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April 7, 2009: Enabling High Throughput Drug Development
Gene Burton, PhD
DNA Bridges, Inc.

Technological improvements over time have always had an impact on the development of the biotechnology industry and never more than today. Since the early days of the industry, the cornerstone of the production side of drug development has been cell line expression. Previous mammalian host expression levels in the 0.25 g/L range have given way to consistent reports of 1-3 g/L. Simple mathematics reflects that the changes from sub 1 g/L expression to those approaching near future 3-5 g/L expression reduces anticipated production volume requirements at least 5-10 fold, more in line with capacities below 1000-2000 L rather than the previous 5000-10,000 L volume requirements for the manufacturing of test drugs.

The significance of these changes is wide ranging on the ability to employ current technological trends in bioprocessing. For example, the use of disposables in manufacturing now becomes an increasingly viable strategy. Pharmaceutical companies and CMOs alike show a growing acceptance of an array of disposable systems, from bioreactors to filtration and storage of bulk drug substance. Multiple options are available in disposable culture systems, such as the Wave system (GE Healthcare), BiostatR Cultibag (Sartorius Stedhim Biotech), Cell-tainer (Lonza/CELLution Biotech), NucleoTM (ATMI Artelis), SUB (Hyclone / Thermo Fisher), Appliflex (Applikon/Stedhim) and the Flexfactory (Xcellerex), and range in working capacities from 2L to 2000L. The comparison of the production and product of these types of systems to stainless steel equipment has been examined and found acceptable by companies like Amgen, Bristol Myers Squibb, Genentech, Baxter, Centocor, DSM and Merck, at volumes as large as 500L. Disposable systems have also been and continue to be developed for downstream process operations. Many components of those operations such as filters, tangential flow concentration/diafiltration systems, connection systems, and sampling systems already qualify as single-use or disposable (limited cycle/use) materials. Recent developments have occurred in areas such as chromatographic media (RhobustTM/Upfront) and filtration-based ion exchange systems (Mustang/Pall), as well as buffer, media and drug substance storage (CelsiusTM/Integrated Biosystems) bag-based applications.

Concerns surrounding the use of disposables are largely on the decrease. Disposables cost estimates have shown an edge (as much as 50% lower for single use systems) over hard piped systems, at least within the scale range currently supported by disposable systems. Harsh chemicals and extremes of temperature are not compatible with disposables nor with protein based drugs – and thus, are largely a non-issue. The questions of extractables and pre-validation of systems have been continuously explored and addressed. Powerful operations aspects for disposables include: changeover cleaning advantages, corrosion control and flexibility, prepackaging, portability, storability and modularization, just to name a few.

Thus, particularly for evolving firms seeking to minimize the high overhead cost of manufacturing, the light at the end of the tunnel is in view. The combination of increased cell culture productivity and the impact of disposables on production systems stand to accelerate and make more efficient an early stage drug development. The seed train capacities of current facilities may very well become the production vessels for tomorrow’s new recombinant drugs.