Effectively crafting your process developmentBy Dr Alan Steven, Senior Principal Scientist, CatSci - 1st April 2020
What is needed to drive effective process development? Understanding how to take a holistic approach to the technical, economic and regulatory factors underpinning your chemistry is crucial. Dr Alan Steven, Senior Principal Scientist at CatSci, explores...
Behind every approved therapeutic should lie an environmentally and economically sustainable manufacturing process, enabling the drug substance asset to be made as efficiently as possible. As part of this drive to meet the evolving health care needs of the world, three broad areas of the drug substance process development must be undertaken.
These are as follows: establishing a sequence of intermediates used to make the active pharmaceutical ingredient(API) or its precursors, developing reagents and solvents used to convert one intermediate into another, and studying a transformation to build a fundamental understanding that allows processes to behave reliably and robustly in a manufacturing facility.
When a contract research organization (CRO) commences a process development project, the customer could want the knowledge for, and access to, a set of manufacturing processes that achieve some or all of the above. This requires the comprehensive consideration and evaluation of various routes under a plethora of processing conditions – a complex operation akin to playing a game of multidimensional chess.
A holistic approach for success
In order to reach a checkmate with your manufacturing process, there needs to be careful consideration of process chemistry, crystallization science and analytical science. All are important and should not be developed independently of each other. With respect to analytical method development, it is critical to avoid defaulting to a particular technique and instead choose an approach best suited for yielding information on the quality attributes of the chosen product. Consider your analytical method as a process as you would the chemistry, with numerous inputs, which could include variables such as flow rates, sample concentration and eluent pH.
When developing the chemistry, one of the most technically challenging areas is catalytic reactions. While this can provide significant rewards, understanding the catalytic cycle requires significant investment in tools and expertise. Moreover, the reaction performance can be negatively affected when the quality of an input material is slightly changed. Another important consideration is that while a catalyzed reaction may present a favourable environmental profile, the whole set of approaches must be considered holistically. This means that you should weigh up the reaction yield and selectivity against others perceived as being outside of the reaction process, such as the sustainability of using the catalyst metal and ligand under consideration.
Crystallization scale-up is arguably an under-appreciated area of process development science. There is no point in developing an efficient way of making covalent bonds in your synthetic route if you have challenges isolating the material. As well as having the scope to purge impurities, it’s also important to comprehend how crystallization and isolation can impact manufacturability and processing times across different scales.
Making your process viable
It is clear that scaling up is a significant technical challenge that could impact the long-term viability of a processing option. Process development scientists may hit a roadblock when having used a set of processes or products in the earlier stages of the project and manufacturing at larger volumes does not proceed as expected. Any reduction in mass transfer efficiency when increasing the scale can affect the rate and impurity profile of a reaction. This can be overcome through careful process development and reducing the number of phases present in a reaction solution.
Aside from technical challenges, another significant influence is the economics impacting the feasibility of a process. For example, a particular reagent could drastically improve yield, but there may be no industry need for manufacturing it in a cost-effective manner. Only when the drug has reached the market could this change through the increase in generated demand.
Differing regulatory considerations also have a substantial impact when evaluating the viability of a process. Take the different attitudes to nitrosamine impurities that may track through to a drug substance. Some authorities will require rigorous testing, whereas others are led by scientific evidence indicating no chance of the impurity reaching the final product. Being able to respond and accommodate these contrasting attitudes is critical.
After considering all technical, economic and regulatory factors, one must also look beyond the chemical reaction itself to ensure viability. There can be insufficient recognition of the fact that the most processing time, solvent usage and energy goes into isolating a product after the reaction is complete. This can lead to substantial downstream processing to remove reaction components in workup and isolation. While reaction yield is crucial, it’s important to keep in mind that a reaction is nothing without an efficient work-up and isolation.
There is no strict rulebook for developing an effective manufacturing process for a drug substance. However, one must always consider all chemistries and technical, economic and regulatory factors as part of an integrated approach that spans the entirety of the drug discovery and development pipeline. Through ensuring an open dialogue between CRO and customer, both can work hand-in-hand to deliver affordable, best-in-class small-molecule therapeutics.