Blend uniformity evaluation during continuous mixing in a twin screw granulator by in-line NIR using a moving F-test

Fonteyne, Margot; Vercruysse, Jurgen; Leersnyder, Fien De; Besseling, R.; Gerich, Ad; Oostra, W.; Remon, Jean Paul; Vervaet, Chris; Beer, Thomas De

doi:10.1016/j.aca.2016.07.020

Cited by 30 publications

(10 citation statements)

References 59 publications

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“…In order to effectively monitor the CQA and system dynamic changes of the mixing process, the pharmaceutical industry is encouraged to adopt new process analysis methods under the American Food and Drug Administration (FDA) guidance on process analytical technology (PAT) [6]. Many techniques such as near infrared (NIR) spectroscopy [7][8][9][10], Raman spectroscopy (RS) [3,11] and chemical imaging (CI) [12,13] have been reported on determination of BU. Compared with the stratified sampling and offline analysis mode, these online methods enable high frequency sampling, multi-point detection, real time and non-invasive process control, as well as increased production efficiency and reduced operation costs.…”

Section: Introductionmentioning

confidence: 99%

“…It is adaptive in nature, offers easier calibrations, and is designed to be suitable for various situations such as scale-up and transfer between different blenders. Currently, the adaptive method was proven to be efficient in both batch and continuous blending processes [8,17]. However, the available applications were product specific, and only a limited number of formulation materials including the APIs of anhydrous theophylline and excipients of lactose monohydrate, microcrystalline cellulose (MCC), corn starch and dibasic calcium phosphate were investigated.…”

Section: Introductionmentioning

confidence: 99%

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Raw Material Variability and Its Impact on the Online Adaptive Control of Cohesive Powder Blend Homogeneity Using NIR Spectroscopy

Shi

Zhiqiang

et al. 2019

Processes

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It is significant to analyze the blend homogeneity of cohesive powders during pharmaceutical manufacturing in order to provide the exact content of the active pharmaceutical ingredient (API) for each individual dose unit. In this paper, an online monitoring platform using an MEMS near infrared (NIR) sensor was designed to control the bin blending process of cohesive powders. The state of blend homogeneity was detected by an adaptive algorithm, which was calibration free. The online control procedures and algorithm’s parameters were fine-tuned through six pilot experiments and were successfully transferred to the industrial production. The reliability of homogeneity detection results was validated by 16 commercial scale experiments using 16 kinds of natural product powders (NPPs), respectively. Furthermore, 19 physical quality attributes of all NPPs and the excipient were fully characterized. The blending end time was used to denote the degree of difficulty of blending. The empirical relationships between variability of NPPs and the blending end time were captured by latent variable modeling. The critical material attributes (CMAs) affecting the blending process were identified as the particle shape and flowability descriptors of cohesive powders. Under the framework of quality by design (QbD) and process analytical technology (PAT), the online NIR spectroscopy together with the powder characterization facilitated a deeper understanding of the mixing process.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Raw Material Variability and Its Impact on the Online Adaptive Control of Cohesive Powder Blend Homogeneity Using NIR Spectroscopy

Shi

Zhiqiang

et al. 2019

Processes

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“…In fact, changes in material throughput related to market demand can also be seen as a disturbance which needs to be compensated for to assure product quality. [8][9][10][11] The next step is to use the acquired knowledge and monitoring tools to control the continuous feeding of the raw materials. Therefore, the concept of continuous pharmaceutical manufacturing does still not completely align with the design, analysis, and controlframework proposed in the FDA's PAT guidance.…”

Section: Introductionmentioning

confidence: 99%

“…7 Recent studies in the field of continuous drug product manufacturing have therefore investigated the potential to continuously detect undesired powder feed rate deviations and their accompanied disturbances in product uniformity at an early stage using process understanding and advanced monitoring tools. [8][9][10][11] The next step is to use the acquired knowledge and monitoring tools to control the continuous feeding of the raw materials. However, few studies go beyond CQA monitoring.…”

