PAT & QbD SUPPLEMENT


various types of formulations ( i.e. solid dose (tablet, capsules), respiratory (inhaled) and intranasal). PAT tools allow measurements, amongst


others, of critical physical and analytical attributes of the product during the manufacturing process. The most widely used PAT tools in the pharmaceutical industries are: Infrared spectroscopy (Near, Mid), UV-Vis, Raman, Fluorescence, Hyperspectral imaging in Infrared and UV-Vis, laser diffraction, etc. The value of using PAT tools is mainly to


increase process understanding and control, hence increasing the probability of meeting the FDA desired state, to help in the submission of new products.


Examples of application Near infrared spectroscopy (NIR), an on-line method to monitor the API form conversion during the drying process of the drug substance manufacturing Near Infrared spectroscopy (NIR) was used as a Process Analytical Technology (PAT) tool to monitor the API forms conversion during the drying process of a drug substance or Active Product Ingredient (API). The API form is a critical attribute of the drug substance, since it is related to stability, efficacy and safety of the product. The off-line, laboratory-based measurement available to measure it is X-Ray Particle Diffraction (XRPD). This check is done on in- process samples only during process development and once the drying process is fixed only one sample check is taken at the end of the process. The advantage of using PAT is to have a real-


time prediction of the API form during drying in order to detect any drift and prevent it. In order to provide routine online


monitoring of the API form, Near Infrared spectroscopy using the diffuse reflectance (DR) probe method is used as the PAT method in order to eliminate the sampling for XRPD and to detect any drift in the API form from Form 4 before it converts into Form 2. This tool when implemented in real-time to monitor the drying process, help avoid any form conversion before it happens during the drying, thus reducing batch failures. The NIR spectra of the API collected during


the drying process shows changes in the NIR peaks over time, indicating the changes in API form. During this experiment, NIR data were


04


European Pharmaceutical Review Volume 16 | Issue 3 | 2011


collected in real-time and samples were taken at different temperatures for XRPD. The API started as Form 4 at 40°C (Class1) and drifted to the Form4 dehydrated at 50°C (Class2) and then at 70°C the API converted into Form 2 (Class3) and finally when the temperature was increased to 100°C the API form was converted into Form 1 (Class4). The XRPD data was used to select the NIR calibration data corresponding to the samples for each API form class. The model was then tested using NIR data collected on other development drying batches where the drying


“The advantage of using PAT is to have a real-time prediction of the API form during drying in order to detect any drift and prevent it”


time and temperature ramping profiles were changed. It is clear that the NIR predictions classification model was able to monitor the API form changes during the drying process of three different batches. Using NIR, it was possible to follow the conversion between API form classes allowing the engineers and the chemist to optimise their drying process settings (temperature, time, using N2


gas or humidified


air, etc.) to make sure the target API form is produced. NIR was also chosen for use as a part of the API drying process control strategy for real-time monitoring to ensure there was no formation of any other form during drying.


Benefits This example shows the benefit of using the NIR- Diffuse Reflectance probe as a PAT tool for real- time monitoring of the API form during the drying process.


The NIR-DR probe allowed:  better understanding in real-time of the API form conversion during the drying process


 detection of drift in the API form allowing to take action to stop the drying before the batch fails


 monitoring the API form conversion in real-time


 to reduce In-Process Monitoring (IPM) / In-Process Control (IPC) sampling for XRPD measurements


Near infrared spectroscopy (NIR), an on-line method to monitor the spray granulation process during drug product manufacturing A fluid-bed dryer was used to run the spray


granulation process followed by the drying process continuously. The API content during granulation and the


%w/w Loss on Drying (LOD) for the drying endpoint were the two critical quality attributes of the process. NIR data were collected on this process from the start of the spraying phase to the end of the drying phase and used to monitor in real-time the API content throughout the process and also to detect the drying endpoint. The online measurement of the API content


(%w/w) given by the NIR-based multivariate model proved a good comparison with off-line samples measured by HPLC in laboratory. This method was used to help in process development and scale up to make sure that API target content is reached and remains consistent during manufacturing. It was not necessary to use it as part of the control strategy of the product because the process was already controlled and robust. However, the LOD drying endpoint was


critical and controlled only with IPC checks taken after a fixed time of drying. If the batch is over- dried, there is nothing to do but fail the batch and send it to waste. However, if the batch was under-dried after three consecutive IPC checks the batch needed a rework to start the drying again. Using NIR was an added value to reduce the


IPC checks and to avoid fixing the drying time by following the NIR predictions of LOD %w/w in order to decide when to take an IPC check to confirm the LOD value and stop the drying process. It is thus possible to release the batch in real-time, avoiding over-drying the product and any possible rework. Comparison between the off-line mass


balance analysis and the real-time prediction of the %w/w water content showed that the NIR measurements are accurate and can be used to quantitatively determine the drying endpoint. Another advantage of using NIR to collect


data throughout the process is the ability to provide quality process signatures that allow comparing variability between batches. In our case, the process signature of API content and LOD (%w/w) from the start of spraying to the end of drying will enhance the understanding and diagnosis of any variability in the intermediate or final product performance. This knowledge is impossible to have using an IPC check at the end of process without knowing what happens during the process to reach the same endpoint.


Page 1  |  Page 2  |  Page 3  |  Page 4  |  Page 5  |  Page 6  |  Page 7  |  Page 8  |  Page 9  |  Page 10  |  Page 11  |  Page 12  |  Page 13  |  Page 14  |  Page 15  |  Page 16  |  Page 17  |  Page 18  |  Page 19  |  Page 20  |  Page 21  |  Page 22  |  Page 23  |  Page 24  |  Page 25