2024-11-07 14:00:00
Pharma Industry: When we talk about operational excellence in pharmacy, one subject often comes to the forefront, that of PAT or Process Analytical Technology. But what is it exactly?
Thomas Ricour: Before talking about PAT, we must start by talking about Quality by Design or QbD. QbD is an approach that has been recommended by the FDA since 2005. Other agencies have followed it, including the EMA in Europe, in line with the principles of ICH Q8. QbD makes processes more agile and more efficient. In summary, it involves moving from an approach where “I make and I control” to “I control while I make”, having built quality during development.
Before QdD, we talked about Quality by testing. We had a variable input raw material, but a fixed process. As a result, the drug product became variable and could go out of specification because the process could not adapt. The QbD accepts that I analyze and adapt – this is the role of the PAT – my process so that the drug product becomes more “capable”. This approach has made it possible to considerably lower the cost of non-quality. With an old approach of Quality by Testing, this non-quality could represent up to 20 to 25% of revenues. Thanks to QbD, the cost of non-quality is estimated at around 1 to 3%. As for PAT, it is only a QbD tool, in the same way as chemometrics, mathematical modeling or experimental plans. PATs without QbD are like a car without a license. One does not go without the other.
Thomas Ricour, co-founder of ProcessControlExpert. (Credit: ProcessControlExpert)
What types of analyzes can be covered by PAT?
TR: PATs are all the analyzes and measurements that we carry out in real time, during the process: in line, on line (in a loop), at line (outside the line). On the other hand, everything that is offline, that is to say the analyzes which require a sample and are sent to a quality control laboratory, falls under Quality by Testing.
It is this ability to produce a result in real time that allows the process to be modified to avoid deviations. For example, in the case of a mixing operation, analyzing the homogeneity of the components in real time can make it possible to adjust the mixing time or the rotation speed of the blades, without having to wait for the end of the mixing operation. initially programmed operation and an off-line measurement to confirm this result.
In other words, with the PAT, we access a signature of the process in real time and an end point for the best possible execution of unit operations, such as the manufacture of APIs, the manufacture of capsules or capsules, the reception and the control of raw materials, mixing, granulation, drying, freeze-drying… We control the process at all points and at all times.
However, near infrared (NIR) technology is often associated with PAT. For what ?
TR: NIR is, in fact, the most common technology, due to its ability to carry out non-destructive testing, as close as possible to the sample in development or production. This technology has therefore become widely established over the last 25 to 30 years. But it is a technology that also has its limits. This is why Raman is increasingly establishing itself as a complementary technology. Thanks to its ability to see through a lot of transparent or even opaque packaging, Raman has particularly established itself in the identification of raw materials. On the other hand, Raman does not see water. Also, we are not going to use it in monitoring the drying of powders, for example. Raman, on the other hand, is very interesting in biotech, for monitoring culture processes in the up-stream phase.
But any other technology used online can be considered PAT. For example, tomography is widely used for very precise analyzes of tablets, particularly for monitoring coatings or mixtures.
You are a PAT and QbD specialist; When do you intervene in pharmaceutical laboratories to introduce these approaches?
TR: We try to intervene as early as possible, in terms of process development. QbD makes it possible to define critical attributes. These are the ones we will then follow online in order to be able to master the process and see if it is consistent and repeatable.
But it also happens that a manufacturer contacts us when he encounters a problem at a stage of his production. For example, a mixture that does not go well and will lead to unmixing. For this, we propose to carry out an analysis using a QbD approach to always determine the critical attributes of the process. PATs will then be useful for tracking these critical attributes. At this stage, we can propose the use of different technologies, with the realization of POC to determine which is the best. This could be Raman, near IR, imaging, online chromatography or the installation of different measurement probes.
In all cases, we are able to intervene, from the control of the raw material to the finished product in its packaging, for liquid, solid, pasty or injectable and biotech products. We can intervene in the entire process or concentrate on the most critical stages.
“For a biotech batch, it’s impossible to wait for the final response from quality control. You need to know what happens during manufacturing. “.
Who are the most demanding: small or large pharmaceutical laboratories?
TR: We have two types of customers. Big pharma which manufactures for itself and which perfectly integrates QbD and PAT approaches, from the development phases, and which we can support. On the other hand, there are CDMOs to whom large laboratories transfer products and who must quickly master a recipe. In this case, PATs are particularly interesting to have more information on the batches manufactured, and to be able to be active and proactive in real time.
It may take a few days or even weeks to install a QbD approach. It will make it possible to confirm the critical parameters to be monitored, when the PAT will then monitor these parameters. If the technology chosen is Raman, implementation will only take a few days. If more specific online analyzers need to be installed, this may take a few weeks, depending on the availability of this equipment from the manufacturer. In all cases, the gain can be very significant, in particular reducing the number of batches to be produced to best adjust the production parameters.
