Given the many pressures on the pharmaceutical industry today, process chemists charged with Active Pharmaceutical Ingredient (API) development for clinical trials face increasingly tough economic and regulatory hurdles.
The pressures to reduce costs while meeting more complex regulatory mandates, as recently reported in the New England Journal of Medicine, create a difficult challenge: how to develop a commercial process for a drug candidate more efficiently and within a much shorter timeframe?
To that end, PCI Synthesis has developed a “Right-First-Time” approach to synthetic route selection that combines both the art and science of API development. In previous articles we’ve discussed the route most likely to succeed in early and late phase drug development. This article will focus more specifically on successful approaches to synthetic route selection that are helpful in shortening the time from synthesis to regulatory approval.
Although drug candidates range from relatively simple structures to highly complex ones, nearly all drug candidates present significant challenges to the process chemist. Every API requires new chemistry never before attempted, with all the pitfalls that it entails.
Initially, as the chemistry is developed, we are working on a small scale and everything seems easy. But that ends quickly and this is where our experience working on hundreds of projects plays an important role in choosing a synthetic route from among hundreds of ways to put molecules together. The literature here is just enormous.
And no, it’s not easy. As the NEJM article points out, although the hypothesis being tested in a clinical trial may seem straightforward, the complexity resulting from the large number of variables involved creates a high-risk business with the highest failure rate for new product candidates of any industry.
It is for managing this risk that PCI Synthesis has developed its “right-first-time” approaches to route selection and scale-up.
In the beginning, we don’t pay too much attention to yields as long as the conversion is relatively decent. Before we start doing experiments, we focus first on things like which reagents to use and how to make the process as efficient as possible. We see what tricks we can use that we learned from other projects. Efficiency is the key. The more efficient the chemistry, the easier to purify and to meet ICH guidelines.
Chemists working in the field of pharmaceutical process research and development are responsible for preparing multi-kilogram quantities of active pharmaceutical ingredient (API) to support clinical and toxicology evaluation studies.
Until the first few kilograms of API are made available, little can be done to progress these clinical and toxicology studies. Given the complexity of the processes involved in scale-up, PCI synthesis believes best practices include at least three kilo scale-up trials of the process while still in the lab, before heading into the far more costly cGMP manufacturing facility for commercial processing.
However, before scale-up is attempted, there are other considerations.
The starting point for most process development programs is the medicinal chemistry route. This route is typically designed to be divergent to allow access to a variety of targets.
But it is only a starting point. The medicinal chemistry route is not usually designed for further scale-up into a commercial process. Consequently it is likely that the process chemist will need to change the synthetic route at least once during the course of the development program.
As we discuss in more depth in our article about scale-up, the performance of a process on an ever larger scale leading up to commercial production can be difficult to predict. Serious issues with the process may not come to light until the process is taken to pilot plant scale.
There are many reasons a process may prove to be less than optimal as scale-up progresses. The different drivers for changing a synthetic route are most commonly influenced by these issues, also commonly referred to as SELECT:
As the life cycle of drug development unfolds, the demands on the synthetic process will change. In early development, the emphasis is very much on timely delivery of bulk supplies of the API using a safe process. Thus, most of the SELECT criteria can usually be satisfied when preparing the first few kilograms of the API or New Chemical entity (NCE) in bulk.
In these early clinical trial stages, the most frequent issue encountered involves patient safety. However, we are also focusing our efforts on attaining the highest yield, the lowest number of impurities, the easiest purification process, the least amount of pressure and most moderate temperature. In other words – the most efficient process.
By the time that a drug candidate reaches Phase III clinical trials, the CMO will need to manufacture perhaps hundreds of kilograms of API and the demands on the process become more acute across the full range of SELECT criteria.
PCI Synthesis’ risk management approach relies on paying close attention to the following at every stage of process development in order to meet our “right-first-time” goals:
Implementing this approach is key to reducing API development time as complexity grows and budgets shrink. As with any risk management plan, the goal is to be proactive in finding and mitigating sources of risk. This is accomplished by removing unwanted variability in each stage of a process.
In clinical trials, the emphasis is on identifying, reducing, and monitoring risks to patient safety, data integrity, regulatory and protocol compliance, and project scope (both budget and timelines).
Paying close attention to these five variables above yields the most advantageous synthetic route.
How has that benefitted our sponsors?
Here’s an example. A sponsor approached us requesting that we manufacture 40 kilos of a product. They provided us with the chemistry. Rather than going full-bore into manufacturing, we first tested the process, as we always do. The expectation was that we would make two 20-kilo batches at a cost of $400,000 each.
In the lab we determined that we could improve the yield by making some changes in the chemistry. However, it would cost an extra $100,000. The sponsor trusted our experienced scientists and agreed to the additional investment. We reworked the process. When we went into the cGMP suite to make the first batch, we ended up with 38 kilos, which was sufficient for the Phase II trial for which the product was intended. We wound up saving the sponsor $300,000 – and provided our customer with an enhanced asset.