Development and Validation of an in-line API Quantification Method Using AQbD Principles Based on UV-Vis Spectroscopy to Monitor and Optimise Continuous Hot Melt Extrusion Process

Abstract

A key principle of developing a new medicine is that quality should be built in, with a thorough understanding of the product and the manufacturing process supported by appropriate process controls. Quality by design principles that have been established for the development of drug products/substances can equally be applied to the development of analytical procedures. This paper presents the development and validation of a quantitative method to predict the concentration of piroxicam in Kollidon® VA 64 during hot melt extrusion using analytical quality by design principles. An analytical target profile was established for the piroxicam content and a novel in-line analytical procedure was developed using predictive models based on UV-Vis absorbance spectra collected during hot melt extrusion. Risks that impact the ability of the analytical procedure to measure piroxicam consistently were assessed using failure mode and effect analysis. The critical analytical attributes measured were colour (L* lightness, b* yellow to blue colour parameters—in-process critical quality attributes) that are linked to the ability to measure the API content and transmittance. The method validation was based on the accuracy profile strategy and ICH Q2(R1) validation criteria. The accuracy profile obtained with two validation sets showed that the 95% β-expectation tolerance limits for all piroxicam concentration levels analysed were within the combined trueness and precision acceptance limits set at ±5%. The method robustness was tested by evaluating the effects of screw speed (150–250 rpm) and feed rate (5–9 g/min) on piroxicam content around 15% w/w. In-line UV-Vis spectroscopy was shown to be a robust and practical PAT tool for monitoring the piroxicam content, a critical quality attribute in a pharmaceutical HME process.

Machine Learning for Process Monitoring and Control of Hot-Melt Extrusion: Current State of the Art and Future Directions

“…Almeida et al [ 35 ] monitored and optimised the concentration of piroxicam (PRX) in Kollidon ® VA 64 using in-line UV–Vis coupled with PLS. They developed one calibration model and two validation data sets; all three data sets (calibration and validation sets) included data from extrusion runs performed on different days.…”

“…Since 2004, many research studies have been reported, in which different machine learning algorithms have been applied to in-process data to analyse product and process parameters in real-time. The applications include the monitoring of product critical quality attributes (CQAs), including the following: the solid state of the polymer/drug [ 2 , 3 ]; API/additive concentration [ 34 , 35 ]; degradation of the polymer [ 36 , 37 ]; the particle size of additive/s [ 31 ]; and mechanical properties [ 33 ]. Other works have examined the monitoring of critical process properties (CPPs), including melt temperature [ 38 ], pressure [ 39 ], and viscosity [ 40 ], and for process fault detection [ 41 ].…”

Innovations in Thermal Processing: Hot-Melt Extrusion and KinetiSol® Dispersing

“…Some of the most commonly used PAT tools include UV-Vis ( 139 , 140 ), Fourier transform near-infrared (FT-NIR) ( 104 , 119 ), and Raman ( 141 , 142 ) spectroscopy techniques. These techniques are simple, fast, and non-destructive to the samples during the HME process.…”

“…A further study on the use of UV-Vis for measuring API concentration in the polymer and API content uniformity was carried out. Analytical models based on the UV-Vis spectra obtained during the HME process were developed as a quantitative method to predict the concentration and content uniformity of piroxicam in Kollidon® VA 64 ( 139 ). The study by Haser et al showed the possibility of in-line monitoring of the solubilization of meloxicam using a UV probe positioned at the die ( 149 ).…”

Novel Cleaning-in-Place Strategies for Pharmaceutical Hot Melt Extrusion

“…To reduce the CV effort, HME would greatly benefit from in-line processes that assess the cleanliness of the material and equipment. Although ultraviolet-visible (UV–Vis) spectroscopy has been shown to be highly applicable to in-line analyses in HME [ 26 , 27 , 28 , 29 , 30 ], e.g., for monitoring the API content [ 30 ], to date no scientific study has employed UV–Vis spectroscopy to detect the API in terms of cleanliness of a material and/or processing equipment. In addition, it is not certain, if an API-free material that is mainly analysed by in-line techniques such as UV–Vis spectroscopy, can also represent an API-free processing equipment [ 9 ], since contaminated material might be trapped in dead spots of the equipment [ 31 ] and contribute to cross-contamination.…”