Mixer equipped with a SentroPAT DA NIR online analyzer. (Credit: DR)
What about the biotech sector?
TR: In biotech, demand is also very high because we are dealing with living material and there is even more variability than when manufacturing chemical active ingredients, for example. For a biotech batch, it is impossible to wait for the final response from quality control. You need to know what happens during manufacturing. Not to mention that, in a yeast fermentation, for example, the use of this or that raw material could also have a strong influence on the final yield. The QbD approach makes it possible to control all these different parameters.
To intensify processes and gain efficiency, manufacturers are increasingly talking about moving from batch to continuous. Does QbD also bring benefits?
T. R. : Precisely, the QbD approach and PAT are becoming essential in continuous manufacturing. In this case, a final measurement would not be sufficient to control the process. Real-time measurement is essential.
Is AI making its way into Quality by Design?
TR: Depending on the technologies used, PAT can lead to the generation of significant data flows. Until now, this data was already analyzed and used via chemometric methods and the use of neural networks to model and predict drift. But the strength of AI is that it can aggregate data from much more diverse sources to build even finer process control models. With AI, we go further. The only downside is that the AI works like a black box and its prediction models are, for the moment, challenged by the FDA which likes things square. Also, AI cannot be used in filing cases. It remains a support tool. The algorithms and mathematical models used in chemometrics are robust models proven and recognized by regulatory authorities.
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Process analytical Technology in pharmaceutical industry PDF
**Interview with Thomas Ricour on Process Analytical Technology (PAT) in Pharmaceuticals**
**Host:** Welcome, Thomas Ricour, co-founder of ProcessControlExpert. Today, we’re diving into the critical topic of Process Analytical Technology, or PAT, and its role in transforming the pharmaceutical industry. Thomas, could you start by explaining what PAT is and its importance in manufacturing?
**Thomas Ricour:** Absolutely! Before we delve into PAT specifically, it’s essential to discuss Quality by Design (QbD). QbD is a proactive approach to pharmaceutical development that aims to build quality into the process rather than relying solely on testing finished products. This shift enhances process efficiency and control, enabling manufacturers to monitor and adjust processes in real-time, which is where PAT comes in. PAT serves as a tool within QbD to analyze and adapt processes as they unfold, rather than waiting for results from traditional quality control testing.
**Host:** That’s enlightening! Can you elaborate on the types of analyses that PAT encompasses?
**Thomas Ricour:** Certainly! PAT includes any analysis that occurs in real-time during production. This can be done in-line, on-line, or even at-line. The key advantage is that it allows manufacturers to receive immediate results. For instance, during a mixing process, we can monitor component homogeneity in real-time, which enables immediate adjustments to the mixing parameters. This continuous feedback loop is vital for maintaining product quality and consistency throughout manufacturing.
**Host:** And how does Near Infrared (NIR) technology fit into the PAT landscape?
**Thomas Ricour:** NIR technology is one of the most prevalent tools in PAT due to its ability to conduct non-destructive testing. It has been used extensively over the past few decades for process monitoring, particularly because it can analyze samples closely to the production process. However, it’s not without its shortcomings, which is why technologies like Raman spectroscopy are gaining traction. Raman can analyze through various types of packaging and is particularly useful in biotech applications for monitoring cell culture processes.
**Host:** Interesting. At what point do you typically engage with pharmaceutical laboratories to implement these approaches?
**Thomas Ricour:** We aim to engage as early as possible, particularly during process development. This is when critical attributes are defined, allowing us to monitor them online. However, we also assist when manufacturers face challenges in their production, such as an unsuccessful mixing operation. We can then analyze using a QbD framework to identify critical attributes that need monitoring, leveraging the right PAT technologies to provide real-time insights.
**Host:** Do you find that smaller or larger pharmaceutical companies are more proactive in implementing PAT and QbD?
**Thomas Ricour:** Both have different needs. Larger pharmaceutical companies typically have a more ingrained understanding and integration of QbD and PAT from the outset. Conversely, Contract Development and Manufacturing Organizations (CDMOs), which handle products for larger firms, often seek our expertise to quickly master recipes and gain real-time batch information. They benefit significantly from the insights provided by PAT as it allows them to be reactive and proactive in managing production quality.
**Host:** And what about the specific demands of the biotech sector?
**Thomas Ricour:** The biotech sector is unique due to its reliance on living materials, which introduces variability beyond what is seen in chemical manufacturing. This makes real-time monitoring and adjustment even more critical. There is a high demand for PAT in biotech to ensure that processes are controlled effectively, especially since waiting for post-production quality control results is not feasible when working with live cultures.
**Host:** Thank you, Thomas. Your insights into PAT and its integration with QbD offer a compelling look into the future of pharmaceutical manufacturing.
**Thomas Ricour:** Thank you for having me! It’s an exciting time in the pharmaceutical industry, and I’m glad to share these developments.