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IS PAT A SILVER BULLET?

Process analytical technologies are beginning to shoot

quality-by-design, model-predictive control into

long-resistant pharmaceutical applications.

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by Jim Montague, executive editor

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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ot 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 manufac-turers need some extra TLC these days so they can begin changing decades-old production practices and adopt pro-cess analytical technology (PAT) methods. Consequently, some of their machine builders and equipment suppliers are lending a hand.

For example, Broadley-James (www.broadleyjames.com) in Irvine, Calif., recently spent a year and more than $1 mil-lion to model and start running batches of donated CHO mammalian cell cultures this past January. The bioreac-tor 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-fi delity process models for testing alternate control strategies and evaluate different means of online fault detection and identifi cation (See Figure 1).

Broadley-James’ BioNet uses a benchtop version of Emer-son Process Management’s (www.emersonprocess.com) Del-taV controllers, HMIs and software to bring industrial con-trol capabilities to its bioreactor system, and uses multi-test BioProfi le Flex bioanalyzers from Nova Biomedical Corp. (www.novabiomedical.com), to examine 15 parameters from a single 1-ml sample every four hours.

The beta test also is using single-use bio-reactors donated by Hyclone (www.hyclone.com). Its 100-liter bioreactor will be used to prove scale-up of Emerson’s mammalian cell model, and results are expected by In-terphex 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 qual-ity product,” says Trish Benton, Broadley-James’ life-sciences consultant. “Incorpo-rating DeltaV mass-fl ow controllers and digital I/O allows us to control several vari-ables at once, makes the vessels all perform the same and gives us a nice, precise digi-tal sequence. Having a well-characterized bioreactor system also means we know bet-ter 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 pharma-ceutical users so much assistance because few seem able to update their manufacturing practices on their own. De-spite a fl urry 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 require-ments; the fact that many drug patents are due to run out by 2010-11, increasing layoffs recently; and profi t margins that still have been large enough to stifl e most produc-tion effi ciency 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 implemen-tation,” says Gawayne Mahboubian-Jones, product devel-opment manager at Optimal Industrial Automation (www.optimal-ltd.com), a U.K.-based PAT system integrator. “The positive forces are the need to reduce the gross ineffi ciency of manufacturing in the pharmaceutical industry and the need to improve product quality by improving process ca-pability 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 conser-vative nature, its unwillingness to learn from outside and the ambivalent response of the FDA and regulators world-

wide. Pharma believes that it’s ‘spe-cial,’ and has to develop all its own solutions to problems.

“The FDA’s PAT guidance was the fi rst real step towards pharma adopt-ing methods pioneered in other indus-tries about 20-30 years earlier. That guidance was driven by the early rec-ognition that the industry was head-ing into a fi nancial 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 fi ve 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 prac-ticing its methods for 20 years as on-

P A T I N P H A R M A

Figure 1. A technician at Broadley-

James checks cell cultures growing

in 7-liter bioreactors sampled every

four hours by Nova Biomedical’s bio-

analyzer and monitored by Emerson

Process Management’s DeltaV.

RUNNING REACTORS

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line 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.”

In fact, the FDA’s 2002 current Good Manufacturing Practices (cGMPs), on which its PAT guidance and quality-by-design (QbD) recommendations are based, reportedly give drugmakers more leeway to make process changes without traditional valida-tion if they make those changes within a pre-defi ned “de-sign space,” according to Brian Stephens, ABB’s (www.abb.com) PAT coordinator for North America. He adds that re-search indicates that using PAT can reduce cycle times from 25 days to 12 days on average.

“The heart PAT is understanding your process and then using that understanding to improve manufacturing oper-ations,” adds Bart Reiter, GE Fanuc’s (www.gefanuc.com) life-sciences global industry manager. “However, espe-cially in pharmaceutical fi rms, this can require changes in organizational thinking, behavior and funding alloca-tions. Many pharma companies have been manufactur-ing the same way for 100 years, so a sea change is needed to shift their focus from just making product and onto manufacturing. This is not a technical problem—it’s a cultural problem. For example, one of our service techni-cians was at a pharmaceutical operation that was still us-ing a ladle in its sugar-coating pans, and I know a guy who reported seeing an operator using a canoe paddle and a stopwatch in a blending operation.”

Control to the Rescue

To improve their process knowledge and understanding, some pharmaceutical fi rms are forming PAT teams and enlisting process control engineers and suppliers to help update their primary and secondary processes from offl ine sample testing to online or at-line principle component analysis (PCA) of multivariable processes and projection of latent structures (PLS) to begin to accurately predict that a given batch will meet its quality parameters.

“Instead of waiting for end-product test results, the FDA’s PAT guidelines say manufacturers can release product before testing if they can prove they have enough knowledge of their entire process and the mul-tivariate analysis tools to accurately predict that they’ll meet required product quality parameters,” says Terry Blevins, Emerson’s principle process management technologist. For example, Emerson’s DeltaV Insight software identifies process dynamics with each loop and at each point of a batch, so users can diagnose, identify gains and make process changes as a batch pro-gresses. He adds that Emerson recently helped Baxter Healthcare (www.baxter.com) avoid $6 million in capi-tal revalidation costs by implementing multi-loop pro-cess control to the distilling process at a new anesthetic production facility.

