Process Analytical Technology PAT is The Key to a Better Process

Process analysis technology permeates every aspect of pharmaceutical production — Improved process understanding, higher process reliability, and fewer rejects: PAT techniques can achieve all this and more.

A lot has changed since America’s FDA decided to incorporate more process analysis technology into pharmaceutical production back in 2003. The objective of the PAT initiative has not changed, however: Still today, it aims to optimize the production of pharmaceuticals and improve process understanding.

Over this time, the market has seen the introduction of a wide range of technologies and sensors suitable for such applications. In general, the FDA initiative does not make any distinction between types of instrumentation provided that its output can be used to draw conclusions about critical process parameters and quality attributes.

In this respect, the limits between process analysis technology and “normal” measurement technology are completely fluid. In many cases, even a simple product temperature measurement system in a granulation process may operate in accordance with PAT criteria.

More elaborate optical procedures such as Raman or NIR are well-known techniques in the production of pharmaceuticals; however, complex systems of this kind are seeing relatively slow acceptance into routine use in production. This is because implementation, method development, and validation are very expensive, and it is this cost that is deterring many production managers from investing in PAT solutions.

Real-time measurement speeds up processes and conserves resources.

Many companies, however, are beginning to rethink their position on the idea. Pharmaceutical companies engaged in research and innovation are particularly aware of the benefits of PAT instrumentation and are conducting intensive work on its applications. This had led, for instance, to NIR becoming the accepted standard for some applications, such as blender monitoring.

It has also resulted to a sharp increase in demand for PAT solutions at Glatt Integrated Process Solutions within the last five years. Glatt is a specialist in integrated process solutions for developing, processing, and manufacturing powder solids, and supports its customers along every link of the process chain.

The company has already been addressing the subject of process analysis technology for many years. The advantages of using process-analytical methods are especially clear: improved process understanding, higher process reliability, and reproducible product quality.

The benefits can most easily seen in real-time measurement: Firstly, resources can be saved during process development, process transfer, and process optimization. Secondly, the optimum process parameters can be identified more quickly because the influence of parameter settings can be monitored directly and displayed in real time during process operation. Many customers therefore also use PAT to optimize the statistical design of experiments; that is to say, the design of experiments required by the FDA.

“Processes consistently benefit from PAT techniques”

At present, PAT is mainly used in process control : Critical quality attributes are displayed in real time, which makes it possible for the machine operator to intervene with enough time to save a production process if predefined limit values are exceeded during it. Finally, PAT can also be integrated into control circuits and initiate specific process phases when product-specific target values are reached, allowing the operator to achieve a reproducible level of product quality.

Process analytics are in fact an indispensable element of integrating intelligent, advanced process guidance strategies. In order to reduce the cost of implementation, method development, and validation for the user, Glatt works with specialist companies during the development of process-analytical methods.

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In doing so, Glatt and its partners Innopharma Technology, Parsum, Sentronic, and Tews Elektronik to provide integrated PAT solutions that cover all current requirements in the production of solids: determining and displaying product moisture, particle size and distribution, as well as the chemical composition and concentration of pharmaceutical mixtures to determine the blend uniformity, for example.

Innopharma Technology has developed a direct imaging system for the real-time, non-destructive measurement of particle size and its distribution in dry and moist granulates and pellets.

Parsum, a specialist in particle measurement technology, has developed the IPP 80 probe to measure particle size distribution in powders, pellets, or granulates in pharmaceutical processes.

The spectroscopy is covered by Sentronic’s diffuse near-infrared reflectance spectroscopy technique, which has been continuously optimized for system solutions in the pharmaceuticals industry over the years.

A Tews Elektronik microwave-based system for real-time monitoring during the process continuously measures surface and core moisture of particles and granulate, regardless of variations in particle size, color, or density. Precise measurement results are achieved in milliseconds.

When is PAT most worthwhile?

The ability to monitor blend uniformity is particularly useful in mixing processes: When is optimum mixing achieved or are there perhaps undesirable segregation effects? Granule size and size distribution are especially important in processes such as granulation, coating, or pelletization.

Changes in particle size are important PAT parameters during the coating stage in the fluidized bed in particular, as there is a direct correlation between the dissolution profile of the substance and the size distribution of the particles. In drying processes, the residual moisture of the product has a decisive influence on the end time and shutting down of the process.

In continuous processes, meanwhile, the application of PAT is important in two respects: as a control system, it not only ensures consistent product quality throughout the long process duration, but also rejects out-of-spec material in good time. Practical applications, such as particle size measurement during a coating process or residual humidity measurement during a rotor process, prove the advantages that can be gained from real-time measurement.

However, the operator can only fully benefit from PAT instrumentation if the control system’s control circuits are closed. In the case of Glatt’s Modcos continuous process system, PAT integration into the specially designed software system Glatt View Conti was planned as early as the development phase.

Product traceability through the system is particularly important in continuously operating systems. By applying PAT in targeted areas after critical process steps, out-of-spec material can be detected, visually traced through downstream processes, and rejected at the end of the process line. In conclusion, PAT tools reduce the number of rejects, shorten process times, and facilitate reproducible product quality.

Furthermore, early application of PAT in product and process development — as well as during transfer — reduces material and time resources spent on these development phases.

PAT also helps to increase the degree of automation and reduce the risk of potential operator error. Finally, process analysis technology facilitates real-time release — paving the way for automated batch release as a result.

Two questions for PAT expert Christian Knopf

Mr. Knopf, how is the PAT instrumentation of a batch process different to that of a continuous process?

Christian Knopf: In both cases, PAT can be used for process control and monitoring purposes. In batch processes, PAT can be used to initiate certain process phases or determine their end points. If a defined level of residual moisture is reached during a drying process, for example, this information can be set as a shut-down criterion for the dryer.

So, in continuous processes, it’s more to do with product quality?

Knopf: In continuous processes, the operator wants to and has to be certain that the product quality remains consistent at all times. Ideally, in continuous processes, PAT is inline—i.e., used in the product flow—which is why probes sometimes need to operate for several weeks without being cleaned. This means that self-monitoring concepts are required. Product and process information can be determined at several checkpoints in continuous processes, meaning that the amount of information covered for the measured product is very high. PAT systems can be used for specific purposes regardless of what information is crucial for quality.

* * C. Knopf is a PAT expert and A. Friese is Head of Marketing at Glatt in Binzen, Germany. Contact: Phone +49-7621-664-348

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