MOISTURE CONTENT MEASUREMENT CASE STUDY This case study is based on a large research-focused health care company with a long tradition in pharmaceutical production and diagnostics. The company was founded by people intricately involved in spectroscopy and process analytical technologies, long before the FDA published PAT guideline in 2004. The experts of the company paved the path for PAT in different companies, overcoming different process issues like window fouling, integration and system prices. The two companies came together accelerating the implementation of this advanced technology in the industry. 1
THE CHALLENGE DETERMINING THE MOISTURE CONTENT OF GRANULES IN A FLUID BED DRYER In tablet production, a drying process is needed to ensure moisture levels are reached after granulation. Granulation is either done in a Fluidized bed or high shear granulator to guarantee particle size uniformity and equal distribution of Ingredients. This process can cause significant delays in tablet manufacturing with room for errors and potential product loss. The challenge lies in accurately and consistently determining the moisture content of granules in a fluid bed dryer, the most common granulation process. The wrong drying conditions can result in damaged particles, uneven product uniformity such as distribution of APIs, and breakable tablets. Wet granulation is typically done in batch process, requiring the drying phase to standstill many times for offline analysis. Alternatively, the process continues blindly based on an operator s experience. Both of these methods extend production time and increase risk that granules are not at optimum moisture content. The best results come from Near-Infrared, NIR, reflectance spectroscopy application for in-line, contact measurement of moisture content in a fluidized bed. The pictures to the left show typical window fouling: the first demonstrates a heated probe tip in a high shear granulator freshly installed. The second picture shows the location probe in between sediments on a fluidized bed wall. The ingredients dried on the lens and later required cleaning at the end of granulation. 2
THE CHALLENGE WINDOW FOULING When the US Food and Drug Administration launched the PAT Initiative in 2004, the company investigated a number of in-process measurement systems. Almost without fail, the single most common factor that interfered with the process and prevented operators from obtaining accurate data was window fouling. The Lighthouse Probe can be used to monitor chemical and pharmaceutical processes in real-time, providing a clear view inside the production vessel, even in difficult conditions. Offering in-process window cleaning and recalibration, the device is fully clean-in-place (CIP) compatible and available in both manual and automated versions. Offering standalone to fully integrated and multivariate functionality, the Lighthouse Probe optimizes production by minimizing variation, reduces waste, provides valuable data, saves money and offers a constantly clear view into the process vessel. The graphs represent data from a 10 minute granulation run on a high shear granulator. It is clear from the graphs that the probe missed an important part of the process due to window fouling. This caused inaccurate readings of moisture until the process was stopped, the probe was cleaned and measurements could resume. The first graph emphasizes when the powder sticks to the probe. The heat from the probe window quickly dries the powder thus moisture Level decreases, demonstrating a trough in the graph. This creates a false moisture reading caused by window fouling. Thanks to the cleaning steps and calibration, the spectra used for modelling can be trusted not to suffer from any bias caused by window fouling. This will generate a very accurate model. 3
THE SOLUTION LIGHTHOUSE PROBE The quest for a better method ended with Lighthouse Probe moisture sensor NIR measurements of moisture in-line and in real-time In-process window cleaning at any time In-process control of window cleanliness at any time. In-process recalibration at any time Eliminates inaccurate calibrations caused by window fouling Full CIP of wash and housing seal Always a clear view inside with The Lighthouse Probe 4
AUTOMATIC CLEANING MECHANISM Product sticking to the observation window is no longer an obstacle with contact measurements. As the sides and windows of a dryer become fouled The Lighthouse Probe TM can use its in-line window scrape and/or wash functionality to keep a clear view at all times. Calibration measurements are also taken without the bias of window fowling resulting in an accurate, automatic calibration. Cleaning The advantage of the window cleaning capabilities in combination with the easy calibration method of the moisture sensor makes this a fast and very reliable tool for online moisture determination. 5
THE RESULTS The test was done with a Glatt dryer and the Lighthouse Probe mounted on, in-line with the sampling unit and the temperature sensor. During the operation the probe was moved between measurement and calibration positions to clean it s windows just before taking a calibration reference. During the first batch, 5 calibration points were recorded to establish the correlation with the offline analysis method. This exercise yielded the calibration values needed to configure the moisture meter. Online Data Offline Data Sample ID LOD RSD LOD1 LOD2 LOD3 Average St Dev Sample 1 1,00 0,042 0,9 0,95 1,04 0,96 0,071 Sample 2 1,07 0,039 1,04 1,09 1,08 1,07 0,026 Sample 3 1,16 0,025 1,06 1,14 1,19 1,13 0,066 Sample 4 1,03 0,025 1,01 1,02 1 1,01 0,010 R² 0,97 RMSEP 0,026% LOD The calibrated system was then used in 4 different batches and the performance was checked by taking samples during the drying and comparing them with the online results. 6
COMMERCIAL BENEFITS The initial benefit comes from the reduction in product waste as line moisture determination always involves the risk of batch failures. Each rejected batch is an enormous financial investment and wastes resources. The use of the Lighthouse Probe eliminates this risk. Longer term, the Lighthouse Probe enables monitoring the moisture content of the granules more carefully thereby helping to produce granules that are easier to handle in the following tableting process and produce a more clinically effective product. These benefits are more difficult to calculate objectively but are potentially much greater. The Lighthouse Probe is a practical solution to the problem of assessing moisture content during the granulation process. It requires the company to take fewer measurements, reduces costs and produces a more effective and consistent product. For further information: sales@indusmation.com 7