Unfortunately, these tasks aren’t made any easier by the fact that batch systems must deal with numerous different operating conditions during their cycles (Figure 2). For instance, feed-fl ow, oxygen and/or reagent demands can vary widely during a typical bioreactor cycle, which can make it hard for sensors and controls to adhere to param-eters and maintain product quality, so PAT projects often need to implement continuous performance monitoring and control functions. Despite the upfront development and confi guration costs, PAT can help users save time and improve quality by moving from manual feeding that can shock batches and increase variability to continuous feed that can improve consistency.

“The ability to sample and test every four hours, which Broadley-James’ bioreactor can do with Nova’s analyzer, ex-

P A T I N P H A R M A

Figure 2. Typical bioreactor and other batch applications must handle numerous

operating conditions, and so they need ongoing performance monitoring of

measurement and control to reduce variability and maintain product quality.

Reagente.g. ammonia

FC203

FC201

Foode.g. glucose

Charge

e.g. Media

AC204

FC202

TT206

TC206

Coolant return

pH

RSP

RSP

Dissolved

oxygen

To harvest

Coolant

supply

Vent

Air

PT208

PC208

TC207

AC205

IT209

LT210

TT207

AT205AT

204

FT203

FT202

FT201

JUGGLING OPERATIONS

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pands our knowledge and allows more impact on the pro-cess,” adds Blevins. “However, these methods need to be de-signed into processes at the product development stage.”

Telescoping Down, Hurrying Up

Likewise, New York City-based Pfi zer’s plant in Ireland re-cently installed near infrared (NIR) spectrometers to moni-tor moisture closer to real time when drying its Lipitor prod-uct. Drying the pills used to take two days, and then samples were analyzed offl ine. However, after jointly developing and installing ABB’s FTPA 2000 NIR analyzers and software, Pfi zer discovered that it was able to dry the pills in one day, and saved about $10 million in one year, says Thomas Buijs, ABB’s produce line supervisor for AAS and remote sensing.

“Traditional pharmaceutical manufacturing wastes huge amounts of time waiting for lab results that come back too late to optimize its processes,” says Buijs. “The key factor is being able to measure closer to real time, which allows bet-ter optimization and reduces cycle time.”

Buijs adds that ABB also helped Novartis, based in Basel, Switzerland, add a small NIR device and battery-powered WiFi equipment to a three-powder blending application in a V-shaped arrangement of two drums to make sure the powders were blended homogeneously. Us-

ing NIR meant that waiting for lab results was no longer needed in this application.

Sound Advice, Growing Interest

“There are articles and training courses on PAT, but the change is also a mindset change on the factory fl oor. As long as pharmaceutical manufacturers think of quality in tradi-tional terms, they’ll continue to fail to understand the need for PAT or how to apply it,” explains Mahboubian-Jones “Pharma has a huge amount to learn, but the biggest lesson is that it’s not unique, that others have similar problems and have developed solutions which make an excellent starting point. One way is to bring in expertise from outside the in-dustry, which is very rare in pharmaceuticals.

“One of my mantras when consulting to the pharma in-dustry 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 fi ne 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 in-dustry and work hard to ensure that you stay close to a cor-porate sponsor.”

P A T I N P H A R M A

Piloting a PAT ProjectIt’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 specifi c 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 suffi cient introduction and education in PAT principles

via many public-domain sources, such as www.fda.gov, www.

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 fl exibility and some

freedom from having to revalidate, but that fl exibility needs

to occur within well-defi ned operational ranges. PAT advises

using methods that don’t introduce new barriers into validated

processes, such as NIR components that require fewer modifi -

cations 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

specifi c 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 pro-

cesses. 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 prod-

uct 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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Despite their refl exive resistance, Benton adds that some folks from the major pharmaceutical fi rms 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 sci-entists don’t quite grasp it yet, and so they’re still skeptical.”

Because its beta test is still running, Benton adds that fi -nal results aren’t available yet. There were also some chal-lenges with getting six sensors installed on the small, 7-liter vessels, which threatened to change the test’s characteris-tics. However, the expected effi ciencies and benefi ts gen-erated by Broadley, Emerson and Nova’s partnership likely will be groundbreaking. “We’re looking at substantially re-ducing 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 particu-lar 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 feasibil-ity plans, brought in IT, developed new applications, con-ducted monitoring and statistical analyses, implemented new processes, trained staff, presented internal case studies and moved toward continuous improvement. The case stud-ies showed people that investing in PAT was worthwhile be-cause 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 tech-nology. 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, mill-ing, drying and compression across multiple products.

Jim Montague is Control’s Executive Editor.

P A T I N P H A R M A

Reprinted with permission from Control Magazine, June 2008. On the Web at www.controlglobal.com.© PUTMAN. All Rights Reserved. FosteReprints: 866-879-9144, www.marketingreprints.com.

ER-00087-June08

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