Section: Introductionmentioning

confidence: 99%

Liquid‐to‐solid ratio control as an advanced process control solution for continuous twin‐screw wet granulation

et al. 2018

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Assuring compliance of intermediate and final quality attributes in a continuous pharmaceutical manufacturing campaign is of utmost importance. Application of corrective actions might be required in real‐time. This work exemplifies the steps needed to identify a linear pulse transfer function for the dynamic behavior of the granule liquid‐to‐solid ratio (%w/w) at the end of the granulation unit of a commercial ConsiGmaTM‐25 production line. Near‐infrared spectroscopy was used to monitor the granule composition in‐line. The outcome for both the tracking and regulator problem using either conventional or model predictive control was implemented and evaluated. Dynamic setpoints were correctly followed and an RMSE of 0.25%w/w with respect to the setpoint was obtained when inducing artificial disturbances. Important practical challenges were also tackled. Examples are fouling, computational limitations, and the limited flexibility of the automation software. Applying the proposed advanced process control solution offers an answer to upstream material flow rate deviations. © 2018 American Institute of Chemical Engineers AIChE J, 64: 2500–2514, 2018

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“…Recently, twin screw granulations (TSG) have attracted considerable attention especially in the area of pharmaceutical formulation development. Most of the reported studies in the past decades or so have mainly described the production of semi-crystalline granules or agglomerates via two major extrusion granulation techniques: (i) wet, and (ii) hot melt or dry granulation [11–14]. The latter being more suitable for the continuous operation as it eliminates intermediate steps by producing free-flowing ready-to-use granules [12].…”

Section: Introductionmentioning

confidence: 99%

Chemico-calorimetric analysis of amorphous granules manufactured via continuous granulation process

Majumder¹,

Rajabnezhad

Nokhodchi

et al. 2018

Drug Deliv. and Transl. Res.

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The current study explores the first case of the implementation of solution calorimetry (SolCal) in order to determine the amorphous content of crystalline benzoyl-methoxy-methylindol-acetic acid (BMA)-a model poorly soluble drug, in the amorphous granules prepared via single-step continuous twin-screw dry granulations (TSG). Amorphous magnesium aluminometasilicate (Neusilin®) (US2) was used as a novel inorganic carrier via a TwinLab 10 mm twin-screw extruder. The BMA/US2 blends were processed at 180 °C and varying drug: carrier ratios of 1:4, 1:2.5 and 1:1 (w/w). Physico-chemical characterisation conducted via SEM, DSC and XRPD showed amorphous state of the drug in all granulated formulations. Reverse optical microscopy revealed a meso-porous structure of US2 in which the drug particles are adsorbed and/or entrapped within the porous network of the carrier. This phenomenon can be the underlying reason for the increase of the amorphous content in the extruded granules. Solution calorimetry (SolCal) study revealed amorphous content of the drug in all formulations quite precisely, whereas the dynamic vapour sorption (DVS) analysis complemented the results from SolCal. Furthermore, an attempt has been made for the first time to interrelate the findings from the SolCal to that of the release of the drug from the amorphous granules. It can be concluded that SolCal can be used as a novel technique to precisely quantify and interrelate the amorphous content to its physico-chemical performances such as drug release from the granulated formulations processed via TSG.

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Blend uniformity evaluation during continuous mixing in a twin screw granulator by in-line NIR using a moving F-test

Cited by 30 publications

References 59 publications

Raw Material Variability and Its Impact on the Online Adaptive Control of Cohesive Powder Blend Homogeneity Using NIR Spectroscopy

Raw Material Variability and Its Impact on the Online Adaptive Control of Cohesive Powder Blend Homogeneity Using NIR Spectroscopy

Liquid‐to‐solid ratio control as an advanced process control solution for continuous twin‐screw wet granulation

Chemico-calorimetric analysis of amorphous granules manufactured via continuous granulation process

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