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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By Jim Montague, Executive Editor

Not many car dealers will drive you home. Not many oven manufacturers will bake cookies for you. And not many mattress companies will tuck you in and check for monsters under the bed.

However, a lot of pharmaceutical and biotech manufacturers need some extra TLC these days so they can begin changing decades-old production practices and adopt process analytical technology (PAT) methods. Consequently, some of their machine builders and equipment suppliers are lending a hand.

For example, Broadley-James in Irvine, Calif., recently spent a year and more than $1 million to model and start running batches of donated CHO mammalian cell cultures this past January. The bioreactor builder is now producing antibodies in six of its 7-liter, benchtop bioreactor systems. It’s conducting this gutsy beta test to prove to potential users that it can accomplish on-line prediction of quality and economic parameters, show the value of high-fidelity process models for testing alternate control strategies and evaluate different means of online fault detection and identification (See Figure 1).

Broadley-James’ BioNet uses a benchtop version of Emerson Process Management’s DeltaV controllers, HMIs and software to bring industrial control capabilities to its bioreactor system, and uses multi-test BioProfile Flex bioanalyzers from Nova Biomedical Corp., to examine 15 parameters from a single 1-ml sample every four hours. 

Figure 1
Running Reactors
A technician at Broadley-James checks cell cultures growing in 7-liter bioreactors sampled every four hours by Nova Biomedical’s bioanalyzer and monitored by Emerson Process Management’s DeltaV.
The beta test also is using single-use bioreactors donated by Hyclone. Its 100-liter bioreactor will be used to prove scale-up of Emerson’s mammalian cell model, and results are expected by Interphex 2009 next March in New York.

“We previously had little information about what was going on in bioreactors. We usually took hand samples every 24 hours and had a pH probe and dissolved oxygen (DO) probe, but we didn’t know much about the quantity and quality of cells. If we had this data, we could introduce more control and make more and better quality product,” says Trish Benton, Broadley-James’ life-sciences consultant. “Incorporating DeltaV mass-flow controllers and digital I/O allows us to control several variables at once, makes the vessels all perform the same and gives us a nice, precise digital sequence. Having a well-characterized bioreactor system also means we know better what needs to go into the next, larger batches when we scale up.”

Catching Up to History

It’s lucky some suppliers are willing to give their pharmaceutical users so much assistance because few seem able to update their manufacturing practices on their own. Despite a flurry of interest and activity when the U.S. Food and Drug Administration’s (FDA) PAT guidelines were released in 2004, many of the subsequent conferences, publications and attention surrounding them have died down, and observers report that inertia has once again tightened its grip. This paralysis seems driven by fears that any process change may trigger revalidation requirements; the fact that many drug patents are due to run out by 2010-11, increasing layoffs recently; and profit margins that still have been large enough to stifle most production efficiency efforts. As a result, there still don’t seem to be more than half-dozen drugmakers with genuine PAT projects underway.

“There are competing forces affecting PAT’s implementation,” says Gawayne Mahboubian-Jones, product development manager at Optimal Industrial Automation, a U.K.-based PAT system integrator. “The positive forces are the need to reduce the gross inefficiency of manufacturing in the pharmaceutical industry and the need to improve product quality by improving process capability and removing the need for end-of-line testing and replacing it with a better method. However, negative forces resisting this change include pharma’s enormously conservative nature, its unwillingness to learn from outside and the ambivalent response of the FDA and regulators worldwide. Pharma believes that it’s ‘special,’ and has to develop all its own solutions to problems.

“The FDA’s PAT guidance was the first real step towards pharma adopting methods pioneered in other industries about 20-30 years earlier. That guidance was driven by the early recognition that the industry was heading into a financial dead-end because of higher drug development costs and fewer new drugs. The industry as a whole still doesn’t really understand what the FDA PAT group understood five years ago.”

Process-Based Background

Joe Alford, who recently retired from Eli Lilly, Indianapolis, Ind., reports that many people think of PAT as only three or four years old because of the FDA’s guidelines, but that his former company and others have been practicing its methods for 20 years as online process mass spectrometry (PMS) and online, high-performance liquid chromatography (HPLC). “These have been tried and true technologies for a long time,” says Alford. “PAT uses them for online and near-real-time testing to monitor process quality parameters and get pre-approval of products. So, instead of waiting hours for test results before harvesting from a bioreactor, PMS now gives enough data so users don’t have to wait. Because the FDA also was seen as part of the problem, its resulting PAT philosophy is that users should do what makes the most sense in their applications and then justify those decisions later.” 

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