November 15, 2010 (Vol. 30, No. 20)
Tony Hitchcock Technical Director Cobra Biologics
Disposables’ Influence Has Extended Beyond Reducing Production Labor Requirements
The development of manufacturing processes and the production of clinical material for new drug candidates is a decisive phase in pharmaceutical development. Decisions made during the early stages of process development have a lasting impact on the manufacturing route for the product and the associated cost of goods. In fact, a significant proportion of the product costs are locked in at the early stages of process development.
In 2008 alone, it was estimated that there were about 3,350 products in Phase I/II development and another 5,900 products in preclinical development. The capacity to develop manufacturing processes in a timely manner is critical to a company’s development pipeline, the ultimate value of the product, and in the case of smaller development companies, financial survival. While larger pharma companies often perform this work in-house, for smaller organizations contract development and manufacturing organizations (CDMOs) are the best solution.
The technical challenges of developing early-stage products range from the generation of monoclonal antibodies, where a number of companies have platform processes and the focus is on throughput and time lines, through to highly novel protein and vaccine products, where full-scale development programs are required. The challenge is to develop robust processes that can produce functional, stable products with the understanding that time lines, productivities, and costs will not be comparable to those achieved from platform processes.
The manufacturing of early-stage products for first-in-man studies presents a number of challenges. First, the processes are frequently poorly defined with limited, if any, large-scale runs having been performed ahead of engineering and cGMP batches. Second, the processes can be variable and therefore operational staff could be relatively unfamiliar with the process. Finally, there is a need for the capability to move from development activities through to the execution of clinical manufacture rapidly.
These first two challenges mean that CDMOs require a highly skilled manufacturing team to perform the process. The third requires effective project management, robust tech transfer, and a flexible production facility. From a manufacturing perspective, there is a need to maintain capabilities to perform a wide range of processes at varying manufacturing scales.
The purchase of equipment represents a significant business risk, and for the manufacture of early-stage products this risk is significantly higher. This is because the operational requirements of the equipment will be less defined, and flexibility is necessary for the wide range of manufacturing processes to be carried out.
Equipment may be used in an intermittent and unpredictable manner, instead of on a high-throughput basis. The pay-back on such investments is difficult to calculate and conventional cost models may not hold. This is especially true for items purchased for specific projects where the lead times and installation and validation costs are in themselves prohibitive. This later cost may exceed the value of the capital outlay.
Plant equipment depreciates in value dramatically and used equipment often retains limited second-hand value, making it difficult to recover any of the capital outlay over a single project. Therefore, project-specific capital costs are comparatively high, a funding challenge for many small development companies.
Inevitably, facilities producing early-stage products are multiproduct facilities and the cleaning of equipment is critical. Product-to-product cross contamination must be avoided. This is especially true where validation of cleaning procedures for the production of investigational and in-market products is required. This is compounded by the fact that many of the products have no clinical history, toxicity, or defined clinical-dose levels, and assays to detect the product may be unvalidated. Therefore, the cost and time lines associated with cleaning-validation programs are extensive.
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.
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.
Tony Hitchcock ([email protected]) is head of manufacturing technologies at RecipharmCobra.