The optimisation of production processes is of paramount importance to all manufacturing industries. This includes utilising synthesis procedures that can be adjusted to meet customer demand, while maintaining high levels of quality. An unchecked error on a production line can result in the loss of millions of pounds, due to the creation of inferior products and the subsequent down-time required while the process is corrected. In many areas involving the synthesis of chemical and biological products, batch processing in large reactors is currently being replaced by continuous flow approaches and multiple parallel small batch (scale-out) manufacturing methods. A large batch approach is well suited to production at a specified rate but the inflexible nature of the process makes it difficult to achieve scale-up or scale-down to meet changing demand. Multiple small batches circumvent this problem, as additional reactors can be brought online as required. However, continuous flow lines provide the most flexible method of meeting changing customer need, as they can be configured to run 24 hours a day, with production volume tailored to meet demand.
Monitoring to maximise efficiency
In order to maximise efficiency and cost-effectiveness, a manufacturing process must be carefully monitored. This might involve checking the consistency and quality of raw materials entering the process, following the individual reaction steps during synthesis to evaluate efficiency, scrutinising the product upon completion, or all three within the same production line. The monitoring method employed often depends on the nature of the process and the quality control levels required. For example, continuous production lines are designed to run concurrently and as such have no natural start or termination points. Therefore, accurate monitoring along the line is essential to ensure that mistakes are spotted and corrected as early as possible to avoid significant wastage. Each monitoring method can be described as being either real-time or off-line:
• Real-time measurements are captured and analysed at the time of sampling, facilitating rapid analysis and decision making.
Off-line testing is carried out significantly after sampling, with analysis requiring sample transport to a dedicated quality control laboratory for in-depth investigation. This approach often provides more information on the sample and the status of the process, but takes more time. Sampling methods can also be further classified as being at-line, on-line or in-line:
• At-line sampling involves the removal of the sample from the process for analysis near the production line.
• On-line measurements are taken by diverting the sample from the production line into a dedicated analysis stream, before returning the sample back into the main processing stream.
• In-line approaches analyse the process stream directly via either invasive or non-invasive methods, without actually removing a sample.
Process Analytical Technology
The pharmaceutical industry has traditionally been slower than other manufacturing sectors when it comes to adopting flexible continuous flow processes. However, this looks set to change in the near future, driven by an ever increasing need to reduce unnecessary wastage and facilitate more efficient scale-up. This trend will be further encouraged by the US Food and Drug Administration’s *(FDA) process analytical technology (PAT) initiative(1). This involves an industry wide effort to understand and optimise every step of the production process.
It stands to reason that continuous flow processes monitored at multiple points along the line, using in-line, real-time sensors, would provide the most efficient means of production. This approach is easy to scale up and down in response to demand, utilising a monitoring solution that provides up-to-date information with minimal impact on the process stream. As well as the environmental benefits afforded by reduced material and energy use, this approach has the potential to decrease production cycle times, minimise batch rejection and facilitate the implementation of automation. Such steps offer significant cost savings, providing a substantial return on investment into real-time monitoring technology.
Optics light the way
Perhaps the main bottleneck that has inhibited the widespread adoption of continuous flow production and PAT in the pharmaceutical industry has been the lack of reliable and accurate real-time solutions for monitoring rapid production processes. However, new methods that promise to provide real-time data at multiple points in the production process are promising to change this. One such solution is the SpectroSens optical technology developed by Stratophase. The system is composed of a highly-engineered microchip containing multiple sensing elements that monitor production status in-line and in real-time. The hardware works by measuring changes in the wavelength of light as it interacts with a liquid present at the surface of the sensor head (Figure 1). The wavelengths recorded are influenced by the refractive index (RI) properties of the media, a characteristic that is predictably altered by changes in liquid composition. Temperature is a factor that can confuse RI measurements, so the sensors also record this information as a separate optical signal, so that the RI data can be corrected accordingly. The incident light and recorded light are provided and detected using the same industrial-quality fibre optical cable, connected to an analysis control unit. This approach reduces the need for a power or electrical supply of any kind making the solution ideal for sensitive, potentially explosive processes. In addition, the lack of a complex input/output system allows the sensor to be positioned in those areas where space is limited.
The use of optical sensors for process status monitoring has several advantages. The small size of the optical microchips and their availability in a diverse array of sensor heads ensures that the system can be implemented in a wide range of settings, including even the narrowest of continuous flow pipes (Figure 2). Multiple sensors can be networked together and connected to a main control unit, allowing data from multiple positions in the manufacturing line to be analysed simultaneously (Figure 3). Data transmitted in the form of light can be transported over great distances without any appreciable loss in quality. Therefore, sensors need not be close to the analysis unit, which can be situated wherever required by the end user. This enables use in multi-step, continuous production processes, even those spanning large physical distances. Perhaps most powerfully, the capture of RI data across the full length of a production process can be used to create an RI ‘fingerprint’, allowing production status to be accurately tracked in real-time. Any significant deviation from optimal condition parameters could be configured to trigger an alarm, thereby prompting further investigation by a production engineer. Such a rapid response system could significantly reduce wastage and time, while minimising the need for regular, often unnecessary, off-line sampling. Future advancements will see companies such as Stratophase expand the measurement options available, using sensor technology to monitor vis-IR absorption, particle content, pressure and viscosity, providing further insight into processes as diverse as mixing, blending, crystallisation and separation.
All production processes require optimisation and accurate monitoring to ensure that quality and efficiency are maximised wherever possible. This is true in all manufacturing settings, but has been particularly well illustrated in the pharmaceutical industry, where the adoption of new processes has been significantly driven by the FDA’s 2004 PAT recommendations. To facilitate flexible and accurate scale-up, production methods have begun to switch towards the adoption of continuous flow processes. However, to be truly beneficial, these approaches require real-time monitoring, so that production problems can be quickly detected and dealt with before significant wastage can occur. Small, in-line optical microchips such as the SpectroSens from Stratophase can be used to provide this information, utilising a network of sensors spanning the entire manufacturing process to provide accurate, up-to-date information. In this way, optical sensors can be used to generate an optimal ‘RI fingerprint’, which can be used to monitor any production process that takes place in the liquid phase. What is more, this technology can be applied equally well in R&D and high-throughput production settings, maximising consistency during production scale-up, as well as ensuring that existing methods do not require upgrading in order to switch to large scale manufacture. Such a real-time approach has the potential to dramatically reduce manufacturing costs, providing a cost-effective solution to production process optimisation.
*FDA, Guidance for industry: PAT — A framework for innovative pharmaceutical development, manufacturing and quality assurance; September 2004