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Page 1: PHARMA'S PROCESS ANALYTICAL TECHNOLOGY

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PHARMA'S PROCESS ANALYTICAL TECHNOLOGY Today's analytical chemists in the pharmaceutical industry are trading lab coats for hard hats CORINNE A. MARASCO, C & E N WASHINGTON

TH E FOOD & D R U G ADMINISTRATION'S RECENT A P -

proval of process analytical technology (PAT) for use in the pharmaceutical industry is being hailed by drug manufacturers because it encourages process opti­mization based on process understanding. Now, an­

alytical chemists in pharma will be able to implement advanced analytical frameworks that have resulted in improved quality in other industries. Chemists who are trained in PAT and who are

able to make the transition from traditional analytical lab-based monitoring have a dis­tinct advantage in employment. As PAT evolves in the pharmaceutical industry the skills that are considered desirable for an­alytical chemists are likely to evolve as well.

PAT allows for the design and control of manufacturing through timely analysis of process parameters that are critical for en­suring an acceptable end point. FDA be­lieves that PAT will encourage the devel­opment of new and efficient tools for pharmaceutical development, manufac­turing, and quality assurance resulting in increased product quality and reduced costs for the industry

Prior to PAT's approval by FDA, quali­ty analysis in pharmaceutical manufactur­ing was carried out by testing intermediates and final products. Products that failed to meet spécifications were rejected. Under PAT, the focus is on both the process and the end product. The goal is to continual­ly generate real-time data to increase the level of certainty throughout the process.

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EMPLOYMENT

Page 2: PHARMA'S PROCESS ANALYTICAL TECHNOLOGY

VISION Good chemistry begins with you. Your perspective, your contribution, your science.

We invite you to share your chemistry with us.

Inside our cutting-edge research facilities in Cambridge, MA, world-class scientists

have all the resources they need to carry out the mission of lifesaving drug discovery.

We now have opportunities for all functional specialties in addition to the following

disease areas: cardiovascular, diabetes, oncology, and infectious diseases.

Our openings include positions in the following areas:

Analytical Chemistry - NMR (BS/MS) Automated Parallel Synthesis ~ Sr. Scientist (PhD) Computer-Aided Drug Design (PhD) Mass Spectrometry-Protein & Small Molecule (BS/MS) Metabolic Science (BS/MS) Organic Chemistry (BS/MS/PhD)

To view descriptions of all open positions and to apply, visit www.nibr.novartis.com

and follow the links to Careers and Job Opportunities.

Novartis is committed to embracing and leveraging diverse backgrounds, cultures, and talents to achieve competitive advantage. Novartis is an equal opportunity employer. M/F/D/V

www.nibr.novartis.com ©2005 Novartis AG

Page 3: PHARMA'S PROCESS ANALYTICAL TECHNOLOGY

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fl) NOVARTIS NOVARTIS INSTITUTES FOR BIOMEDICAL RESEARCH

The New Pathway to Drug Discovery

Page 4: PHARMA'S PROCESS ANALYTICAL TECHNOLOGY

EMPLOYMENT

According to data from the American Chemical Society Office of Member In­formation, the pharmaceutical industry is the largest employer of analytical chemists. The U.S. Bureau of Labor Statistics is projecting that overall employment of chemists is expected to grow anywhere from 10 to 20% through 2012, with most of that growth concentrated in pharma­ceutical and medical manufacturing and in scientific research and development serv­ices firms. Although those forecasts are conditional, analytical chemists are nonetheless expected to play a significant role as PAT implementation evolves, ac­cording to the analytical community in general as well as people interviewed by C&EN. Given the range of tasks that an­alytical chemists currently perform in the pharmaceutical industry, it is likely that PAT will offer them new and expanding opportunities in the future.

PROCESS ANALYTICAL measurements can be taken one of three ways: at-line, where the sample is removed and analyzed close to the process stream; on-line, where the sam­ple is diverted from the manufacturing process to an analyzer and possibly returned to the stream; and in-line, an invasive or noninvasive process that analyzes the sam­ple while it's part of the process stream.

PAT has been used extensively in other industries such as petrochemicals for years, but the pharmaceutical industry has lagged behind largely because of perceived regu­latory barriers.

"PAT is a formalized way of looking at things that many pharmaceutical manu­facturers have been doing informally," ac­cording to Elizabeth Fowler, vice president of quality and regulatory affairs at Xcel-lerex, a Marlborough, Mass., provider of contract services for process development and manufacturing for biopharmaceuti-cals. "It's also making sure that you use the data you collect and analyze them to in­crease process understanding and improve process control and efficiency PAT guid­ance encourages innovation to bring more control into the process and makes it eas­ier to implement new techniques for mon­itoring approved processes."

