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While single-use technologies can be used for filtration, storage and at connection points in egg-based vaccine production, their use multiplies in cell-based applications.
Quality assurance (QA) is vital for vaccine manufacturers, typically accounting for 70% of total vaccine development and production time.1 Compounding this challenge are the time-to-market issues vaccine manufacturers face in protecting populations from emerging diseases such as avian flu. For these and other reasons, total US vaccine manufacturers dropped from 25 in 1973, to approximately five at present.2 The introduction of good manufacturing practices (GMPs) in 1980, which caused manufacturing costs to skyrocket, was also responsible for the exodus of companies from the market.3 The attempt in 1993–1994 to provide universal healthcare in the US, which forced 50% discounts on vaccine makers in exchange for government-purchasing of one-third of the nation's supply, caused the vaccine supplier market to shrink even further.2
However, the tides have turned, especially for the five biggest vaccine makers. This is partly because of the pipeline of new prophylactic and therapeutic vaccines, particularly those targeting cancer and AIDS. Companies involved in vaccine manufacture would now agree that the rewards exceed the challenges in this market.
This sentiment is echoed in the following statement concerning one of the vaccine industry's five dominant players: "Vaccines now represent an important element of GlaxoSmithKline's growth strategy, and were, uncharacteristically, the main focus of a pipeline update during the summer of 2005."3
While larger manufacturers with extensive experience and the economies of scale to profit from the lower margins associated with this class of drug have certain advantages over smaller makers, vaccine producers of any size can benefit from reducing cleaning/cleaning validation steps, and improving separation and purification processes.
Wide-scale adoption of disposable technologies represents one of the most sweeping changes to take place in the biopharmaceutical industry. This is because disposables eliminate the need for cleaning and cleaning validation, processes that are time-consuming, expensive and wrought with potential compliance pitfalls. In fact, 30–50% of all FDA warning letters are cleaning related.4 Considering the time vaccine manufacturers dedicate to QA, the complete omission of this particularly challenging task can drastically speed up production.
Disposable technologies are used in numerous steps throughout the vaccine production process. At connection points, disposable technologies enable two fluid pathways to be connected in a matter of seconds without the need for a laminar air-flow cabinet or tubing welder.
Disposable filters and chromatography membranes minimize opportunities for operator error, and can be disposed of after use to avoid cleaning and cleaning validation. When combined with single-use bags and tubing, these technologies form fully-integrated disposable systems that can be supplied preassembled and presterilized by gamma irradiation to further reduce process steps.
Advances in drug development and production not only come from new technologies, but also from the application of different technologies to existing processes. One example is favouring ultrafiltration over size exclusion chromatography (SEC) to separate and purify conjugate vaccines, which protect infants and young children from infectious diseases such as meningitis and invasive pneumonia. There are at least 30 steps involved in conjugate vaccine production, and the use of ultrafiltration instead of SEC during fractionation for protein and saccharide components can significantly reduce this number and the complexity of the separation step.
Capture and purification steps in virus- and plasmid-based gene therapy and vaccine purification applications are additional areas of inefficiency in drug production. A disposable, prepacked membrane column can remove contaminants of up to 100 times the speed of resin-based chromatography, while providing efficient capture of large molecules. This is because conventional chromatography is highly inefficient and limited because of the speed that large molecules, such as plasmids, diffuse through the media's pore structure. However, anion-exchange membranes that use a microporous membrane with active quaternary ammonium chemistries linked directly to the membrane surface can overcome these inefficiencies.
By using three-dimensional structures with open (0.8 μm) pores, active chemistry groups are immediately available for binding. With over 200 novel viral and DNA-based vaccines in development today, this technology has the potential to change the timetable for bringing these new vaccines to market.
While egg-based vaccine production has certain limitations in terms of development time, downstream processing can be a significant source of new efficiencies. The move towards cell-based vaccine development will further speed the production timetable, especially as disposable technologies can be used for a greater number of steps in this process. While single-use technologies can be used for filtration, storage and at connection points in egg-based vaccine production, their use multiplies in cell-based applications. For example, disposable technologies can be used for media preparation, clarification, buffer preparation, capture and polishing chromatography steps, filling in downstream processes, and for venting and cell harvesting in upstream processes.
As newer vaccine production methods take hold and more effective technologies are applied to these processes, the industry will be better equipped to handle vaccine demand, whether to stem a pandemic outbreak, protect against bioterrorism or ensure that everyone receives their annual flu shot.
Dr Hélène Pora is marketing director for biopharmaceuticals at Pall Life Sciences (France).
1. H. Pora, Genetic Engineering News, 15 May (2005).
2. G. Roth, Contract Pharma, November (2005).
3. C. Sheridan, Nature Biotechnology, November (2005).
4. Presentation by H. Pora at Phacilitate Conference, January 2005.