PAT: A New Dawn for Drug Product Quality - Pharmaceutical Technology

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PAT: A New Dawn for Drug Product Quality
Leading experts share insight on the current and future direction of process analytical technology.


Pharmaceutical Technology
Volume 34, Issue 2

Challenges in PAT

PharmTech: What are challenges in using PAT tools and how are these resolved?

Strother (NIR spectroscopy): NIR instruments are widely used in PAT applications simply because there are fewer challenges in implementation than other techniques such as HPLC or mass spectrometry. NIR instruments are considerably more robust and less finicky than other analytical instruments. Also, multiple components in a mixture can be measured simultaneously from a single collected spectrum.

That being said, there are a few challenges facing users who depend on NIR for process information. NIR isn't as sensitive as other techniques and dispersive instruments are somewhat slow and don't provide the highest spectral resolution. One way to improve on sensitivity, spectral resolution, and speed is to use a Fourier-transform NIR instrument. The nature of these instrument designs allows them to collect a large amount of high quality spectral data rapidly in just a few seconds.

A second challenge is in interpreting the spectral data to provide answers and results. Spectral peaks and information that identify a specific component and concentration aren't as obvious to the human eye as with mid-IR spectra or mass spectroscopy. Fortunately, we can take advantage of common computers to perform chemometric statistical analysis on the NIR spectra. This approach allows us to tease out subtle spectral features that would otherwise not be obvious. Relying on computers to perform the Fourier transform and chemometric analysis leads to a secondary advantage in that these instruments become very easy to use. A good software package will allow a user to just push a button to collect a spectrum and return a result. Even better for PAT applications is that the instrument can be integrated in the process-control system and work autonomously without need of human interface.

Mattes (NIR spectroscopy): Implementation of instrumentation on-line or in-line is a challenge in a regulated environment due to limited access and production schedules. Training of facility personnel as well as operators and developers helps to expedite the implementation cycle. The training is also important to minimize the down-time of the process.

Dobbs (UPLC): To offer a specific example of resolving challenges in UPLC, the Patrol UPLC system began as a collaborative effort between Waters and a major pharmaceutical company to bring real-time LC to the manufacturing floor. This pharmaceutical company required that the Patrol UPLC System operate in an at-line mode, where a manufacturing floor operator simply would drop a barcoded sample tube into the system, and in an online mode, where the system automatically would draw sample directly from multiple manufacturing slipstreams. The company also required that the Patrol UPLC system have the automated capability of switching analytical methods and columns based on information from the sample vial barcode and/or instructions from the factory's distributed control system (DCS). Remote access to the system was also of critical importance to enabling monitoring the system from anywhere in the facility or from any of its worldwide facilities.

In another case, the customer stipulated that there could be no deviation from the existing workflow. The preexisting workflow consisted of the operator drawing a sample from a process-scale reactor into a barcode-labeled vial and transporting it to the off-line QC laboratory and waiting 6-10 hours for an actionable answer from QC. With the at-line version of the Patrol UPLC system, after the sample is drawn, the operator presses a green start button on the touchscreen, which unlocks a sample introduction port door, into which the sample tube is placed for analysis. The system immediately reads the barcode to confirm chain of custody and validates with the DCS and laboratory information management system that the loaded sample is a correct sample during the designated time window. If the sample is appropriate to analyze, the system will take custody, complete the analysis within 60 seconds to 5 minutes, calculate the results instantaneously, and send them to the DCS. The entire analytical process can be reduced from over 6 hours using an off-line laboratory to less than 15 minutes. Also, if an incorrect sample is mistakenly placed in the analyzer, the system will notify the operator immediately after the barcode is read via the touchscreen interface. If the vial is not removed after a specified time period, the system will send an email notification/error message to a specified list that may include the operator, a process engineer, and the line manager.

Another important characteristic is that the online version of the Patrol UPLC system runs under full automation without operator interaction. The system receives a signal from the DCS to begin the automated sample-extraction process from the manufacturing slipstream. Once the system aspirates the sample, it may require some sample preparation in the form of a dilution (usually up to a 1:50 ratio of 1 part sample to 50 parts of diluent), a solvent exchange, solubilization, or a derivatization reaction. Automated sample preparation is completed in under 90 seconds if no hold times are programmed, and the sample is analyzed. Like the at-line version, analysis can typically be completed within 60 seconds to 5 minutes. Results are calculated instantaneously and sent to the DCS.

Vaisman (particle-size analysis): Rather than being a ruggedized modification of a laboratory analyzer, Insitec is a true process system with continuously purged optics, modular design, and no moving parts in operation. This compact system can be easily integrated into pilot-and production-scale operations.

An extremely important part of analyzer integration is ensuring the 'representativity' of the analysis. Any analyzer, be it an in-line probe or on-line slip stream is dependent on representativity of the sample it actually sees. Moving powder often tends to segregate, so to ensure sampling representativity, flow conditions must be evaluated and, frequently, the use of a flow homogenizer will be necessary to counter segregation.

Freeman (powder-flow techniques): Powder-flow tools are used at-line and, therefore, require an operator to sample the product from the process before measuring the powder-flow properties. In-line technology maybe more desirable for PAT, but PAT should ideally focus on identifying measurement techniques that provide the most relevant and representative data. For instance, a process engineer doesn't care if the particle's size changes from batch to batch, as long as they can process the powder through to final product while ensuring the tablet's quality attributes are met. The at-line measurement of powder-flow properties will help the engineer predict subsequent process behavior and if the measured data deviate significantly, variation in process performance should be expected.

Dubois (NIRCI): In general, NIRCI is not used on-line or in-line, but rather at-line. Numerous studies have shown that the product and process understanding obtained with this technique often enable the use of 'simpler' sensors on-line to monitor markers of specific phenomena. This approach has proven to be economically beneficial because it provides the monitoring required to ensure product quality, without requiring the financial investment and technical challenge that might arise from acquiring chemical imaging in real time or in moving systems.


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