What led FDA to realize that PAT was worthwhile, Fowler says, "is a desire to en­sure that the agency is doing what it can to protect public health through ensuring product quality and to bring down the cost of drugs. The manufacturers' perception has been that FDA approvals were based on paperwork, not on science, and all the paper in the world doesn't make a high-quality product. Product failures—espe­

cially ones that might have been caught early on—are more expensive to fix after­ward than they are during the manufac­turing process."

Prior to FDA's support, PAT in the pharmaceutical industry was conducted on a "don't ask, don't tell" basis because of the regulated environment. Many analyt­ical chemists currently using PAT have ei­ther picked it up on the job or transitioned from another industry that uses it.

Andrew J. Lange, senior principal sci­entist at Pfizer in San Diego, says: "The people I know are either engineers or they started as analytical chem­ists who morphed into process analytical scientists. There is also a subset of peo­ple working in pharmaceu­ticals who have been re­cruited from the chemical industry The majority of an­alytical chemists have never set foot inside a manufac­turing facility; what they do is get samples from the fac- Wasylyk tory to analyze, but the sam­ple is then out of its native environment. In process analysis, you're making mea­surements in situ, and there are a host of considerations specific to that environ­ment that you don't consider in the labo­ratory The advantage is you're looking at the material as the process is going on."

Lange began as an analytical chemist in the technical operations area, as opposed to the quality operations area, which mea­sures samples in the lab. "Technical oper­ations involved process support, process start-up, and troubleshooting," he says. "I was the sole analytical chemist in techni­cal operations, and the rest were mostly organic chemists and engineers. My tran­sition into the process analytical realm was straightforward as a result."

John M. Wasylyk, principal scientist in analytical R&D at Bristol-Myers Squibb, New Brunswick, N.J., has been working in PAT over the past decade. "We've been doing in-line analysis for years, simply in terms of pressure monitoring and turbid­ity—simple techniques that have been around for years," he says. "The analytical chemist either works with people who are doing PAT or wears two hats running both traditional methods and new technology There are spectroscopists who use and are versed in PAT techniques, but the tech­niques are only as good as the primary methods behind them, such as high-per­formance liquid chromatography gas chro­matography, or UV analysis."

Steve Doherty, who works in process analytical measurement technology for Eli Lilly in Indianapolis, says that 13 people in his group perform PAT. The four senior scientists in the group all came from the commodities chemicals industry "It's fair­ly common," he says. "Right at the time that companies are trying to grow process analytical functions, the downturn in the pharmaceutical climate makes it hard to justify personnel increases, so most of the hiring is done byword of mouth."

"By bringing pharma­ceutical manufacturing to a state in which we under­stand the processes very well, we can control the critical process parameters, which must be within a par­ticular range for the final product to meet its quality attributes," Fowler says. "By bringing everything in the process to its desired state, you can improve product uniformity and quality by making the process much more consistent."

According to Rick E. Cooley a team leader in the manufacturing science and technology division of Eli Lilly: "Think of process analytics as taking the lab and mov­ing it next to where the sample originates. The traditional way is to take the samples to a remote lab for processing and analy­sis. In PAT, you take the analysis and con­nect it directly to the process, eliminating the transmission of the sample from the process to the lab.

"People have been doing feedback process control for years in pharmaceuti­cals," Cooley says. "But what they've been measuring isn't based on the critical quali­ty attributes of the product. If I want to mill an API {active pharmaceutical ingre­dient] to a certain particle size, then I need to run the mill at a certain rpm. The con­trol may be on maintaining the mill at that speed. Under PAT, I measure the critical quality attribute and change the process to achieve that. % u validate a process under a certain set of operating parameters, then try to control the operations parameters with the assumption that you'll get a qual­ity product out of the process. If there is a variation in the equipment or the raw ma­terials, the variability shows up in the end product. Now, FDA is asking us to measure and predict the attribute and to change the process to keep it under control."

Bristol-Myers Squibb and other com­panies use multiple probes in reaction ves­sels in the lab prior to pilot plant and man-

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Page 5: PHARMA'S PROCESS ANALYTICAL TECHNOLOGY

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Eli Lilly and Company is an equal opportunity employer.

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Page 6: PHARMA'S PROCESS ANALYTICAL TECHNOLOGY

EMPLOYMENT

ufacturing, Wasylyk says. "With PAT we can get closer to the reaction and the processes in the manufacturing, pilot plant, and developing stage," he adds. 'Are there side products, by-products, or degradents that form? How do we improve the quali­ty of our product? You use an FTIR probe, a Raman probe, an N I R probe, and a probe to monitor crystal growth. Hope­fully one of the tools or all four will pro­vide some knowledge. In the reactions we run, a spectroscopy tool won't provide a big advantage for rapid robust reactions that go correctly and work quickly However, the next reaction or process maybe long, arduous, and haz­ardous, so those are the ones that you want to put PAT to the test."

