Cost is driving the increased use of process analytical chemistry instrumentation in all industries, including pharmaceutical manufacturing. One way that companies can improve quality and reduce operating costs is by controlling the chemistry of the process.
Process analytical instrumentation provides the measurement tools that provide the information that companies need to optimize their processes, ensure the safety of their employees, and meet appropriate mandated environmental regulations.
The FDA Process Analytical Technologies (PAT) Initiative encourages the use of innovative and readily available analytical tools to monitor and control the processes. For example, techniques and methods that operate on the basis of continuous interface with a reliable sample of the process fluid are being evaluated.
Pharmaceuticals are usually manufactured in batches, and laboratory test methods applied to samples extracted from the process are used to evaluate quality. The industry has relied on laboratory testing to resolve process, product, and quality issues for the last century. In off-line analysis, a sample is extracted from a sample point and physically transported to a laboratory where the analysis is completed using sophisticated and flexible measurement equipment. The PAT Initiative encourages manufacturers to supplement off-line analysis with a combination of at-line, on-line, in-line, and non-invasive analyses.
In at-line analysis, a sample is extracted from the process and transported to a dedicated analyzer located close to the process. On-line analysis employs an automated sampling system that extracts, transports, conditions, and delivers a sample to a clean and calibrated instrument and then disposes of the sample after the analysis is complete. Analysis may be intermittent, as in the case of a gas chromatograph, or continuous, as in the case of spectroscopic instruments. In-line analysis means that the analysis is carried out in situ using a probe equipped with a sensor that is inserted into the process. The advantage of non-invasive analysis is that no part of the instrument or probe contacts the process fluid, so the barrier between the process and the external environment is not compromised.
How Does PAT Enhance a Process?
PAT implementation calls for the right process analytical tools to monitor each critical product attribute in real time during the course of the process. A sensor must yield process fluid measurements that are reliable, repeatable, and validated. It is equally important to have process controls in place so that adjustments can be made based upon the analyses. Detecting and correcting errors, process deviations, or upsets while the process is moving forward can result in more efficient and tightly controlled process.
PAT implementation requires identifying the relevant technologies that can be applied to a specific process and product, as well as the use of effective data acquisition and management systems to handle the volume of data that will be generated. It also requires advanced automation concepts and techniques and tools, including intelligent devices that can communicate with each other and make appropriate repeatable, validated decisions without human intervention.
An integrated PAT system operating with the correct selection of analytical methods and technologies, sensors, and process controls can help ensure that the specified product quality will be achieved when the process is completed. It can reduce process cycle times, rejects and reprocessing, and scrap. It can utilize raw materials and energy more effectively and increase yield. In addition, the increased use of automation and process controls has the potential to improve operator safety, reduce human error, improve efficiency, and manage process variability. At statistically appropriate confidence levels, a PAT system may eliminate some finished product release testing. All of these results enhance the process and reduce manufacturing costs.
What is NeSSI?
The development of the concept of small smart sample and sensor systems began in the late 1990s in response to an industry-wide need to improve the performance of process analyzer sample systems. In the process industries, it was generally conceded that sample systems can account for as much as 80% of the problems with analyzer systems. In addition, while the analytical instruments, computers, and software had become more sophisticated, capable, and user friendly over the past 25 years, sample system technology had remained essentially unchanged.
In early 1999, the Center for Process Analytical Chemistry (CPAC) at the University of Washington became the forum for the end-user community to consider the possibilities for miniature modular sample systems. In late 1999, the Instrumentation, Systems and Automation (ISA) Society, through a subcommittee of SP76, Composition Analyzers, began an effort to develop a standard for an interface seal between a modular flow path substrate and necessary functional fluid control components.
A plenary paper presented at the 14th Forum on Process Analytical Chemistry (IFPAC) in January 2000, Process Analytical Systems: A Vision of the Future, by J.J. Gunnell and P. van Vuuren of ExxonMobil Chemical Co. addressed the costs associated with process analyzer systems and proposed rethinking the approaches to design, build, install, and operate them. They postulated that a savings of 40% of the total cost to build the systems could be achieved by reducing the cost of sampling systems, reducing the cost of sample transport, and eliminating the need for analyzer houses. They also estimated that a savings of 35% of the cost of ownership could be achieved by increasing the number of analyzers a technician could support, eliminating the need for a dedicated site analyzer engineer, and reducing the cost of the spares holdings.
The paper identified three enabling technologies necessary to capture the level of savings described:
- Modular sampling system components
- Open architecture communications buses
- ASIC (application-specific integrated circuits) and sensor-on-a-chip technologies
A miniature modular approach to sample system design and construction, based on technology developed for semiconductor gas handling systems, was suggested for consideration.
