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.