A Modular Approach to Process Analysis

FDA's Push for Broader PAT Adoption Gets a Boost from NeSSI Effort to Standardize and Modularize Sampling Systems

While elegant in concept, the change from manual, laboratory-based analysis to real-time, online instrumentation has long been problematic.

While it's hard to argue the potential gains in reduced variability and improved control promised by implementing what the FDA refers to as "Process Analytical Technologies" (PAT), wide adoption has been limited by the need for complex, expensive and custom-built systems for automatically extracting process samples and conditioning them for analysis.

Now, visionary process analytical chemists in the petrochemical and chemical process industries, spurred by the successful use of modular sampling systems and manifolds for the analysis of ultra-pure gases in the semiconductor industry, have launched a major effort to define and adopt a new generation of modular process analyzer sampling systems, sensors, connectivity (communication between the sensor and control computer) and the diagnostics and intelligence to optimize their performance.

Ultimately, the effort promises to package analytical technologies in modular, shoe-box-size black boxes that contain the sampling system as well as combinations of analytical instruments.

"It's a platform for implementing microanalytical instrumentation," explains Mel Koch, Ph.D., director of the Center for Process Analytical Chemistry (CPAC) at the University of Washington, Seattle. Microanalytical instrumentation implies the use of ever smaller instruments "and ever smaller sample sizes "to reduce waste and increase instrument response times. "As soon as you do that, you increase the capability of things that go on--in combinatorial chemistry, in process development, in optimization and control."

Formally created at the ISA Expo 2000 meeting of the Instrumentation, Systems, and Automation Society (ISA) of Research Triangle Park, N.C., the New Sampling/Sensor Initiative (NeSSI), is a vendor-neutral and non-affiliated effort that operates under the auspices of CPAC. Since that time, it has evolved and broadened into "an ad hoc industry initiative to drive permanent change in how we do process analytical chemistry," says Peter van Vuuren, ExxonMobil Chemical, Baytown, Tex.

Their plan: to facilitate three generations of development and evaluation of modular sampling systems, associated software and plug-and-play hardware, open standards for communication and hardware for miniaturized analytical instrumentation.

History and Lore

Exactly when the concept of a modular sampling system first originated is hard to pin down. Work that started as early as 1994 and resulted in a patent for a "Modular Sample Conditioning System" may represent the beginnings. (U.S. Patent 5,841,036, was filed in August 1996 and issued to Don Mayeaux, president, A+ Corporation, Prairieville, La., in November 1998.)

However, it appears that the industry-wide initiative on the need for new approaches to sampling started within the Oil and Petrochemical Industry Focus Group at CPAC.

"There was a consensus that the sampling problem was not unique to the petrochemical industry," recalls CPAC director Koch, who formerly had global responsibility for analytical sciences at Dow Chemical. The group realized that sampling was a concern in the food and consumer products, pharmaceutical, biotech and the chemical process industries, and that there was a need for projects in sampling and sampling systems, he says.

"The CPAC group wanted to develop a concept for a flexible and smart sampling system that would be low-maintenance, require lower volumes--smaller samples--and be amenable to microanalytical devices," elaborates consultant Jim Tatera of Tatera & Associates, Inc., Madison, Ind. "The modular approach really took off when people piggybacked the concept with the ISA's SP76 standard for a modular sampling interface, allowing it to move forward with some flexibility and interchangeability."

FDA Support

As a tool for process analytical technology, NeSSI clearly falls under FDA's process analytical technology (PAT) initiative. "I think it has a valuable place in the manufacture of drug substance," says Ajaz Hussain, deputy director of FDA's Office of Pharmaceutical Science and chair of the agency's PAT subcommittee.

And despite the FDA's professed support and the technology's demonstrated potential, Hussain recognizes that regulatory concerns will likely slow the implementation of NeSSI-based technologies. "The PAT initiative was designed to essentially remove perceptions that regulatory agencies won' understand this new technology and remove the [regulatory] hurdles for bringing it in [to new and existing processes]," he says.

In addition, the research exemption or safe harbor concept (for allowing the testing of new technologies in a manufacturing context) should facilitate implementation of PAT-related technologies, notes Paul David, associate fellow in chemical process R&D for Pfizer in Skokie, Ill. "Industry must be allowed to learn from the results of NeSSI-based measurements without the threat of FDA enforcement action--assuming there is no risk to the safety and efficacy of the product," David says.

Inspector training should help, too. "FDA people who will review or inspect PAT-based applications will have specialized training and certification," Hussain says. "PAT-based applications won't be handled in a routine way."