CPAC put forth a New Sampling/Sensor Initiative in August 2000 in “an effort to facilitate the state-of-the-art evaluation (and ongoing development) of the next generation modular sampling system designs.”
NeSSI is a miniature modular approach to building process analyzer sampling systems. The concept is manifested in a series of modular blocks or contained U-shaped flow components, each having an inlet and outlet. When placed side by side and joined together, these modular components create a channel that accommodates the flow of a sample stream through the system.
Individual fluid control components are surface mounted to this base, or substrate, to perform required conditioning and control operations on the sample stream. A manifold arrangement enables the connection of multiple streams, results in a small footprint, and allows for tight integration of components and sensor-based control devices.
The functional fluid control components of NeSSI are configured so that both the inlet and the outlet ports are located on the bottom face. The ports are precisely positioned according to the seal interface standard, ANSI.ISA 76.00.02-2002, Modular Component Interfaces for Surface-Mount Fluid Distribution Components – Part 1: Elastomeric Seals, issued by the ISA to facilitate the development of modular systems. The standard allows the functional components to be attached directly to substrates (surface mounted), aligning the inlet and outlet ports over the appropriate ports on the substrate. It also ensures that functional components from all manufacturers will interface with the substrates of all manufacturers.
As mentioned, miniature modular technology had its genesis in gas handling systems in the semiconductor industry. The mission of a modular gas handling system in the semiconductor industry is to deliver a quantifiable amount of pure gas to a point of use. Miniature modular technology has helped achieve semiconductor industry objectives; the systems are more compact, provide a reduced internal volume and wetted surface area, and are easier and require less labor to construct than a conventional system.
The mission of a process analyzer sampling system is to deliver a small sample that is repeatable, properly conditioned and prepared, and truly representative of the process fluid. A wide variety of fluid control components and sensors are required. It can be anticipated that similar success will be achieved by applying miniature modular technology to process analyzer sampling systems.
NeSSI Generation I proved the feasibility and practicality of miniature modular technology applied to analyzer sampling systems. Generation II represents the embodiment of automated systems populated with intelligent devices that will operate intrinsically safe and communicate via an open-architecture communications bus and will take these systems to the next level of capability. The evolution from Generation I to Generation II will involve an interim configuration, Generation I.5, which will utilize conventional I/O technology for communications purposes. In the future, Generation III is envisioned to be populated with microanalytical devices, to operate intrinsically safe, and to utilize wireless communication.
How Does NeSSI Enhance PAT?
The application of miniature modular technology has expanded beyond its original scope of improving analyzer sampling systems. Today the technology is being used in laboratories and pilot plants as well.
The pharmaceutical industry employs off-line laboratory analysis as the primary method for resolving all used process, product, and quality issues. Advantages include the sophisticated instrumentation, as well as the trained laboratory personnel; the disadvantage, however, is that the transport, transfer and actual measurement are generally slow. PAT generally offers faster and more frequent analysis. Integrating PAT and miniature modular technology can increase analyzer up-time and provide even more information about the process. Additional benefits of miniature modular technology include:
- Space on skid-mounted equipment in a manufacturing suite is generally at a premium. Modular platforms may be used at any sample point in off-line, at-line, or on-line analytical systems. Modular technology reduces the footprint of the system and shortens the transport lines to the analyzer, speeding up sample preparation. Analyzers may be placed closer to the process.
- Modular process analytical systems may be built small and travel with the process during scale up and development.
- Modular systems may be arranged to accurately mix liquids and gases, as well as to meter the volumetric or mass flow of the mixtures into a reactor.
A second enabling technology for an improved sample handling system portion of a process analyzer system is the use of open-architecture communication buses. The communication bus that will be employed on NeSSI Generation II systems is being developed to accept the automated version of the surface mount components of all manufacturers in a “plug and play” fashion, similar to the seal interface standard. Intelligent devices are being developed that will allow the system to make informed and competent decisions about the control of the process without human intervention. Adding intelligent NeSSI systems to PAT implementation should help contribute to the overall understanding and control of the pharmaceutical manufacturing process.
The third enabling technology for process analytical chemistry instrumentation systems is the use of application-specific integrated circuits (ASIC) to miniaturize the sensors and analyzers down to the scale of a complete lab on a chip. However, with the exception of those devices that can live and make their measurements inside the process lines and vessels, a platform will be needed to support the instruments. NeSSi will be the likely choice to perform that function.
Numerous industry and governmental analyses and reports regarding future technology needs that will enable the various segments of the process industries to reach their next level of performance to remain competitive all echo a common message — intelligent closed loop control is a must. PAT is an effort to move the pharmaceutical industry in that direction. NeSSI is a tool to support that effort.