Real Time Release Testing: Analytical Methods and Innovations - Pharmaceutical Technology

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PharmTech Europe

Real Time Release Testing: Analytical Methods and Innovations
A roundtable moderated by Angie Drakulich.

Pharmaceutical Technology
Volume 35, Issue 2

Sampling plans

PharmTech: How should sampling plans be approached when using PAT and RTRT compared with traditional sampling methods?

Vaisman (Malvern Instruments): Usually, PAT instruments access larger amounts of sample than would be used for laboratory analysis. On-line instrumentation would typically use automated sampling, in contrast to traditional off-line techniques that tend to rely on grab-sampling at the end of the process. Sample preparation is usually relatively limited for PAT systems to achieve the measurement rates required for continuous monitoring.

Farquharson (Real-Time Analyzers): The best place to monitor reactors is in-situ (i.e., inside the reactor). This can be accomplished using a long-rod fiber-optic probe. However, efforts must be made to keep the probe head clean. In-situ measurements allow for true real-time monitoring. This is significantly better than traditional grab-sampling, which is primarily used to determine whether the end-point had been reached. This, of course, can lead to incorrect analysis and action, specifically if the reaction is running hot or cold (i.e., high yield or low yield).

Equipment failures

PharmTech: What is the best practice to date for handling an equipment or analytical instrumentation failure during RTRT?

Godec and Yourkin (GE Analytical Instruments): The implementation of analytical backup procedures is a requirement, and can be achieved by using redundant equipment or backup laboratory procedures.

Farquharson (Real-Time Analyzers): The best approach is to have internal analyzer diagnostics. For example, we use a process Raman analyzer that constantly monitors a number of parameters, such as the laser power and the unit temperature. It is also possible to implement diagnostics to avoid other failures, such as issuing a warning if the analyzer indicates a constant value due to a coating forming on the optical interface.

Advances in instrumentation

PharmTech: What have been some recent advances in analytical instrumentation to facilitate PAT implementation in solid-dosage manufacturing? Also, what would be helpful for further PAT implementation?

Godec and Yourkin (GE Analytical Instruments): In solid-dosage manufacturing, NIR has benefitted customers trying to understand variation in the process and to improve process understanding. The holy grail with any PAT implementation is the ability for pharmaceutical manufacturers to now have the ability to monitor and control critical processes to achieve product and process robustness. The tool for this achievement would be accurate and reliable on-line analyzers, regardless of the method.

Vaisman (Malvern Instruments): One relatively recent advance is the development of spatial filter velocimetry for high-shear granulation.

Probes that use spatial filter velocimetry can be installed directly in the granulator to provide real-time measurement of the growing granulate. Working across the size range 50 to 6000 microns, such probes are sufficiently robust to measure accurately in the damp, sticky conditions that exist within the vessel. The data provided is extremely useful for endpoint detection, a key processing requirement.

Looking ahead, accurate and reliable in-line measurement of blend homogeneity and the continuous monitoring of segregation, during roll compaction, and in the tablet press, remain important long-term goals.

Redman (Mettler-Toledo AutoChem): Process analytical companies continue to innovate for specific unit operations as challenges arise. Real-time monitoring of granule size in a high-shear wet granulation step is especially challenging, as the sticky mass is difficult to sample and adheres to any instrumentation within the process equipment. The process also occurs so quickly that off-line sampling and analysis is impractical. Mettler Toledo has developed hardware and software solutions to enable probe-based FBRM technology to measure the granulation process in real-time. A hardware-based mechanical scraper uses an intermittent wiping mechanism to remove granulated product that sticks to the probe window. On the software side, advancements in digital signal processing allow the FBRM system to detect particles and granules that are physically stuck to the window. These stuck particles are then eliminated from the measurement to ensure the integrity of the real-time process data.

For the future, it is important that industry continue to develop best practices by collaborating with regulatory agencies, consultants, and process analytical technology suppliers. The wide range of regulatory roadblocks and business incentives continue to make RTRT and PAT overall a confusing route. Greater clarity of the current situation and the path forward will greatly accelerate development and implementation of solutions.

Farquharson (Real-Time Analyzers): Raman, FT-IR, and NIR have great present and future value to PAT. The development of process-worthy FT-Raman spectrometers can overcome the limitation of dispersive systems currently in use (e.g., X-axis instability and fluorescence interference).

Although, large spot and transmission Raman have improved representative analysis of capsules, pills, and tablets, analysis is still inaccurate and/or slow (i.e., both modifications reduce sensitivity). Future designs may alleviate this problem.

Be sure to check out the additional features related to this article on powder processing and on industry and regulatory expectations


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