The Use of a Closed Feed Frame for the Development of Near-Infrared Spectroscopic Calibration Model to Determine Drug Concentration.

PURPOSE: This study evaluates the use of the closed feed frame as a material sparing approach to develop near-infrared (NIR) spectroscopic calibration models for monitoring blend uniformity. The effect of shear induced by recirculation on NIR spectra was also studied. METHODS: Calibration models were developed using NIR spectra obtained in the closed feed frame for two cases. For case 2, blends that flowed through the open feed frame were predicted with the model. The shear effect of the feed frame on the blends was assessed through the characterization of powder properties before and after recirculation. RESULTS: The physical characterization of the blends confirmed that the powder properties were not altered after recirculation within the closed feed frame. Both calibration models provided highly accurate predictions of the test sets with low bias (0.03% w/w and -0.06% w/w) and relative standard error of prediction (1.9% and 3.7%), respectively. The predictive performance of the calibration models was not affected by the shear effect. CONCLUSION: Recirculation within the closed feed frame did not change the physical properties of the blends studied. The prediction of blends flowing through the open feed frame was possible with a calibration model developed in the closed feed frame. The closed feed frame could reduce the materials needed to develop calibration models by more than 90%.

Identification of Four Similar Cell Culture Media According to their Glucose, Glutamine, and Pyruvate Content by Handheld Raman Spectroscopy.

PURPOSE: This study describes the first efforts to build a spectral library to identify four cell culture media in powder form with spectra obtained with a handheld Raman spectrometer. These complex mixtures contain over 30 components and are among the most widely used cell culture media. METHODS: A total of 32 spectra were collected for the four Dulbecco's Modified Eagle Medium cell culture media and pure materials (glucose and L-glutamine) in powder form. The spectra were preprocessed using standard normal variate with second derivative, and the barcode method before performing principal component analysis (PCA). RESULTS: The PCA model differentiated the pure glucose and the cell culture media according to the glucose concentration along the first principal component. The second principal component differentiated the three cell culture media with high glucose content according to the pyruvate concentration. The correlation coefficient showed that powdered cell culture media with high glucose concentration have a higher correlation with pure glucose, when compared with the cell culture media with low glucose. CONCLUSION: The Raman spectra made it possible to differentiate the four DMEM in the cell culture media from the majority of the external samples used in the method evaluation. However, sample heterogeneity affected the predictions. Additional studies are needed to improve the method's ability to differentiate the DMEM with high glucose.

Evaluation of a compact composite sensor array for concentration monitoring of solutions and suspensions via multivariate analysis.

Compact composite probes were identified as a priority to alleviate space constraints in miniaturized unit operations and pharmaceutical manufacturing platforms. Therefore, in this proof of principle study, a compact composite sensor array (CCSA) combining ultraviolet and near infrared features at four different wavelengths (280, 340, 600, 860 nm) in a 380 × 30 mm housing (length x diameter, 7 mm diameter at the probe head), was evaluated for its capabilities to monitor in situ concentration of solutions and suspensions via multivariate analysis using partial least squares (PLS) regression models. Four model active pharmaceutical ingredients (APIs): warfarin sodium isopropanol solvate (WS), lidocaine hydrochloride monohydrate (LID), 6-mercaptopurine monohydrate (6-MP), and acetaminophen (ACM) in their aqueous solution and suspension formulation were used for the assessment. The results demonstrate that PLS models can be applied for the CCSA prototype to measure the API concentrations with similar accuracy (validation samples within the United States Pharmacopeia (USP) limits), compared to univariate CCSA models and multivariate models for an established Raman spectrometer. Specifically, the multivariate CCSA models applied to the suspensions of 6-MP and ACM demonstrate improved accuracy of 63% and 31%, respectively, compared to the univariate CCSA models [1]. On the other hand, the PLS models for the solutions WS and LID showed a reduced accuracy compared to the univariate models [1].

An innovative sampling interface for monitoring flowing pharmaceutical powder mixtures.

A chute was designed following the principles of the Theory of Sampling to minimize the variations in powder flow and provide all particles in the flowing blends with the same opportunity of being selected as a sample. The design also reduces the thickness of the chute to allow the analysis of a higher portion of the flowing blends by a near infrared spectrometer. The blends that flowed through the chute had Carr's index values that fluctuated between 23 and 25 percent, indicating passable flowability. A powder fowling evaluation demonstrated that there was no powder accumulation at the inspection window of the chute. The mass flow rate profiles indicated that the system achieves mass steady-state in approximately 30 s and a throughput of 30 kg/h which makes it suitable for continuous manufacturing operations. An in-line NIR calibration model was developed to quantify caffeine concentrations between 1.51 and 4.52 % w/w. The spectra obtained from each experiment had minimal baseline variation. The developed NIR method was robust to throughput changes up to approximately ±7 %. The test blends in the caffeine concentration range between 2.02 % w/w and 4.02 % w/w met the dose uniformity requirements of the Ph.Eur. 9.0, chapter 2.9.47. Variographic analysis was done to estimate the analytical and sampling errors which yielded values below 0.01 (%w/w)2. The obtained results showed that this chute could also be used in a continuous manufacturing line or other applications with flowing powders.

