By Dave Simko, Swagelok Company
Pharmaceutical manufacturers have relied upon laboratory testing to resolve process, product, and quality issues for the last century. Analysis is performed off-line; that is, a sample is extracted from the process and transported to the laboratory for analysis.
However, taking the laboratory to the sample changes the way the analyses are conducted. Off-line analyses can be replaced with at-line, on-line, in-line, and noninvasive analyses. The FDA Guidance for Industry, PAT-A Framework for Innovative Pharmaceutical Development, Manufacturing, and Quality Assurance, promulgated in final form in September 2004, encourages the use of available process analytical tools to support innovation and efficiency in pharmaceutical processing. Miniature modular platform technology provides the means to build and install compact sampling systems, sensor arrays, and complete miniature process analyzer systems. Such systems have been installed in chemical processing plants and refineries. Combining process analytical technology (PAT) with miniature modular platform technology allows the analyses to be made at the process line and the results to be made available immediately.
This article discusses PAT and analyses that bring the analyzer close to the process line, the results of applying miniature modular technology in analyzer systems in processing plants, cleanliness issues and solutions, and specific potential applications of the combined technologies in pharmaceutical processing.
FDA PAT Initiative
The goal of the FDA PAT Initiative is to reduce pharmaceutical development and manufacturing costs by improving quality, reducing rejections, and reducing the time to market. It encourages the use of up-to-date scientific principles and innovative, readily available analytical tools to monitor and control the processes by operating on the basis of continuous interfacing with a reliable sample of the process fluid being evaluated.
The intent of this guidance is to describe a scientific, risk-based regulatory framework to support innovation and efficiency in pharmaceutical development, manufacturing, and quality assurance. The PAT framework is a system for designing, analyzing, and controlling pharmaceutical manufacturing through timely measurements of critical quality and performance attributes of raw and in-process materials and processes to ensure final product quality. The framework consists of two parts: a set of scientific principles and tools fostering and supporting innovation; and a strategy for regulatory implementation that will accommodate innovation.
The scientific principles and tools relate to all of the following:
- Multivariate tools for design, data acquisition, and analysis
- Process analyzers
- Process control tool
- Continuous improvement and knowledge management tools
Another goal of PAT is to enhance the understanding and control of the manufacturing process. Thorough understanding of a process is achieved when:
- All critical sources of variability are identified and explained
- Variability is managed by the process
- Product quality attributes can be accurately and reliably predicted for the materials used, process parameters, manufacturing, environmental, and other conditions
The result should be improved quality with higher production yields, fewer rejects with less scrap and rework, lower energy costs, and an improved environmental footprint-all leading to lower costs.
The New Sampling/Sensor Initiative (NeSSI™)
Industry has indicated a need for miniaturization. In addition, numerous industry organization and government reports consider miniaturization an enabling technology that will help ensure the continued growth of each specific industry reporting.
It is generally accepted that sample systems account for as much as 80 percent of the problems with analyzer systems. Over the past three decades, analytical instruments have become more sophisticated and capable, and the computers and software that drive the systems have become more powerful and user-friendly. However, during that same time frame, the way sample systems are designed and installed has remained relatively unchanged.
Concept development for small, smart sample and sensor systems began in the late 1990s. The process industries wanted to improve the performance of process-analyzer sample systems in an effort to reduce the cost to design, build, and install the systems, as well as the cost to operate and maintain them over their projected service life.
The New Sampling/Sensor Initiative (NeSSI) was released by the Center for Process Analytical Chemistry (CPAC) at the University of Washington in August 2000. CPAC stated that the initiative was “…an effort to facilitate the state-of-the-art evaluation (and ongoing development) of the next generation of modular sampling systems.”
NeSSI Generation I, the mechanical embodiment of a miniature modular system, proved the feasibility and practicality of miniaturized sampling systems. Generation II, the embodiment of automated systems populated with intelligent devices that communicate via an open architecture communications bus, will take these systems to the next level of enabling capability. Generation III is envisioned to be populated with microanalytical devices, to operate intrinsically safely, and to utilize wireless communication.
NeSSI: The basic concept
A modular system incorporates a flow channel through a system that routes system fluid sequentially through a series of functional components that operate on or interface with the fluid stream. The functional components may regulate and monitor pressure, measure and control flow, monitor temperature, remove particulates and moisture from a gas stream, or vaporize a liquid (see Fig. 1).
Figure 1. This representative modular system routes fluid through a series of surface-mount components, including valves and filters, that operate on or interface with the fluid stream. The substrate layer provides the flow path through the system, and the manifold layer provides the flow path between two or more parallel substrates. In this design, a standard O-ring provides a leak-tight seal between each surface-mount and substrate flow component and between the substrate and manifold components. Surface-mount components can be serviced easily from the top of the assembly without disturbing any other components. Courtesy of Swagelok Company.
