PAT Looms over Pharma

Many Pharmaceutical Manufacturers Have Been Dragging Their Heels on Adopting Process Analytical Technology (PAT) Techniques for Years, but Now the Pressure Is On

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This article was printed in CONTROL's June 2009 edition.

By Rich Merritt

The pharmaceutical industry has taken a beating during the past two years.

Generic drugs, particularly from India and Southeast Asia, are putting price pressures on domestic manufacturers. As patents run out on today’s drugs, more generics will flood the market.

Consumers are getting more vocal and less willing to pay prices that U.S.-based drug companies charge. If President Obama gets his national health care program through Congress, most likely it will include limits on drug prices. This will further cut into drug company profits.

In addition, major quality issues have plagued the drug industry over the past two years, severely damaging its reputation. On April 20, 2009, the Associated Press (AP) reported that some drugmakers are releasing chemicals such as codeine, antibiotics and sex hormones into drinking water.

Finally, hanging over the heads of pharma is the Process Analytical Technology (PAT) initiative, a Sword of Damocles that is one stroke of a government pen away from changing from an advisory to a requirement.

So, the pressure is definitely on pharma to adopt PAT. Meanwhile, while pharma has been dragging its heels on PAT, other industries have been using PAT for years—whether they realize it or not.

PAT’s Not a Rule—Yet

The PAT initiative requires that information from process analyzers be used to control processes in real time. It was developed for the pharmaceutical industry by the U.S. Food and Drug Administration (FDA), which, everyone fears, will actually enforce it some day. So far, it’s just advisory, and not a regulation. The AP story might be the final straw that makes the FDA require drug companies to track emissions with analyzers and integrate those results into the process control system.

Many of the pharmaceutical PAT applications we read about in the trade press aren’t doing process control; they’re just gathering information from analyzers. Therefore, many of those who think they already are doing a PAT application do not; they’re just gathering data too.

Conversely, many users in the chemical, petrochemical and other industries deny they’re using PAT, but they’re acquiring data from process analyzers and using it to control processes. So, they’re performing PAT-like functions in the true spirit of PAT without even realizing it, and without saying so.

The real kicker is that the chemical and petrochemical industries are far ahead of pharmaceutical companies in their use of real-time process analyzers for control purposes. Pharma could learn a lot from other analyzer users, but pharma has its own agenda, economic reasons and political considerations that keep it from embracing PAT.

PAT or Not?

Even when a drug company is doing real-time control with a process analyzer, it’s reluctant to call it PAT. Or maybe sometimes it’s difficult to differentiate between PAT and just good engineering practice. For example, Raylo Chemical division of Gilead (www.gilead.com) in Edmonton, Alberta, Canada, uses on-line analyzers to ensure quality of its active pharmaceutical ingredients and advanced intermediates (Figure 1). 

“The compounds we produce are used in various human applications from cancer treatments to antivirals,” says Rob Pastushak, Raylo’s senior technical supervisor of pharmaceutical manufacturing. “The majority of our business involves exports to the United States. If we don’t receive FDA approval, we’ll go out of business. We must clearly demonstrate that we control every aspect of our manufacturing process at all times, and that our instruments are properly calibrated on a regular basis.

“If our process is off even slightly, the cost implications are significant. A small 1%-2% increase in the target commercial yield is translated as 100% pure profit. Likewise, a consistent loss of 1-2% of the commercial target yield translates as lost profit. You don’t stay in business long with this type of performance.”

Measuring pH is critical to the process, so Pastushak selected a DolpHin pH sensor from Foxboro Measurements & Instruments (www.ips.invensys.com). To ensure that the product comes out of solution with the proper pH, Raylo typically dilutes the organic mixture with water. This mixture must then be measured for pH and adjusted until the right balance is achieved. To adjust the pH, Raylo pump-circulates the solution through the bottom of each vessel to the top, where the  sensor measures pH in a slurry loop. Based on signals from the pH sensor, pre-made caustic or acid solution is added until the right level is achieved. If the pH remains stable for two minutes, the pH test for any secondary crystallization level ensues. The pH analyzer provides reactive, real-time pH measurements, which are key to reducing cycle time.

“The results have been consistent from batch to batch,” says Pastushak. “As soon as we add a solution to adjust pH, the probe responds immediately and provides the new pH reading. We’ve found it to be accurate to ±0.03 pH, which is well within our target limits.”

Raylo, however, is only one of a few pharma companies that will admit to using real-time analyzers to control a process.

Where’s PAT?

As Jim Montague reported last year in Control, “There still don’t seem to be more than a half-dozen drugmakers with genuine PAT projects underway,” (“Is PAT a Silver Bullet?”, June ’08, p. 54). A recent article in another publication uncovered only one more new application, in biotech.

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