoring. “Design of Experiment” (DOE) testing will be applicable to other areas, for example, evaluating the effects of changes in formulation on thermal characteristics or post-process variables. These parameters tend to be the same across any product undergoing freeze-drying, but as the characteristic of cytotoxic is the concentrated amount of the active ingredient, particular attention to detail will be crucial.
Variables and Risk Identification
QbD also seeks to identify potential risks in advance. For toxic compounds, this covers both the process risks as well as the final product nature in the context of drug administration. Understanding the impact of each of these will enable the definition of tolerances and implantation of controls.
Scaling up to production
Where development for research and pilot scale has been undertaken from a QbD perspective, many of the Quality Attributes will also be applicable to production although the tolerances should be re-evaluated with the different equipment and handling in mind.
Establishing 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 will allow us to establish a Design Space that provides repeatable, consistent and provable results.
Quality and experience with cytotoxic compounds at BTL
Since opening of a facility dedicated to cytotoxic for such work, BTL has conducted both small and large projects covering product characterisation, formulation development, cycle development, scale-up and transfer. With such experience we are ideal to assist with implementing QbD. We can help identify and define the Quality Attributes that are relevant for your product, including characterising the product and process requirements. We are also familiar with the capabilities of freeze drying equipment and how the different specifications of temperature variation and process control can impact on final product quality. We can help you devise a way forward to maximise your design space, limit product losses due to process variations and maximise efficiency.cycle development, cytotoxic, formulation development, production, QbD