Development Of Process Analytical Technologies Research Articles

A Nondestructive and Rapid Method for the Determination of Triamterene Content by Transmission Raman Spectroscopy Combined with Chemometrics

Background: Triamterene is a potassium-conserving diuretic mainly used in the treatment of edematous diseases. Although there are some methods to measure the content of triamterene, the existing methods have the characteristics of sample destructiveness and low flux, making it difficult to meet the needs of online monitoring. In recent years, transmission Raman spectroscopy (TRS), as a new technology for the determination of drug content, has emerged as being nondestructive and rapid and provides a new method for the determination of triamterene content. Objective: In this study, we used transmission Raman spectroscopy combined with partial least squares (PLS) approaches to establish a six concentration levels model for measuring the content of triamterene. The model was applied to determine whether tablets are commercially available. Method: Firstly, TRS was used to collect the spectra of the principal components and mixed excipients of triamterene, and the feasibility test was carried out. Secondly, six concentration levels were determined by the design of experimental (DOE), and hand-made tablets were prepared to obtain corresponding spectra. The content prediction model was established by the PLS method, and the content of triamterene was determined by high-performance liquid chromatography (HPLC) to correct the model. Finally, the model was applied to the determination of triamterene in commercially available tablets. Results: The results showed that the established model was successfully applied to the determination of triamterene. The values of RMSEC (0.0089783) and RMSECV (0.0097241) of the final model were very low and close to each other. The relative error of 12 hand-made tablets predicted by this model was less than 5% compared with the results determined by HPLC. In addition, in the process of applying the model to the determination of the content of commercially available tablets, the accuracy of the model can be significantly improved by adding the spectrum of commercially available tablets. The corrected model was used to determine the content of triamterene in two commercially available tablets. The results showed that the relative error was less than 5%. Conclusion: We described a new strategy to analyze the content of active pharmaceutical ingredients (API) in triamterene tablets by TRS with PLS. The established model has the advantage of non-destructive and rapid quantitation, which can provide a new method for real-time monitoring of production lines and promote the development of process analytical technology (PAT).

Halfway to Automated Feeding of Chinese Hamster Ovary Cells.

This paper presents a comprehensive study on the development of models and soft sensors required for the implementation of the automated bioreactor feeding of Chinese hamster ovary (CHO) cells using Raman spectroscopy and chemometric methods. This study integrates various methods, such as partial least squares regression and variable importance in projection and competitive adaptive reweighted sampling, and highlights their effectiveness in overcoming challenges such as high dimensionality, multicollinearity and outlier detection in Raman spectra. This paper emphasizes the importance of data preprocessing and the relationship between independent and dependent variables in model construction. It also describes the development of a simulation environment whose core is a model of CHO cell kinetics. The latter allows the development of advanced control algorithms for nutrient dosing and the observation of the effects of different parameters on the growth and productivity of CHO cells. All developed models were validated and demonstrated to have a high robustness and predictive accuracy, which were reflected in a 40% reduction in the root mean square error compared to established methods. The results of this study provide valuable insights into the practical application of these methods in the field of monitoring and automated cell feeding and make an important contribution to the further development of process analytical technology in the bioprocess industry.

Real-time in situ monitoring of CRM-197 and polysaccharide conjugation reaction by fluorescence spectroscopy.

Aims: Process analytical technology (PAT) is increasingly being adopted within the pharmaceutical industry to build quality into a process. Development of PAT that provides real-time in situ analysis of critical quality attributes are highly desirable for rapid, improved process development. Conjugation of CRM-197 with pneumococcal polysaccharides to produce a desired pneumococcal conjugate vaccine is a significantly intricate process that can tremendously benefit from real-time process monitoring. Methods: In this work, a fluorescence-based PAT methodology is described to elucidate CRM-197-polysacharide conjugation kinetics in real time. Results & conclusion: In this work, a fluorescence-based PAT methodology is described to elucidate CRM-197-polysacharide conjugation kinetics in real time.

