PAT SUPPLEMENT


James Brenner: Extrel understands that your application is different from anyone else’s. Therefore, we adopt a partnership approach. Through our comprehensive support and training by our application chemists, we empower our customers to take advantage of the mass spectrometer’s ease of use and flexibility, allowing pharmaceutical researchers and manufacturers to perform to the required standard and/or develop the next standard.


“PAT allows the pharmaceutical industry to move more towards continuous, rather than batch, manufacturing processes. How well do vendors appreciate the performance requirements and quality expectations of PAT measurement techniques which may be used for real time assurance and release of commercial material produced using continuous manufacturing processes?”


Mario Becker: Having also implemented PAT solutions in high throughput food processes, Sartorius application engineers are well aware of the requirements of continuous manufacturing. Being applied in a rough environment, analytical systems have to be robust and to do their job without cumbersome maintenance or adjustments. Besides high cleanability and long term stability, intelligent calibration routines as well as special system designs, e.g. redundant lamps in NIR-systems and process adoptions preferably without fibre-optics are required. Furthermore, data pre-treatment for statistical evaluation and advanced control routines need to be embedded.


James Brenner: The MAX300 is one of the fastest online analysers on the market, but the speed at which you collect data has no value unless the accuracy of that data is reliable. The Hydrocarbon industry has been relying on Extrel for the supply and support of online process mass spectrometers for nearly 50 years now. This industry has required some of the most stringent performance expectations of any industry and these expectations have been met and exceeded on a regular basis. The pharmaceutical industry should expect nothing less than the same consistency and performance, especially when the quality of your medicinal products will have


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European Pharmaceutical Review Volume 16 | Issue 6 | 2011


a direct impact on the lives and well being of millions of people.


Frédéric Despagne: Before the pharmaceutical industry started looking at continuous analysis, we were one of the first companies supplying FT-NIR analysers for real-time monitoring of continuous processes in refining, petrochemical or semiconductor applications. While the incentives in those industries may differ slightly, most expectations of the end-users are no different from pharmaceutical industry. They want rugged analysers with minimal maintenance, maximal uptime, easy inter- facing to plant controls and compliance to applicable standards. Our pharmaceutical customers appreciate that we make them benefit from this process expertise, and together with them, we adapt the solutions to accommodate specificities of pharmaceutical industry regulations.


John Richmond: Qualification of any PAT analyser is extremely important and necessary for the regulatory authorities. With laboratory based measurements, it is relatively straight - forward to perform a daily PQ (performance qualification) test to ensure that the analyser is working to specification. However, in process and particularly in continuous manufacturing this presents some challenges. However, with Bruker’s innovative hardware design and software we have developed automated protocols for auto-referencing, an internal validation unit (IVU) and software plug ins that perform the tests required under the USP1119, and PHEur (2.2.40) monographs to ensure complete compliance with cGMP manufacturing requirements.


“ICH Q2A and Q2B, which deal with the validation of analytical methods, were written many years ago and were, understandably, heavily biased at that time towards laboratory measurement techniques. How should these guidance documents be revised and rewritten to reflect the PAT/Quality by Design approach to pharmaceutical development and manufacture?”


James Brenner: Extrel has had success in the creation/rewrite of these types of documents when customers take advantage of the


MAX300’s ability to seamlessly transfer from the research phase to pilot scale and ultimately onto full production. By providing different area classification versions of the same analyser, the MAX300 allows customers to scale up to full production economically, essentially making the process mass spectrometer a laboratory measurement technique at the beginning of product development; bypassing the need for method change.


Frédéric Despagne: Indeed parameters addressed in guidelines and pharmacopoeias are assessed off-line. They are acceptable for laboratory applications and occasional instrument performance qualification, but insufficient for assessment of fitness for purpose during process analysis. Ideally, guidelines should recommend ‘on-the-fly’ diagnostics. In an industry highly concerned with risk assessment, the confidence one can have in an analytical reading is as important as the reading itself. We pay great attention to ensure that every measurement generated by our analysers is well qualified. As an example, our latest analysers are now pre-configured with a set of PAT-specific diagnostics related not only to the instrument, but also to some potential process upsets or artefacts.


John Richmond: Q2A & Q2B were devised in 1995 before the PAT era and reflect best practice at that time. However, the guidance with respect to Specificity, Linearity, Accuracy, Precision, Quantitation Limits and Detection Limits should be revised to reflect real time process monitoring and should include robustness and repeatability of process measurements. As an example, there should be guidance on the use of ‘semi-quantitative’ methods such as conformity index or moving block standard deviation measurements for assessing the uniformity of a particular blend.


Mario Becker: ICH Q2A and Q2B are well- thought out guidelines, however there is no mention of real-time or online/inline results being generated or evaluated. Main drivers for the change in developing an analytical method are cost reduction in product development and production while avoiding any increase in risk. To apply the QbD approach for analytical methods the concept of an analytical target profile (ATP) has been developed. For sure, the ATP does not describe the method but it sets


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