The flow path is established in a substrate. Each position on the substrate has two or three ports on the top surface. Two of the ports are the inlet to and outlet from a fluid-control component that will be mounted there. The third port, if required, is located between the inlet and outlet ports and is used to connect multiple fluid streams.
The functional components are configured such that both the inlet and the outlet ports are located on the bottom face, according to an open-architecture seal-interface standard. The components are bolted directly onto substrates (surface-mounted), aligning the inlet and outlet ports over the appropriate ports on the substrate.
A number of manufacturers offer substrate systems that meet the recently released seal-interface standard, ANSI/ISA 76.00.02-2002, Modular Component Interfaces for Surface-Mount Fluid Distribution Components-Part 1: Elastomeric seals, ensuring interchangeability of the functional components of all manufacturers of those devices (see Fig. 2).
Figure 2. The ANSI/ISA 76.00.02-2002 specification establishes properties and physical dimensions that define the interface for surface-mount fluid-distribution components. (Derived with permission from ISA: www.isa.org.)
MPC: A solid platform
One of the embodiments of NeSSI technology is the use of modular platform components (MPC). The basic building block of the MPC system is a flow component. The most common configuration is a U-shaped channel that is formed by welding two 316L stainless-steel elbows together. Two flow components placed side-by-side define a position for a surface-mount component. Several flow components arranged side-by-side define a single-stream flow path system. A complete system may include additional sample streams, as well as other streams for calibrating the analyzer, transporting a sample, or purging and cleaning a system. All of these streams must be manifolded together to connect the flow paths (see Fig. 3).
Figure 3. Built with modular platform components (MPC), this miniature modular system is one example of a NeSSI Generation I sample-handling system. Courtesy of Swagelok Company.
An MPC system consists of three layers-a substrate layer that provides the flow path through the system, a manifold layer that provides the flow path between two or more parallel substrates, and a layer of surface-mount components that provide the functionality. The substrates and functional devices needed to build the Generation I systems are available from a variety of manufacturers.
Electrodes for measuring pH and conductivity are available in surface-mount versions. Some manufacturers of optical devices (UV-VIS and mid-IR, for example) are adapting chambers for their devices and configuring them for surface mounting. Constituent analyzers for moisture and oxygen are currently available.
Clean sampling systems
In general, all sample systems consist of an amalgamation of valves, fittings, small vessels, and tubing, as well as other kinds of specific fluid-control components.
Some of the important concerns in designing and building clean sampling systems are:
- Seal design
- Surface finish
Leakage is a key consideration that impacts cleanliness. Leakage is defined as unwanted flow of fluid into or out of a contained volume. Inboard leakage is flow into the system from outside containment. Outboard leakage is flow out of containment into the surrounding environment. Internal leakage is flow across internal seals within containment.
Leaks can be real or virtual. A real leak is the result of seal failure. A virtual leak appears the same to a leak detector but, in fact, is the release of trapped volumes inside containment; outgassing of materials; or the release of unwanted materials that are absorbed, adsorbed, or chemisorbed on internal surfaces.
Seals are another key consideration in the design of components for service in clean systems. The seals used in small sampling-system components are either static or dynamic seals. Failure of static seals is usually associated with vibration, over-pressurization, or degradation of the seal member due to temperature or chemical attack. Dynamic seals must seal effectively where motion is involved. Failure of dynamic seals is usually associated with wear on the seal member due to the sliding or rotating action of one of the seal surfaces. Temperature, corrosion and contamination may also be factors.
Components intended for service in clean systems must be designed to operate cleanly. Sample systems built with miniature modular technology result in greatly reduced internal volumes and internal surface areas, minimizing entrapment. The flow path through the component should be as smooth as possible so that the component can be completely purged and cleaned. Whenever the fluid stream must change direction, clean-sweep radii should be used to avoid eddies that could trap fluids and make purging and cleaning more difficult.
Surface finish is described as the difference between the “peaks and valleys” of a machined surface. As the difference increases, so does the roughness. A smooth surface finish is especially important on the metal seal members, since rough surfaces sliding through or rotating within an elastomer or plastic seal can cause rapid wear and premature failure. An effective way to reduce or eliminate wear and leakage, reduce breakaway and operating torques, and increase the service life of sliding and rotating seals is to improve the surface finish of the metal components of the seal.
Enhanced surface finishes on small components for analytical chemistry instrumentation systems also contribute to overall system cleanliness beyond leak-tight performance. It is necessary to clean the systems between runs by purging with a clean gas or solvent. Finer surface finishes reduce the surface area exposed to the system fluid, reducing the amount of material adsorbed or trapped in the “valley” of a rough surface, making purging and cleaning quicker and easier.
