Fluidised bed granulation of two APIs:QbD approach and development of a NIR in-line monitoring method

The study focused on the fluid-bed granulation process of a product with two active pharmaceutical ingredients,intended for coated tablets preparation and further transfer to industrial scale.The work aimed to prove that an accurate control of the critical granulation parameters can level the input material variability and offer a user-friendly process control strategy.Moreover,an in-line Near-Infrared monitoring method was developed,which offered a real time overview of the moisture level along the granulation process,thus a reliable supervision and control process analytical technology(PAT)tool.The experimental design’s results showed that the use of apparently interchangeable active pharmaceutical ingredients(APIs)and filler sorts that comply with pharmacopoeial specifications,lead to different end-product critical attributes.By adapting critical granulation parameters(i.e.binder spray rate and atomising pressure)as a function of material characteristics,led to granules with average sizes comprised in a narrow range of 280–320μm and low nongranulated fraction of under 5%.Therefore,the accurate control of process parameters according to the formulation particularities achieved the maintenance of product within the design space and removed material related variability.To complete the Quality by design(QbD)strategy,despite its limited spectral domain,the microNIR spectrometer was successfully used as a robust PAT monitoring tool that offered a real time overview of the moisture level and allowed the supervision and control of the granulation process.

Real-time monitoring and fault detection of pulsed-spray fluid-bed granulation using near-infrared spectroscopy and multivariate process trajectories

Pulsed spray is a useful tool forgranule size control in fluid bed granulation.To improve the quality control of pulsed-spray fluid bed granulation,a combination of in-line near-infrared(NIR)spectroscopy and p「incipal component analysis was used to develop multivariate statistical process control(MSPC)charts.Different types of MSPC charts were developed,including principal component score charts,Hotelling's T2 control charts,and distance to model X control charts,to monitor the batch evolution throughout the granulation process.Correlation optimized warping was used as an alignment method to deal with the time variation in batches caused by the granulation mechanism in MSPC modeling.The control charts developed in this study were validated on normal batches and tested on four batches that deviated from normal processing conditions to achieve real-time fault analysis.The results indicated that the NIR spectroscopy-based MSPC model included the variability in the sample set constituting the model and could withstand external variability.This research demonstrated the application of synchronized NIR spectra in conjunction w让h multivariate batch modeling as an attractive tool for process monitoring and a fault diagnosis method for effective process control in pulsed-spray fluid bed granulation.