Fiber optic technology has already radically altered the telecommunications field, by carrying highly multiplexed data at great speeds over vast distances. Now these capabilities have been packaged into a class of robust optical microchip sensors. SpectroSens technology (Stratophase Ltd., Hampshire, U.K.) (see Figure 1) enables measurements to be made in places where it is not possible to take laboratory equipment. In addition, the optical nature of the network of sensors means that all electrical components are housed in the control and readout unit, which can be situated far away from the point of measurement. As a result, SpectroSens is intrinsically safe even in explosive environments, enabling multiple, highly accurate measurements to be taken in real time at single or numerous locations—a distinct benefit to a broad spectrum of industries.
Figure 1 - SpectroSens optical microchip.
The technology has many possible applications; it can potentially be used within the fields of chemical processing and bioproduction. With its fiber optic technology, SpectroSens can measure and analyze multiple parameters at numerous locations, simultaneously. This will enable scientists to produce a “fingerprint” of the sample without the need to stop the production process. This real-time, networkable reporting, for example, of reaction conditions and feedstocks, can lead to decreases in batch-to-batch variability and significantly reduced waste.
Further applications of SpectroSens include first responders and clinical point-of-care measurements. The single-point detector can rapidly identify the presence of specific biohazards by carefully attaching antibodies against the biological epitope to the detection surface. Soldiers on the battlefield will be able to receive a near-instantaneous, clear “yes/no” response for the presence of hazardous biological entities, e.g., anthrax. In the clinical point-of-care arena, the technique has the potential to provide doctors, nurses, and health-care support workers with the rapid results they need to be able to contain drug-resistant “superbugs” such as methicillin-resistant Staphylococcus aureus (MRSA).
Making production processes flexible
The chemical processing side of pharmaceutical production has traditionally been carried out as a large batch process. In such a process, the product’s quality control is measured by testing both the feedstock prior to production and the resultant final product. This process has a number of drawbacks, the main one being its inflexibility. Each batch must be of the same size; therefore scaling production up and down requires the implementation of a new system built specifically for the production scale required. The testing of the product brings about its own drawbacks. It can be very costly to carry out the test only once the product is complete if the results show any contamination or poor active ingredient concentration. In such instances, the entire batch will need to be disposed of properly (which is a costly process in itself). Furthermore, the production facility will also then need to be fully cleaned and checked, putting the operation out of service for a few days or even weeks, which presents a cost in terms of lost opportunity.
Figure 2 - Schematic of a simplified sensor network showing optical sensors at each of three feedstock flows and the resultant output of the reaction process. N.B. the control unit integrates with the flow valves to provide real-time process control.
SpectroSens is well-equipped to handle these problems. Its ability to sense a multitude of parameters across the entire production process means that reactions and concentration levels can be monitored throughout (see Figure 2). This in turn leads to a rapid response time, should the readings show an undesired result, meaning that whole batches do not need to be sacrificed. The technology is based on advanced fiber optic components, such as Bragg gratings, and provides highly versatile and scaleable sensing solutions. Each sensor array placed throughout the production process can be designed to measure a range of important parameters, including refractive index and temperature, with new measurements such as VIS-IR absorption, particle content, pressure, and viscosity currently being tested.
The use of Bragg gratings
Figure 3 - The wavelength of light reflected from the grating depends on the refractive index of the material in the sensing window.
This multiparameter measurement is achieved by transmitting a broadband light source via a small fiber optic cable to a Bragg grating within the chip, while the sample passes across the sensor surface (see Figure 3). The grating then reflects a precisely defined wavelength of light, which is determined by the optical properties of the liquid in the sensing window. The reflected light, which is directly related to the parameter being measured, travels back along the optical cable to the readout unit. Furthermore, the liquid under test reaches all of the individual sensor areas located on the chip simultaneously, enabling each chip to take multiple measurements using a single readout unit.
Figure 4 - Optical microchip sensors can be configured in a vast array of formats, from in-line flow cells (as seen here) to in situ fermentation probes.
One of the key benefits offered by the SpectroSens optical microchip approach is that, despite the multiparameter capabilities, only a single fiber optic supply is needed for each sensing head, since the measurements are all based on the interaction of the sample with specific wavelengths of light. Therefore, even a complex multipoint measurement setup requires only a small number of optical fibers, all of which can be driven from a single SpectroSens control and data processing unit. Furthermore, due to the efficiency of fiber optic signal transmission, this can be positioned many hundreds of meters away from the measurement point, adding to the flexibility, and enhancing safety if flammable chemicals are in use. The small size of optical microchips and their inherent versatility make them well suited to implementation in a vast array of sensing heads (see Figure 4), offering a wide variety of system configurations.
