Preparing for process validation & commercial manufacture
Dr Rebecca Matters, process development team leader at Onyx Scientific, explores the early stages of process validation in API development
As an API advances through the stages of clinical development and overcomes its many challenges, the possibility of commercial production brings both excitement and apprehension. Delivering consistent, high-quality material at earlier stages does not prove that a process is suitable for commercial supply.
To achieve reliable production of high-quality material at a commercial scale, it is necessary to identify the critical quality attributes( CQAs) and critical process parameters( CPPs) that influence them and maintain appropriate control. This process is labelled process validation( PV), which the FDA defines as“ the collection and evaluation of data, from the process design stage throughout production, which establishes scientific evidence that a process is capable of consistently delivering quality products”.
These activities are split into three distinct stages: process design, process qualification and continued process verification. For this discussion, it is assumed that the synthetic route is fixed and that the process design is both cost-effective and sustainable.
Before formal validation begins, the process design phase focuses on understanding how each element, from raw materials to analytical methods, affects product quality. This foundation ensures that every stage of manufacturing can be controlled, measured and reproduced at scale.
To validate a process successfully, these elements must align both harmoniously and simultaneously. This
Typical scale-up process equipment used for early-phase through to low-volume commercial manufacture
relies on several areas of expertise collaborating, each playing a vital role in embedding quality and control throughout the manufacturing process, which are discussed below
Raw materials: Defining the starting point
APIs are often structurally complex and the overall synthetic route to the final target compound can involve many stages. Impurities and intermediates that appear early in the synthesis are usually removed or transformed during later steps before the API is isolated.
For this reason, it is not always necessary for every part of the synthesis to be performed under GMP conditions. Instead, manufacturers define a synthetic intermediate as the point where formal GMP oversight begins. This compound becomes the regulatory starting material( RSM), the point at which the process must meet the highest quality and documentation standards.
For a synthetic intermediate to qualify as an RSM, it must contribute a significant structural fragment to the API and be fully characterised, meaning its identity, purity and structure are clearly understood. As the RSM directly influences the quality of the API, there must be analytical methods in place to detect any impurities present.
The behaviour of these impurities should be tracked through fate and purge studies, which demonstrate whether they are removed, converted or carried forward into later stages. These studies justify the RSM’ s purity
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