PAT implementation projects don’t have to be complicated. Leveraging supplier expertise and documentation can significantly reduce engineering efforts, help shorten project timelines and reduce commercial risk. The cost benefits can be significant, explains Alon Vaisman, Applications Development Manager Pharmaceuticals of Malvern Instruments.

Prompted by the FDA’s Process Analytical Technology (PAT) initiative and subsequently by the advent of Quality by Design (QbD), pharmaceuticals companies have invested substantially in projects to improve process control. Today there are few that do not have a PAT, QbD or other group, and many have partnered with academic institutions conducting research in related areas. However, when the question of cost savings resulting from PAT and QbD is raised, there is rarely a clear answer.

Determining ROI

Return on investment (ROI), the usual business driver for improvement projects, can sometimes seem elusive in the pharmaceuticals industry. However, quality is the key. The cost of a single out-of-spec batch may dwarf the investment in the PAT system that would have saved it. When PAT is deployed at a critical point in the process and can influence the quality of the product . at a step where specifications are tight and risk of failure is high (narrow design space), for example . ROI can be substantial.

Influencing the process while it is running is relatively new in pharmaceuticals manufacturing, requiring real-time, or near realtime, data and a decision-making (open- or closed-loop control) system that acts on the process. Such systems maintain product specifications through minor feed variability and generate an alarm when something goes wrong so the process can be stopped.

These control systems are widespread in industries where manufacturing is continuous. The pharmaceuticals industry is moving towards continuous manufacturing, but the transition may span decades and batch manufacture remains the norm. Compared with continuous processes, batch processes spend more time in transient states, where product losses and variability can be higher.

A PAT system offers dual benefits: tight control of the steady state portion of the process and swifter transition times that reduce product losses. An example is the installation of an Insitec online particle size analyser by Malvern Instruments to monitor and control active pharmaceutical ingredients (API) milling. This closed-loop system automatically controls the milling process and eliminates offline testing, which alone could save tens of thousands of dollars per milling campaign.

A similar online particle size analyser in a consumer health products plant is monitoring the final product after jet-milling and sieving steps, activating an alarm if particle size is out of spec. Outof- spec material is then diverted until the process is back on track. Before online particle size analysis, around US $200,000 worth of product was scrapped each year, but since its installation, no batches have been rejected on the basis of size.

Building advantage

In the examples cited, ROI is achieved because the PAT system:

  • is deployed in commercial manufacturing
  • is monitoring a critical control parameter
  • provides information in real time, allowing timely action
  • uses measurement principles the same as/easily comparable with the existing QC method.

Unlike many PAT tools that require complex statistical modelling to apply the data, particle size analysis by laser diffraction is well understood. Bringing this technology to the factory floor therefore carries a lower risk and gives direct payback through labour reduction and real-time product release.

Once a target application is identified, implementation starts with an engineering study to test the system in the process, and determine all application and integration requirements. Here the applications expertise of the supplier as well as the ability of the analytical unit to exchange information with other system components are important. Standard data exchange protocols (such as OPC) and flexible instrument control software (such as Malvern Link) allow Insitec analysers to operate as embedded and standalone units, with local operation or remote control.

Taking the consultative approach described here with its upfront engineering streamlines later commissioning, process qualification and validation. This approach also supports project justification and minimises unknowns. As more companies follow this route, it is increasingly clear that the right technology used in the right place will pay for itself . and more!