Applications in bioproduction
The production of biopharmaceutical products such as antibodies and vaccines is another area in which the application of the SpectroSens technology could bring about significant benefits. The fermentation of biopharmaceutical products is notoriously unpredictable, with reactions being very time critical. However, with the multipoint, multiparameter functionality permitting instantaneous results, the entire fermentation process can be precisely monitored to ensure very high reproducibility and clear determination of the desired endpoint. Furthermore, since SpectroSens uses only light at the point of measurement, the sensors are intrinsically safe and spark free, removing any chances of ignition.
Accordance with new initiatives
The SpectroSens technology is well within the guidelines of the FDA’s process analytical technology (PAT) initiative.1 PAT has essentially become an industry-wide effort to understand and optimize every step of the pharmaceutical manufacturing process, by developing monitoring capabilities that permit timely control. The ultimate aim is to enhance production efficiency by reducing production cycle times, minimizing batch rejection, enabling real-time release, increasing the use of automation, and facilitating continuous processing. In addition to the obvious cost benefit of achieving this, there is also a clear environmental dividend, since there will be an associated reduction in energy and material use.
In turn, the PAT initiative forms one part of a wider FDA guidance on Good Manufacturing Practice (GMP), as defined in the document, “Pharmaceutical cGMPs for the 21st Century—A Risk Based Approach.”2 One of the key concepts in this is the implementation of Quality by Design (QbD) principles, which harness the suggestion by Juran3 that quality can be planned into a process and therefore that bad planning is a major cause of poor quality.
Implementing measurement processes to enable PAT requires that sensors be placed at critical points in the production process to ensure that it can be effectively controlled in a timely manner. Furthermore, there is no single parameter that can provide a complete picture of the quality of the sample at any one point. As a result, multiple parameters need to be measured and analyzed to provide a fingerprint of the sample. The SpectroSens technology is currently being expanded to meet these requirements precisely. Equally, in the past, integrating such a complex system of sensors and analyzers had been difficult to achieve with the available sensor technologies, and also led to large increases in the number of electrical and electronic components in the production facility with potentially hazardous consequences. As discussed earlier, the SpectroSens alleviates these hazardous concerns and simply delivers readable, usable results in real time.
Single-point applications
Figure 5 - Disposable sensor chip.
The SpectroSens technology can also be used by first responders and clinical point-of-care as a one-off, disposable sensor chip (see Figure 5). In this instance, antibodies to specific biological entities can be carefully attached to the detection surface, effectively activating the sensor to the target of interest. Once the SpectroSens detector is used out in the field, the sensor delivers a clear “yes/no” response, allowing the user to make critical decisions quickly.
One possible application is for soldiers on the battlefield investigating the presence of biothreats, e.g., anthrax spores. The SpectroSens is durable and gives precise readings in multiple terrains, and Stratophase is part of a funding consortium, working with the U.K.’s Ministry of Defence (MOD) on developing the SpectroSens technology as a rugged, battlefield-deployable detection system. In clinical point-of-care, the availability of real-time results for the presence of harmful bacteria (for example, MRSA) could provide a powerful weapon in the battle to contain the spread of such drug-resistant pathogens, which not only offers better outcomes for infected individuals, but also much more efficient, cost-effective control of “superbugs.”
Conclusion
Accurate, real-time sensing technologies promise to provide the tools to move many diverse processes forward. For example, the pharmaceutical production processes of yesterday are soon to become a distant memory. SpectroSens is leading the way in enabling true inline measurements for real-time analysis of production quality. With the drive for more efficient continuous-flow techniques and the FDA introducing a series of guidelines to ensure that quality is the central consideration, this technology could not be more timely. The intrinsically safe nature and versatility of the system, which allow it to be applied to traditional chemical production as well as bioproduction and biodetection at any possible scale, offers solutions to many of the challenges of PAT. Furthermore, with the recent outbreaks of foot-and-mouth disease (in the U.K.) and MRSA (globally) showing how quickly such diseases can spread if not detected and neutralized quickly, SpectroSens promises a robust and dependable rapid detection system. Whether the requirement is for multiparameter measurements in various locations throughout an entire production process, or a simple, rapid “yes/no” response, SpectroSens delivers.
References
- FDA, Guidance for Industry: PAT—A Framework for Innovative Pharmaceutical Development, Manufacturing and Quality Assurance; Sept 2004.
- FDA, Pharmaceutical cGMPs for the 21st Century—A Risk Based Approach; Final Report, Sept 2004.
- Juran, J.M. Juran on Quality by Design. Free Press: New York, NY, 1992; ISBN: 0029166837.
Dr. Watts is Business Development & Commercial Officer, Stratophase Ltd., Unit A7, The Premier Centre, Premier Way , Romsey, Hampshire SO51 9DG, U.K.; tel.: +44 (0) 1794 511226; fax: +44 (0) 8704 580754; e-mail: [email protected].