Small Is Beautiful

"Our philosophy is to minimize the variability of a chemical process during development and scale-up so that expensive continuous monitoring is not needed in commercial production," Pfizer's Paul David says. "We are interested in the NeSSI concept, especially the introduction of microanalytical instrumentation for these systems, and can envision using several of these devices as sensors."

As a potential application, David describes a NeSSI device with pH, redox or nano-liquid chromatograph, used to measure components in the condensed phase of a chemical reaction. "A NeSSI device with a mass spectrometer or nano-gas chromatograph could be used to measure gases evolved during a reaction," he adds. "We are following developments with the NeSSI initiative through our participation in CPAC and are anxious to test these devices once microanalytical tools become available."

Other compelling possibilities are a single NeSSI instrument that combines many different spectrometers or one that is miniaturized to fit into NeSSI-standardized modules, observes Steve Arrivo, research associate, Pfizer Global R&D in Ann Arbor, Mich. "Another advantage to miniaturizing your sampling and analysis system is greatly reducing the amount of sample required for the analysis, particularly for highly potent or toxic compounds

, as well as reducing the amount of drug needed for scale-up studies."

"The biggest advantage of the NeSSI approach is that it provides us with a standardized design and a smaller footprint for the sample system," says Rajko Puzic of Imperial Oil's Products and Chemicals Division in Sarnia, Ontario, Canada. "It also provides a standardized approach that greatly simplifies the design effort

, because it provides for a [standardized] substrate and components that are carefully designed and defined for the particular application."

"We feel the new technology will increase reliability and reduce the space required for sample conditioning and analytical equipment installations," concurs Bac L. Vu, analytical specialist for Dow Chemical, Freeport, Tex. "It will also give us greater flexibility in terms of where we install the sample conditioning system; we won't be limited specifically to installing systems in analyzer shelters," he says. "Another goal is to expand the implementation of sampling system and process analytical technology near the sampling point or directly in the process pipe or vessel."

"People have asked the question, "Will NeSSI standardize analytical system design?" says Rob Dubois, senior analyzer specialist with Dow Chemical Canada, Fort Saskatchewan, Alberta.

Dubois' answer? "Sort of."

"Having standards such as SP76 certainly help, as will a sensor/actuator communication standard," Dubois explains. "However, most analytical systems have personalities to accommodate nuances in specific processes or measurements. Consequently

, NeSSI systems need to be flexible and highly configurable to work within the constraints of simple--but not inflexible--mechanical, electrical and software standards."

Mark D. Weiss is a Rockland County, N.Y.-based freelance writer. He can be reached at

markweiss@mjet.com.

 

 NeSSI: The Next Generations

The development of the first generation of components compliant with the New Sensor New Sampling/Sensor Initiative (NeSSI) was relatively straightforward because the ISA's SP76 standard was developed and approved quickly, and vendors either already offered or quickly adapted existing components. In addition to various flow controllers, valves, regulators, pressure gauges, etc, NeSSI-compliant, surface-mountable oxygen, moisture, pH and conductivity sensors also are available.

As currently envisioned, the specification for Generation II NeSSI systems involves definitions for:

Temperature-programmable substrates to maintain sample temperatures and dewpoints.

Smart, compact pressure, temperature and flow sensors to provide measurements for validation and control.

"Combi-valves," a pneumatic valve and solenoid combination component for controlling flow of sample and validation fluids.

A

Sensor Actuator Manager (SAM), a management and communications interface to standardize repetitive operating tasks and provide a gateway to an Ethernet LAN.

A standardized graphical human machine interface to allow the interrogation and field-adjustment of the sampling system as well as analyzers interfaced to it.

A

Serial multi-drop sensor bus to simplify communications and connectivity.

Standards for area-classified, temperature controlled enclosures.

Though formal specifications, development and evaluation of NeSSI II-compliant devices are in progress: If all goes according to plan, NeSSI II-compliant components should be commercially available in summer 2005.

The vision for third-generation NeSSI-compliant systems includes wireless connectivity as well as "labs-on-chips" and other microanalytical devices. In fact, "NeSSI has provided a very interesting reason and enabling tool for miniaturization of analytical [instrumentation}, observes explains Mel Koch, Ph.D., director of the Center for Process Analytical Chemistry (CPAC) at the University of Washington, Seattle.

"The majority of the 20 research projects now underway at CPAC involve building instrumentation that will be NeSSI-compatible, part of the Generation III concept. When some of these projects started at CPAC in the mid-1990s, critics in the oil and petrochemical industry thought we were wasting our time because they were accustomed to large sampling systems attached to large process analyzers," Koch says. "However, once a few of the NeSSI units were built and attached to an analyzer, even something as small as a process GC, the engineers started asking why the analyzer had to be so big. Now they are not only appreciative of miniaturization technology, but are encouraging its development."

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