The relationship be­tween FDA and the phar­maceutical industry is Koch changing under PAT. For example, FDAhas set up "safe harbor" al­lowances for industry to implement PAT on existing processes and avoid regulato­ry repercussions. Also, to increase the like­lihood that New Drug Applications are accepted, "FDA is bending over backward to help us," Wasylyk says. "They toured various pharmaceutical manufacturing and pilot plants in order to learn about these techniques. We are encouraged to contact them prior to filing about the tools we're using or the data we have collected in order to formulate and communicate our implementation plans."

CHEMOMETRICS is another essential tool in PAT implementation; specifically, sta­tistical knowledge and an understanding of how the chemometric packages work are essential. "We push for the process chemists to learn experimental design, how to perform multivariate analysis, and how to change multiple parameters to shorten the experimental time you have in order to come up with the best chemical process," Wasylyk says.

Says Fowler: "The interactions in even a single step in a process can be very com­plex, and there are any number of differ­ent variables that could be adjusted. Mul­tivariate analysis will tell you which variable has a major effect on the inconsistency you're seeing and which factors interact. % u need to explore the effect of various conditions on obtaining the desired result, and from those data you can derive the critical process parameters. If a critical pa­

rameter doesn't stay within the range, it al­ters the desired product quality"

Understanding scientifically the multi­variate relationships and applying this knowledge in different scenarios is bene­ficial. "Being able to do pattern recogni­tion is more powerful in terms of speed as opposed to having a perfect analytical as­say" Cooley says. "In manufacturing, being precise is more important than being ac­

curate. You can adjust for a bias as long as you under­stand it. You should be able to answer the question, Is this the same thing I pro­duced yesterday, and is it within the limits of what I need to make? This is where chemometrics and those tools come in to tell you whether what you are mak­ing is within the limits of what you define as good."

There are questions over how to handle the vast amounts of data generated

by the process analyzers. The amount re­quires not only a data management system that can handle the volume and types of da­ta generated but also one that raises ques­tions of procedures, questions that FDA is looking to industry to solve. "Most large companies have automation functions," Doherty says. "In the regulated manufac­turing industries where you keep the raw data for the process, how much do you archive? Do you need two wavelengths to demonstrate the completion of the run? Do you need to save all the spectra?"

A few academic centers focus specifi­cally on training in process analytical chemistry, such as the Center for Process Analytical Chemistry (CPAC) at the Uni­versity of Washington, Seattle, and the Measurement & Control Engineering Center at the University of Tennessee, Knoxville. But in general, during their ac­ademic training, students have little ex­posure to industry's requirements and needs compared with the time that's de­voted to teaching theory

"The challenge is for academics to train people to develop these skill sets that are going to be needed," CPAC Director Melvin V. Koch says. "The analytical chemist is going to have to learn more than traditional analytical science because PAT is going to force people to develop tech­nologies that provide the answers."

Koch, who had an industrial career be­fore becoming director of CPAC (C&EN, May 17, 2004 , page 40), emphasizes a multidisciplinary and multi-industrial ap­

proach. "We're working across 10 aca­demic departments and with 30 indus­trial partners. If you have graduate stu­dents who are trained to work on a team with engineers and data-handling experts, they are absorbed [into the workforce] and become productive quickly. Other industries have been doing PAT for a long time, and they have been able to train people internally. The brain drain from traditional industry into pharmaceuticals is a short-term solution. Some universities I've dealt with are asking whether they even need an analytical depar tment , rather than how to broaden its impact to affect programs like PAT."

Analytical chemists are but one com­ponent of a large PAT team. "Most people I know in PAT have exceptional people skills," Doherty says. "To solve problems with process analyzers, you need manage­ment support and team skills because you can't be the lone specialist in the ivory tow­er. You need to be articulate and be able to influence people. We're starting to hear more about ROI [return on investment}, long-term cost of ownership, and eco­nomic efficiencies, and we need to be able to talk in those terms with production per­sonnel to sell our technology"

Cooley recommends other skills, such as "manufacturing experience, an under­standing of process unit operations, and a basic understanding of chemical engi­neering principles and processing equip­ment. Multiple areas of expertise are use­ful: engineering, automation, information technology finance, and regulatory expe­rience; all those areas in manufacturing are driven by ROI."

The most successful chemists, howev­er, are those who subscribe to continuous learning. "We got into science because we like to learn and try new technologies and applications even though we have ad­vanced degrees," Wasylyk says. "We have not given up on learning. A number of us have taken extra courses on chemomet­rics, for example." He adds that he's also learned those jack-of-all-trade skills that come in handy, such as splicing fiber-optic cable in case a cable breaks at 3 AM.

What will help future recruitment is FDAs support for PAT. "PAT is sexy now Historically I had difficulty recruiting peo­ple before FDA promoted PAT," Cooley says. " You're taking off the lab coat and put­ting on a hard hat, but people didn't see the job as being very glamorous because it was­n't getting any recognition. FDAhas legit­imized process analytical, and it's consid­ered agood career move because now senior management is paying attention." •

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