By: Roger McDonald

I have worked in the Pharma and fine chemical world for over 20 years, and it is true to say that I have never before experienced such dramatic changes as are now sweeping through the industry. While we have seen mega-mergers frequently, supply-base consolidations and the emergence of the Asian outsourcing drive; I do not recall that the need for the basic driver of the industry of innovation and the search for better medicines has ever come under threat. However, this is a debate which is now happening. Can we afford better treatments? More importantly, who pays?

In this environment, where funding for new development projects is very difficult to obtain, project budgets get squeezed. Unless I have a persecution complex, it seems that chemistry is often deemed a necessary evil rather than the driver behind the project. This may occur because most biotech companies are run by biologists? The result is that budgets for development and scale up of drug substance chemistry are forever under pressure.

Such challenging environments may be viewed in a positive way, in that they force companies, and I think of my own company here, to reappraise the way we do things. The opportunity is to learn, adapt and become a better company.

At Cambridge Major Laboratories (CML) the biggest change we have made is to accept that clients rarely want to hear about process development. We can develop a wonderful process, but only if we are prepared to do it for free and yesterday! Thus we have modified our strategy in early phase projects to one of managing risk; how can we best use our tremendous experience to be able to guarantee delivery on time, in the right quality and of course at acceptable cost.

At CML we are fortunate to have a team of highly experienced chemists. The operating change is to apply that experience in a slightly different way .In fact, we believe that this experience is now of even greater value than before.

This approach to managing risk requires a clear understanding of the basis of safe operation. While safety has always been at the core of what we do, we recognized that in such accelerated programs, it might be possible that corners get cut. This possibility is of course totally unacceptable.

The CML Approach to Safety Health Environment (SHE)

The starting point for review of the CML SHE Management system was that it had to fit our business model. We did not want to find that projects were delayed by extended and unnecessary safety studies or reporting regimens, driven by paperwork rather than science. The approach we took was to examine the way projects are iterated and this exercise also provided a good opportunity to streamline our project management system.

We decided to implement a rigorous “gated” or “milestoned” project management system, into which we integrated a similarly “stepped” approach to process safety, a critical part of the overall SHE system. The SHE management system was enshrined within a newly-written manual addressing all critical aspects of SHE policy.

The Process Safety Assessment (PSA) is a critical part of the operational SHE system. Understanding the nature of the chemistry under investigation and how it can be safely accommodated within the production environment (equipment) is fundamental to process development. The second point is critical to be able to make a judgment with regards to accommodation; it is of course a prerequisite to be able to fully understand the capabilities of every part of a designated reactor train. The CML plant is young and very well designed. Our operators and chemists are very experienced and are involved at all stages of plant / train build.

The “gated” approach to project management requires regular project team meetings at which a decision is made with regard to the next phase of work. This approach actually starts at the project proposal stage before CML is even awarded the work. The designated project manager will consult with key team members with regard to technical aspects of chemistry, SHE considerations, analytical requirements and production requirements. CML will submit a proposal based on this assessment. Assuming the work is awarded, it is iterated in a “gated” or “stop-go” fashion; starting with a formal “kick-off” meeting, weekly internal project meetings are supplemented by more formal assessments, when all key team members are present at the time of key decisions. An increase in scale from lab to kilo lab constitutes a key decision and prompts a PSA. Only when the PSA is accepted by the SHE manager can the work commence. The principle is that a “process-fix” is instigated and a basis of SHE established before the process is run at larger scale.

This approach effectively parallels the way in which CML will manage the technical aspects of the project, a good example would be the continuous assessment of actual yields versus the assumptions made in the project proposal. This assumption has to be proven at each scale-up and results are always discussed with the client before going up further in scale. This approach is central to managing risk. We may advise splitting batches or even changing chemistry, but the client needs to be involved. Of course in an ideal world we would be given more time (and funding) to perform more development work but in today’s world, the focus is on “fit-for-purpose”.

The SHE system is underpinned by multiple SOPs and Working Instructions (WI), CML has a dedicated “Calorimetric test Strategy”. This is an important SOP and defines the approach CML will take to generating data to assess the nature of caloric reactions. CML has invested in Mettler Toledo RC-1 equipment for both US and European sites and equipped with experienced pilots to generate and interpret data. DSC is a routine tool but for ARC or more specialized studies CML employs the services of external companies.

A rigorous approach to process safety is of course only one aspect of SHE. The impact of our operations on the local environment is crucial to the sustainability of the business and a commitment to the continual minimization of environmental impact as a whole is a philosophy key to the sustainability of our industry.

Innovation is not just about chemistry. CML continues to innovate in the way we deliver to our clients, offering the safest, risk-managed solutions to support their clinical development programs.