PAT guidance delivered to drug industry

Conventional pharmaceutical manufacturing is generally carried out using batch processing, with laboratory testing conducted on collected samples to evaluate quality. While this is effective, the downside is that quality problems are often detected too late to avoid the loss of the affected batch. Using PAT, it is hoped that problems will be picked up early, in real time, allowing remedial action to be swiftly taken.

The PAT guidance is part of the FDA's cGMP revamp, which came to a conclusion a few days ago and was designed to overcome a hesitancy by pharmaceutical companies to apply innovations in the manufacturing processes, in part because of uncertainty about how the regulator would respond to any changes.

This has led to a situation in which many manufacturing procedures are treated as being frozen, and process changes are managed through regulatory submissions, said the FDA, and this is undesirable from a public health perspective as quality control is not advancing alongside technological improvements.

The mantra that has emerged over the last few months at the FDA is: 'quality cannot be tested into products, it must be built in'. And this requires a system of designing, analysing and controlling manufacturing processes through timely measurements of critical quality attributes.

These could be as simple as the temperature and pressure in the batch reactor and the analytical testing of in-process materials, but companies have already developed their own interpretation of the guidance for specific applications.

For example, in partnership with GlaxoSmithKline, Axsun Technologies has developed an analyser (NIR-APS) that provides near infrared monitoring of drying processes, while Mathis Instruments has a technology based on thermal effusivity to evaluate, monitor and control the uniformity of powders, liquids and creams, all in real time.

The FDA believes that the net result of PAT is a reduction in production cycle times, prevention of rejects, scrap and re-processing, the ability to release product in real-time, according to demand, and increases in automation to improve operator safety and reduce human errors. And the latter is particularly timely, given yesterday's news that Chiron had its license to produce flu vaccines suspended for three months after human error led to a serious contamination incident.

Other potential benefits to manufacturers, according to the FDA, are improved energy and material use, increased capacity and the elimination of some scale-up issues.

For its part, the FDA has provided comprehensive guidance on the technologies that can be used in PAT, including process analysers, process control systems and knowledge management tools. More information is available on the agency's website​.

The FDA also plans to set up a dedicated PAT team to monitor chemistry manufacturing and control (CMC) and provide training and guidance.