Dynamic monitoring of glycine crystallisation with low power ultrasound reflection spectroscopy

Crystallisation processes are ubiquitous in the food and pharmaceutical industries and the development of process analytical technologies (PAT) for on-line, in situ monitoring is essential to ensure process efficiency and to optimise product quality. Current PAT, many of which are based on electromagnetic waves, have a range of limitations including an inability to accurately measure opaque solutions. Low power (<10Wm−2) pulsed acoustic techniques, such as ultrasound reflectance and velocimetry, have the benefit of being non-material altering, affordable, non-invasive and can study opaque systems without any dilution. Here, we present an improved in-situ ultrasound technique which is corroborated with optical turbidity in the measurement of the MSZW of glycine in water with good agreement. A Mann–Whitney U test was conducted, and no significant difference was found in the measurement of the MSZW between the two techniques. Density data were used with velocity measurements from the improved technique to calculate adiabatic compressibility of glycine solutions, which is an important and useful physical property when studying phase transitions. A frequency space analysis has been performed on the acoustic time domain measurements, and the data suggest the presence of scattering bodies in the metastable zone.

Development of process analytical technology to monitor the cell secretome during differentiation of pluripotent stem cells

Background & Aim Induced pluripotent stem cells (iPSC) offers a renewable source for reliably and robustly generating off-the-shelf cell products for regenerative medicine. A number of differentiation protocols have been developed and PSC-derived cells have been used in a variety of animal models to treat disease and progressed through to clinical trials in Asia and more recently the United States. However, the manufacturing processes for expansion and differentiation of iPSC cells remain reliant on poorly scalable technologies with limited in process monitoring despite typically > 14 days of culture and manipulation required; increasing the risks and costs of batch manufacturing failure. The industrialisation of pluripotent stem cell-derived cell therapies requires the development of process analytical technologies (PAT) for the monitoring and control of large-scale cell differentiation bioprocesses. The extracellular microenvironment provides fertile hunting ground to determine the impact of processing conditions on process outcome with the myriad of molecules consumed and produced by cells during differentiation alluding to cell state and potential cell fate. PAT that targets the spent media enables control of critical processing parameters to maintain product critical quality attributes without requiring cell-based analysis to be conducted. Methods, Results & Conclusion Using two exemplar differentiation processes, going from induced pluripotent stem cells to, either, definitive endoderm or cardiomyocytes, we have characterised the cell secretome with respect to metabolites and secreted proteins, and performed multi-parametric analysis to determine potential biomarkers for monitoring future large-scale differentiation processes using cost- and time-effective PAT alternatives.

Methods to Assess Mixing of Pharmaceutical Powders.

The pharmaceutical manufacturing process consists of several steps, each of which must be monitored and controlled to ensure quality standards are met. The level of blending has an impact on the final product quality; therefore, it is important to be able to monitor blending progress and identify an end-point. Currently, the pharmaceutical industry assesses blend content and uniformity through the extraction of samples using thief probes followed by analytical methods, such as spectroscopy, to determine the sample composition. The development of process analytical technologies (PAT) can improve product monitoring with the aim of increasing efficiency, product quality and consistency, and creating a better understanding of the manufacturing process. Ideally, these are inline methods to remove issues related to extractive sampling and allow direct monitoring of the system using various sensors. Many technologies have been investigated, including spectroscopic techniques such as near-infrared spectroscopy, velocimetric techniques that may use tracers, tomographic techniques, and acoustic emissions monitoring. While some techniques have demonstrated potential, many have significant disadvantages including the need for equipment modification, specific requirements of the material, expensive equipment, extensive analysis, the location of the probes may be critical and/or invasive, and lastly, the technique may only be applicable to the development phase. Both the advantages and disadvantages of the technologies should be considered in application to a specific system.

On-line attenuated total reflection infrared (ATR-IR) spectroscopy combined with advanced chemometrics for investigating the synthesis process of 3,5-diamino-1,2,4-triazole

The synthesis process of 3,5-diamino-1,2,4-triazole (DAT) was investigated by on-line attenuated total reflection infrared (ATR-IR) spectroscopy combined with advanced chemometrics method. The principal component analysis (PCA) was used to analyze the IR spectra matrix, which was in order to obtain orthonormal column and the number of principal components. Then the pure IR spectrum of every substance was obtained by mutual information least dependent component analysis (MILCA). The possible synthesis mechanism of DAT was deducted based on the changes of functional groups in the IR spectra. The geometric configurations of intermediates were optimized with the density functional theory (DFT) at B3LYP/6-311G*(d, p) level, and the vibrational frequencies were calculated simultaneously. The results by MILCA method agree well with quantum chemical calculation method, thus which demonstrated the reliability of MILCA. The present study proves that on-line ATR-IR spectroscopy combined with advanced chemometrics method can be applied to study the chemical synthesis mechanism and provide a strong technical support for the research and development of process analytical technology (PAT).

