Validation and Robustness

A traditional mantra used in the sector is ‘the process is the product’. This statement goes a long way to explaining how complex biologics can be manufactured in a safe manner. A strict definition of the process is made which has validated limits within which the process must run.

By operating in this fashion, one seeks to produce a consistent product which has proven efficacy from clinical trials. The US Food and Drug Administration (FDA) defines this act of process validation as ‘establishing documented evidence which provides a high degree of assurance that a specific process will consistently produce a product meeting its predetermined specifications and quality attributes’. This reliance on defining the process to such a high level arises from the difficulty in defining by analytical techniques biological products, particularly biopharmaceuticals, to the necessary degree of accuracy.
The key end-point of process development is demonstration to the regulatory authorities that the final large-scale process can indeed be operated consistently (typically three repeats are required). To ensure this and that subsequent manufacture is reliable, it makes logical sense that the process is designed such that the validated limits of operation are in robust regions, that is, the variability natural to such processes will be tolerated by the process and it will remain within its validated limits. To assist in developing such robust processes, many companies now embrace the principles of ‘quality by design’. Key to this strategy is the judicious use of monitoring and control strategies within the process.
Traditionally, this involves approaches such as absorbance measurements, gel electrophoresis and HPLC analysis; however, with the advent of more state-of-the-art technologies such as mass spectrometry, a greater degree of monitoring and hence confidence in the process is now envisaged. These more advanced approaches are being actively encouraged by the FDA via their Process Analytical Technology (PAT) initiative.