In-line monitoring of low drug concentration of flowing powders in a new sampler device.

A novel sampler device for flowing powders was tested to quantify drug concentrations as low as 0.76% w/w in pharmaceutical powder blends. The sampler device was developed based on the powder flow behavior within a tablet press feed frame, following the principles laid down in the Theory of Sampling. Two Near-Infrared (NIR) spectroscopic calibration models were developed with powder blends that varied from 0.52 to 2.52% w/w and 1.51-4.52% w/w. The calibration models were able to determine caffeine concentration in test set blends with root mean square error of predictions and bias below 0.1% w/w. Samples were collected from the sampler device and analyzed by ultraviolet-visible (UV-Vis) to determine the caffeine concentration. A high agreement between the in-line NIR predictions and the sampled UV-Vis results was found. The paddle wheel speed in the sampler can be varied up to ±10% without affecting NIR predictions; however, the models did not respond adequately to a 25% increase in this speed. Variographic analysis showed that the sampler device may quantify low drug concentrations with nugget effects below 0.0050 (%w/w)2. This study demonstrate that the sampler device may handle throughputs up to 45 kg/h, without significantly affecting the physical properties of powder blends.

A sampling system for flowing powders based on the theory of sampling.

An innovative chute and stream sampler system for flowing powders has been developed and tested. The system is designed for representative sampling based on the principles of the Theory of Sampling (TOS). The sampling system was used in combination with near infrared (NIR) spectroscopy to determine the drug concentration of flowing powders. The system is comprised of three parts: a chute, a stream sampler and a sample collection port. The NIR spectra were obtained at the chute, before entering the sampler, and as the powder flowed through the stream sampler. Samples were also collected from the sample collection port to be analyzed using an ultraviolet-visible (UV-Vis) reference method to determine drug content. A total of eight pharmaceutical powder blends, ranging in concentration from 10.5(%w/w) to 19.5(%w/w) of caffeine, were used to test the sampling system. Materials were characterized before blends were made to provide information on flow properties. The throughput of the system was between 30 and 35 kg/h based on the flow properties of the blend. Drug concentration was effectively determined at the chute and stream sampler. The NIR calibration models showed low root mean squared errors of prediction, 0.65(%w/w) and 0.51(%w/w), for the chute and stream sampler respectively. The NIR calibration models also showed low bias values -0.36(%w/w) at the chute and 0.057(%w/w) at the stream sampler. Significant agreement was obtained between the results from the nondestructive NIR versus the destructive UV-Vis method. Variographic analysis was performed to estimate the analytical and sampling errors when determining the drug concentration at the chute and stream sampler respectively. The variographic analysis showed low analytical errors, 0.103(%w/w)2 and 0.181(%w/w)2 at the chute and stream sampler respectively. The analysis also showed that the minimum practical error (MPE) was around 0.2(%w/w)2 at both chute and stream sampler.

Method transfer of a near-infrared spectroscopic method for blend uniformity in a poorly flowing and hygroscopic blend.

The challenges in transferring and executing a near-infrared (NIR) spectroscopic method for croscarmellose (disintegrant) in binary blends for a continuous manufacturing (CM) process are presented. This work demonstrates the development of a NIR calibration model and its use to determine the blending parameters needed for binary blends at a development plant and later used to predict CM process blends. The calibration models were developed with laboratory scale powder blends ranging from 4.32%-64.77 (%w/w) of croscarmellose and evaluated using independent test blends. The selected model was then transferred to the continuous manufacturing development site to determine the croscarmellose concentration for spectra collected in real-time. A total of 18 development plant runs were monitored using an in-line NIR spectrometer, however, these spectra showed high baseline variations. The baseline variations were caused by the poor flow of the material within the system. An inconsistent bias which varied from 2.51 to 14.95 (%w/w) was observed in the predictions of croscarmellose. High baseline spectra were eliminated and the bias was significantly reduced by 42-51%. Experiments at lower flow rate speeds did not show significant changes in baseline and bias values showed more consistency. The calibration model was then transferred to two NIR spectrometers installed at-line at the commercial site, where powder samples were collected at the beginning middle and end of each CM plant run. The NIR calibration model predicted disintegrant concentration from the powder samples. Results showed the bias values for the NIR (1) varied from 0.74 to 2.21 (%w/w) and NIR (2) from 0.28 to 3.39 (%w/w). Average concentration values for both equipments were very close to the reference concentration values of 43.18 and 50.98 (%w/w). The study showed the model was able to identify flow issues, identified as baseline shifts, that could be used to alert to problems in the powder bed that may warrant diversion from a production line. These powder flow problems such as air gaps and inconsistent powder bed height affected the NIR spectra collected at the development plant and provided results with high bias. A lower bias was obtained in samples collected at line after blending.