BLOG: Fit for Purpose

At Cobra we have worked on the development of both naked plasmid DNA and viral gene therapy products for over 20 years. After some rather extended development times, it has been very rewarding to see a number progress out of Phase II clinical studies and customers wanting to take these products into Phase III studies.

This, though, brings some interesting dilemmas from a manufacturing perspective. When you are involved in production of material for early clinical evaluation, time scales are of the essence; budgets are restricted and material requirements relatively small. The consequence of this is that manufacturing processes are often poorly optimised, if at all, and the approach to process development is often “we’ll fix that after Phase II”. Now, when projects are progressing out of Phase II, the approach “don’t change anything from the Phase II process’ is adopted. Whilst one can see the logic behind this approach from a risk and quality perspective, especially taking into account the lack of clinical experience with these products and the adage that “process defines the product”, it does potentially carry greater risks. Not least, it makes huge assumptions about the quality and consistency of the outputs from the existing process.

From my perspective, there needs to be an acceptance that changes in manufacturing processes are not only inevitable, they may well be desirable. Early stage processes are just that - processes that meet the manufacturing requirements for small patient studies and often nothing more. In contrast those intended for Phase III need to be as close as possible to those that will be used for in-market supply. There is a significant gap between these two requirements and a suitable bridge needs to be put in place to join up them up.

In terms of scale, whilst for products such as antibodies there is a wealth of experience in process scale up and large scale manufacturing, for some of the more advance therapies with virus and plasmid DNA we are entering unchartered waters. Most manufacturing processes have been producing material for less than 100 patients. We are now faced with the requirement for developing processes that will not only meet the needs of Phase III studies, but also be the basis for in-market supply. This will require up to a 100 fold increase in scale on current production processes and this, from a manufacturing perspective, is no trivial task.

In my experience, it is critical to understand the end game and to establish a road map on how that can be achieved, including critical issues such as product comparability and the analytical techniques required to demonstrate this. It will need to address key issues, such as potential in-market needs, acceptable costs of goods, the need for dedicated production facilities, the possible use of flexible single-use facilities and potential production strategies. Other issues to consider are about how far it will be possible to scale the production approach with current available technologies and whether these goals are achievable using single or multiple stream production systems.

Once we have an understanding of these development programmes, we will then need to put this knowledge in place to achieve those long term requirements. Only then will it be possible to take these products forward, based on the knowledge that the manufacturing processes are fit for purpose and will be able to meet the potential an increasing number of people now see for them.