Modular platform technology may be employed in many applications, concentrated in three areas: laboratories, pilot plants, and process plants.
In the lab, bench space is always at a premium. A miniature modular system frees up space and reduces clutter. NeSSI systems are easy to develop, assemble, and install. In addition, NeSSI systems are flexible, so it is easy to reconfigure experimental apparatuses, add or remove devices, or expand the scope of the system (see Fig. 4).
To help reduce waste of expensive analyzer gases, a simple assembly for metering a carrier gas, such as trace analytical-grade helium, can be built on a NeSSI platform. During normal operation, the required flow is routed through a relatively large valve. When not needed, the flow is diverted through a fine metering valve at a predetermined minimal rate, reducing the amount of gas wasted.
A modular system can also assist in the mixing and distribution of laboratory gases. More than 15 separate gases can be controlled individually or in multiples to enable blending and mixing to a predetermined “recipe.”
In pilot plants, personnel safety, cost, and space are issues as well. Pilot plants prove that a product created in small quantity in a laboratory can be manufactured economically in large quantities, so scale-up is important. In the pharmaceutical industry, the lengthy scale-up process begins in small reactors on a lab bench, is followed by manufacturing scale up and process design, and finally reaches the larger-scale pilot plants that produce product for clinical testing. At the front end of this process, innovative new technologies that embrace the intent of the FDA PAT Initiative may be implemented, evaluated, and validated for application downstream where systems are larger, more extensive, and must be more robust.
In process plants, continuous on-line analyses require networked systems capable of making multiple measurements at multiple points. There are numerous points where clusters of sensors installed on a modular platform can make multiple measurements.
All process plants, especially those involved in the manufacturing of pharmaceuticals, use water of various quality levels in abundance. The most common measurements required are pH and conductivity, followed by dissolved oxygen (DO), oxidation-reduction potential (ORP), and turbidity. A small platform, measuring about 4.5 inches by 6 inches, equipped with electrodes mounted directly onto the substrate by means of the ANSI/ISA 76.00.02 seal-interface standard, can be used to measure the pH and conductivity of water at a single point.
A multiple stream selection platform may be used to switch the fluid stream going to an analyzer from multiple sample streams to purge, wash, or cleaning streams to vent or disposal lines. NeSSI platforms permit such switching capabilities in conveniently small packages. For example, a four-stream selection module consisting of 19 functional fluid-control components can be built on an overall 7.5-inch by 12-inch platform.
The PAT Initiative specifically recommends an increasing use of at-line, on-line, and in-line analyses, as well as the current off-line methods. Modular platforms may be used in all of these categories of analysis.
Modular platform technology has moved well beyond its initial scope. In the process industries, it has been successfully employed in laboratory, pilot plant, and production plant applications. It has been used in extractive on-line sample systems where the mission is to deliver a minimal, properly conditioned sample to an analyzer and in in-line systems that require a steady flow of fresh process sample past an electrode or probe. It has been used in gas and liquid distribution systems where the mission is to deliver a quantifiable amount of fluid to point of use. It has also been demonstrated and used in discrete manufacturing applications where liquids and gases are used for reasons other than analytical chemistry.
Modular platform technology is an enabling technology that allows scientists and engineers to do things they weren’t able to do in the past. It is simple to conceive and configure systems that are easy to assemble, install, operate, and maintain. These features are what make modular platform technology the enabler that it is.
Miniature modular platforms and measurement systems implemented as part of the PAT Initiative will help open the door to innovative solutions for implementing up-to-date process analytical chemistry methods and techniques into pharmaceutical manufacturing processes.
- CDER, U.S. Food and Drug Administration. Guidance for Industry, PAT-A Framework for Innovative Pharmaceutical Development, Manufacturing, and Quality Assurance. September 2004.
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- De Palma, Angelo, PhD, Contributing Editor, “PAT 101,” Pharmaceutical Manufacturing, July/August 2004.
- “New Sampling/Sensor Initiative (NeSSI) – Information Package”, The Center for Process Analytical Chemistry, University of Washington, Seattle, August 1, 2000.
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Dave Simko is manager of marketing resources for Swagelok Company. He has worked extensively in North America, Europe, Japan, China, and Southeast Asia. He has broad technical knowledge of all the company’s core markets and industries served. His recent efforts have been focused on the biopharmaceutical industry. Prior to joining Swagelok, Mr. Simko spent several years in the aircraft gas turbine industry. He has a degree in mechanical engineering, holds several patents in the area of valve and fitting design, and has published numerous technical articles and papers. He is a member of the American Society of Mechanical Engineers (ASME), the American Institute of Chemical Engineers (AIChE), and the Instrumentation, Systems, and Automation (ISA) Society.