Is PAT a Silver Bullet?

Ready to Kill Some Werewolves? Process Analytical Technologies (PAT) Are Beginning to Inject Quality-by-Design (QbD), Model-Predictive Control, Risk Management and Other Well-Known Process Control Methods into Long-Resistant Pharmaceutical Applications

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“One of my mantras when consulting to the pharma industry is, ‘Go out and learn what others have done with the same processes.’ Food and beverage uses many of the same processes as pharma OSD, while fine chemicals is strongly parallel to pharma API, and the brewing industry would be a very useful lesson for pharma biotech. So start small, look for low-hanging fruit, set aggressive time scales, be prepared get help from external experts, look outside the pharma industry and work hard to ensure that you stay close to a corporate sponsor.”

Despite their reflexive resistance, Benton adds that some folks from the major pharmaceutical firms want to learn about PAT and use Broadley-James’ bioreactor system. “We’re seeing a lot of interest from the automation guys in the pharma plants,” says Benton. “However, many of the scientists don’t quite grasp it yet, and so they’re still skeptical.”

Because its beta test is still running, Benton adds that final results aren’t available yet. There were also some challenges with getting six sensors installed on the small, 7-liter vessels, which threatened to change the test’s characteristics. However, the expected efficiencies and benefits generated by Broadley, Emerson and Nova’s partnership likely will be groundbreaking. “We’re looking at substantially reducing the usual 18 months spent on process development, getting more and better quality data that can be used for all ranges of scales, and securing accurate predictions of actual performance if we change the control on a particular variable.”

Onto the Plant Floor

Though some drugmakers have PAT in their R&D facilities, moving it into actual processes is another ball game entirely. Pedro Hernandez, Ph.D., QbD and PAT leader at Wyeth’s (www.wyeth.com) Pharmaceutical Development Center in Puerto Rico and New York, explains that his company began this migration three years ago by acknowledging at all levels that Wyeth needed QbD and real-time monitoring.

“We needed and used champions and end users in our organization who committed to saying it was OK to make time for PAT,” says Hernandez. “Then we drafted feasibility plans, brought in IT, developed new applications, conducted monitoring and statistical analyses, implemented new processes, trained staff, presented internal case studies, and moved toward continuous improvement. The case studies showed people that investing in PAT was worthwhile because it will give us better knowledge and control of our unit processes. You could see the lightbulbs go off in their heads. It's about culture and philosophy, as well as tools and technology. It's a commitment and recognition that QbD, PAT and achieving continuous quality assurance is everybody's responsibility.”

As a result, Hernandez adds that Wyeth presently uses PAT to monitor several unit processes like blending, milling, drying and compression across multiple products. 

Jim Montague is Control’s Executive Editor.

For expanded coverage, videos about Broadley-James, audio interviews, and PAT stories and other resources from Control’s sister publication, Pharmaceutical Manufacturing, please visit and read the online version of this article on its landing page at www.controlglobal.com/PAT

Piloting a PAT Project

It’s not easy to get a process analytical technology (PAT) model and project up and running, but there are a few basic steps that pharmaceutical manufacturers or other process users can take to make sure they implement the most useful solution for their application, according to several veteran phamaceutical manufacturers, process control engineers, system integrators and equipment suppliers.

  • Be absolutely clear about why you’re seeking to implement PAT and what you want to do with it. PAT should be tied to a specific business initiative, such as reducing cycle time or adopting lean manufacturing. This goal should determine the resulting PAT model’s target and identify how online process measurement can help accomplish it. This can be used for any of the three main PAT tools, which include monitoring, control and optimization.
  • Secure sufficient introduction and education in PAT principles via many public-domain sources, such as www.fda.govwww.ifpacnet.org, www.ispe.org, www.cfpa.com, www.ich.org and www.pharmamanufacturing.com.
  • Sell the PAT project to organization’s members. Securing management buy-in is critical. Align the PAT model with value that management wants to unlock from its processes. Don’t make PAT project too bottom-up or too top-down. Try to meet in middle and make PAT project grow from there.
  • Run experiments needed to qualify the proper design spaces needed by your PAT model and methods. The U.S. FDA’s PAT guidelines give users added operational flexibility and some freedom from having to revalidate, but that flexibility needs to occur within well-defined operational ranges. PAT advises using methods that don’t introduce new barriers into validated processes, such as NIR components that require fewer modifications to existing equipment. 
  • Because implementing PAT can risk touching already-validated systems, conduct a production pilot, preferably in a process development lab. This can help users better determine the specific design space allowable for PAT in their application and point them to the right smart transmitters or other devices they can drop in for the least impact on their validated processes. For example, smart process control devices with very predictable inputs and outputs often can be dropped into every device and phase of a process, while still ensuring that the overall system is properly bounded.
  • After the pilot is completed, check the results to make sure they’re predictable and meet the application’s original product release criteria. Once you have a tested and viable PAT method, it should be standardized so the organization’s other users and sites can implement cookie-cutter versions into their applications.
  • Track performance and results at each site and use feedback to constantly improve your PAT model and methods.
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