Jonathan Knight, VP New Product Development at Cambrex, dissects the route used to manufacture APIs, highlighting those steps that can make a process ideal.
Jonathan Knight, VP New Product Development, Cambrex
Jonathan Knight
During a drug’s clinical development, the focus is very much on producing API material — with an emphasis on speed — and the route used to manufacture the molecule is rarely altered past Phase IIa. It may be that only as the demands for product increase throughout the clinical stages, and into commercial manufacturing, that the synthetic route is scrutinised, and process chemists and engineers look to adapt it.
Frequently, there are issues with synthetic routes where innovator biotech companies simply have not had the time, or resource, to dedicate to route development. These include the use of expensive key intermediates; poor and expensive registered processes; detrimental environmental footprints; and challenging steps to scale up using commercial scale equipment. Route evaluation is common for contract manufacturing organisations (CMOs) once the market has been established for a drug, several years after launch.
Route evaluation
The economics of the route are driven by the cost of starting materials, the number of synthetic steps, yields, process time and robustness of the process. Manufacturing on a smaller scale, with steps that may involve chromatography, chiral resolutions or multiple functional group protection and de-protection steps may be acceptable, but once the volumes of batches become higher, in many cases, these must be removed.
When assessing a route, the obvious place to begin is to look at the cost and availability of the key starting materials, as well as the overall cost of goods, to see if these are limiting factors. One must also be aware of any patent restrictions that should be avoided, and the potential to protect the intellectual property of a new route which could give an enormous commercial advantage.
The environmental impact of the route is also a factor to be taken into consideration. The use of chlorinated solvents on a large scale is increasingly restricted, and the cost of energy and waste becomes of greater importance as process volumes and manufacturing scales increase. Using alternative solvents which reduce the impact on the environment and demand less energy are obviously beneficial.
The robustness of the route and the reproducible purity of final products is of paramount importance. Having steps that require multiple work up procedures and purifications not only increases the overall process time spent in the plant, but can also potentially reduce overall yields. With ever tightening rules on elemental impurities in final API material, removing a metal-catalysed step can bring great improvements, particularly if that step is near to the end of the overall synthesis.
As well as purity, the physical characteristics of the end-product may determine a need to change a process. If the end-product is difficult to handle, for example, carrying a high electrostatic charge, it may be that the final recrystallisation solvent used needs to be changed.
What is an ideal process?
Cheap, readily available starting materials that can be converted in the fewest number of synthetic steps which are atom efficient— by which molecular weight is constantly added to the target molecule rather than being taken away — are fundamentals to efficiency. Additionally, the route should be convergent, rather than linear, as well as robust, reproducible and high yielding.
For ease of manufacture, reducing the number of isolation steps within a process is desirable, so being able to telescope processes throughout the synthesis can reduce the overall process time of each batch, and reduce the quantity of solvents used. Being able to utilise standard plant equipment efficiently throughout a process avoids unnecessary investments to manufacturing facilities, and can reduce bottlenecks and delays where certain steps may be scale-limited by availability of equipment. Additionally, having a manufacturing strategy that limits and manages the waste produced by a particular process is important, and using solvents that can be reused and recycled within a process — albeit according to stringent regulatory parameters — can be greatly beneficial in terms of the economics.
Identification of the key drivers for change from the outset is important, be it any of the factors discussed. There may not be a perfect process, and practicality may dictate compromises within route development, but it is important to set key project goals, and to consider all aspects of a process to strive to meet them.