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Nov 15, 2010 (Vol. 30, No. 20)

Impact of Single-Use Biomanufacturing Systems

Disposables' Influence Has Extended Beyond Reducing Production Labor Requirements

  • Technology Adoption

    It is hardly surprising, therefore, that there has been widespread adoption of single-use technologies throughout the industry over the last five years. Over this period, single-use technology has extended beyond single-use bags, transfer sets, and membrane filters. The industry has seen rapid advances in the offering from suppliers with respect to processing, monitoring, and sensor equipment. There has also been a fundamental change in the business models of some suppliers, where the primary focus has switched from capital equipment to single-use consumables.

    Such has been the rate of progress; the industry has developed to a point where, for some product areas including mammalian secreted proteins and viral products derived from mammalian or insect cell lines, it is possible to build processes entirely from single-use technologies.

    The use of the technologies within the CDMO industry has brought about a change in CDMO business models, with a move away from seeing plant and facilities as the selling asset, to one where flexibility and speed are the major drivers with companies focusing on product areas to which single-use technologies can be applied.

    Initial capital outlay is lower as a result of more simplistic and standardized designs. In addition, there is a large reduction in design, procurement, and validation costs. Reduced equipment lead and installation times mean that decisions on expenditure do not need to be made as far in advance of facility requirements, reducing business risk.

    Returns on capital outlay can be achieved in shorter time frames, which is critical if the equipment has been purchased with borrowed capital. Finally, the simplification of installation processes and the reduction in validation times within manufacturing suites reduces lost manufacturing capacity.

    One of the greatest impacts of single-use systems has been on facility turnaround and cleaning; the decreased need for cleaning and the availability of items such as pre-packed chromatography columns, bioreactors, and filtration systems reduces process set-up times and the need for equipment turnaround during production. The facility clean-down at the end of the process may be no more than a line clearance, and the elimination of the need to demonstrate product removal from product-contacting equipment represents a huge savings in time and effort.

    The impact of the adoption of single-use technologies is not limited to the equipment used to perform the manufacturing operation. A number of case studies have been presented for the development of facilities based solely on the use of single-use equipment. In some cases facilities have been designed on the premise that buffer and media will be procured and the facility therefore requires no water or steam systems, representing extensive cost savings.

    The concept of regarding single-use systems as closed systems leads to the potential for performing manufacturing processes in grade D (Class 100,000) areas compared to grade C (Class 10,000), which has the potential to further reduce operational costs.

  • Process Development

    From a product perspective, the use of single-use systems impacts the manufacturing processes that are being developed prior to transfer to GMP and the approach taken to those transfers. Single-use systems have inherent limitations with regard to pressure, flow rates, mixing and temperature control, in-process monitoring, and (in the case of bioreactors) mixing and oxygen transfer and CO2 stripping rates. 

    Processes, therefore, need to be developed with these limitations in mind and may well be developed, if feasible, using scale-down versions. Some techniques, such as clarification by centrifugation or product separation by gradient chromatography, cannot be readily adopted and alternative approaches may be required.

    Equipment such as membrane systems and chromatography resins that are available in pre-packed formats and process operations that can be performed in single-use systems are often preferred. This approach is likely to give rise to more simplistic processes that are optimized not necessarily toward maximum productivity, but toward platforms that can be readily transferred into GMP using existing formats.

    Within the biopharmaceutical industry there is, to some degree, the concept of the process defining the product. Therefore, if the process has been developed based on single-use technologies, there will always be a reluctance to move away from this approach, unless there are overwhelming technical or commercial reasons to do so.

    Products may therefore be locked into the existing single-use technologies at an early stage, hence the continued support by suppliers for early-stage development companies, despite the fact that they generate significantly lower sales than in-market users.

    As the product progresses from development through to clinical supply, the ability to transfer out of development and into manufacturing facilities, including subsequent transfer to additional facilities, is critical. Single-use technologies give rise to more widespread standardization of manufacturing equipment. Therefore, a pilot plant area can use identical equipment to that being used in GMP manufacturing facilities and processes can, in theory, be more accurately transferred without the need to try to accommodate for differences in plant and operational procedures. This in turn reduces tech-transfer risk.

    In conclusion, while the use of single-use technologies was initially regarded in the area of early-stage product development as simply being operationally convenient, and as a way of reducing labor requirements in development and manufacturing facilities, it is now increasingly apparent that these technologies are having a much more profound impact on the biopharmaceutical business.

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