A key characteristic of biological structures is that they tend to be extremely large molecules with complex three dimensional structures, which are critical for their functional activity within the body. It is therefore entirely possible that a single vial of biological medicine could contain a heterogeneous mix of molecules all transcribed and translated from the same gene, but with subtle differences derived via post-translational modification processes.
These different forms can exhibit varying levels of biological activity which may either have a positive or negative affect on safety and efficacy; either way it is clear that we must achieve comparability with the product profile tested in clinical trials. Given that quality cannot be tested into the product, manufacturers have previously achieved product consistency through process consistency during scale-up and transfer and between batches and campaigns.
Quality by design (QbD) perhaps allows manufacturers to operate processes within a design space so long as a target product profile and critical attributes are met; however, in either case a successful filing with the regulatory agency will require the manufacturer to understand the sources of variation, detect the presence and degree of variation, understand the impacts on product attributes and implement control measures proportioned to the risk presented.
Of course this is not to say that all process variation will necessarily have a negative impact on product quality; indeed many sources of variation will not. Nevertheless as custodians of a process that generates product to make sick people better, now or in the future, we believe there are four main sources of bioprocess variation which must be fully understood and managed: biological, raw materials and consumables, operational inputs and the environment.
A survey of participants in our recent webinar revealed that biological variation was their main concern with raw materials and consumables coming in a close second. Variability in product quality can occur if changes are made to cell lines, media or other cell culture conditions between the small-scale and manufacturing-scale, while elimination or at least reduction in human error during operations through automation can be demonstrated to increase process consistency and robustness.
You can read our article, Understand and Controlling Sources of Process Variation: Risks to Achieving Product Critical Quality Attributes, which was published in the October 2014 issue of BioProcess International Magazine. The article describes what we mean by these sources of variation and looks at ways in which they can or have been controlled. The role of analyzers or sensors linked to automation as a means for controlling processes to ensure final product can also be achieved through three steps at the end of a purification process: virus filtration, final ultrafiltration and final bulk sterilization. Pressure sensor readings can be fed back to the automation to control the process and minimize variation.
To learn more, view our webinar on Understanding and Controlling Bioprocess Variatio
This post was contributed by Nick Hutchinson, Market Development Manager (Pharma & Biotech), Parker domnick hunter Process Filtration, UK.
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Combining unique and innovative SciLog® sensing and control technologies with renowned filtration expertise, Parker domnick hunter's integrated and flexible automated single-use systems allow complete control of bioprocessing steps enabling consistent product quality. Visit our website to find out more about Parker domnick hunter's single-use solutions.