Monitoring lubricant addition using passive acoustic emissions in a V-blender

The development of process analytical technologies (PAT) can improve the efficiency and product quality during pharmaceutical manufacturing. The objective of the current research was to investigate the potential application of passive acoustic emission monitoring to detect changes due to lubricant addition and its dispersal in a V-blender. Trials were conducted with sugar spheres and two placebo formulations of pharmaceutical granules in a V-blender. Vibrations from acoustic emissions were measured using PCB Piezotronics accelerometers with ICP signal conditioners. A wavelet filter was applied to the measured acoustic emissions to remove vibrations from the tumbling motion of the V-shell, allowing a focus on information about particle motion and interactions within the V-shell. Three signal features were identified in the acoustic emissions with each feature being attributed to phases of the particle motion within the V-shell. The maximum feature amplitude was found to vary with lubricant dispersal; both particle flowability and the coefficient of restitution had an impact on the acoustic emissions amplitude. Particle flowability changes were correlated to how the lubricant interacted with the solid's surface which was observed from scanning electron micrographs. The measured vibrations from passive acoustic emissions reflected changes in particle motion and interactions within a V-blender as the lubricant dispersed demonstrating the potential of passive acoustic emissions measurements to monitor blending processes inline and in real time.

Monitoring method for macroporous resin column chromatography process of salvianolic acids based on near infrared spectroscopy

To study and establish a monitoring method for macroporous resin column chromatography process of salvianolic acids by using near infrared spectroscopy (NIR) as a process analytical technology (PAT).The multivariate statistical process control (MSPC) model was developed based on 7 normal operation batches, and 2 test batches (including one normal operation batch and one abnormal operation batch) were used to verify the monitoring performance of this model. The results showed that MSPC model had a good monitoring ability for the column chromatography process. Meanwhile, NIR quantitative calibration model was established for three key quality indexes (rosmarinic acid, lithospermic acid and salvianolic acid B) by using partial least squares (PLS) algorithm. The verification results demonstrated that this model had satisfactory prediction performance. The combined application of the above two models could effectively achieve real-time monitoring for macroporous resin column chromatography process of salvianolic acids, and can be used to conduct on-line analysis of key quality indexes. This established process monitoring method could provide reference for the development of process analytical technology for traditional Chinese medicines manufacturing.

The effect of granule moisture on passive acoustic emissions in a V-blender

The development of process analytical technologies (PAT) can improve the efficiency and product quality during pharmaceutical manufacturing. The objective of the current research was to investigate the potential application of passive acoustic emission monitoring to detect changes in solids moisture content as the solids tumble in a V-blender. Trials were conducted with wooden beads, sugar spheres and two placebo formulations of pharmaceutical granules in a V-blender. Vibrations from acoustic emissions were measured using PCB Piezotronics accelerometers with ICP signal conditioners. A wavelet filter was applied to the measured acoustic emissions to remove vibrations from the tumbling motion of the V-shell, allowing a focus on information about particle motion and interactions within the V-shell. Three signal features were identified in the acoustic emissions with each feature being attributed to phases of the particle motion within the V-shell. The maximum feature amplitude was found to vary with solids moisture content; both particle mass and flowability had an impact on the acoustic emissions amplitude. Particle flowability changes were correlated to a critical moisture content obtained from solids drying profiles. The measured vibrations from passive acoustic emissions reflected changes in particle motion and interactions within a V-blender as the solids moisture content varied demonstrating the potential of passive acoustic emissions measurements to obtain critical process information inline and in real time.

Passive acoustic emissions from particulates in a V-blender

Context: Regulatory agencies are recommending the development of process analytical technologies (PAT) to improve the efficiency and product quality during pharmaceutical manufacturing.Objective: The objective of the research was to investigate the potential application of passive acoustic emission monitoring of a V-blender.Materials and methods: Trials were conducted with sugar spheres, lactose or MCC in a V-blender. Vibrations from acoustic emissions were measured using PCB Piezotronics accelerometers with ICP signal conditioners.Results and discussion: A wavelet filter was applied to the measured acoustic emissions to remove vibrations from the tumbling motion of the V-shell, allowing a focus on information about particle motion and interactions within the V-shell. The ideal sensor location was determined to be the lid of one of the V-shell arms due to the impact of the tumbling particles on the lid and transmission of the vibrations from other particle motion within the V-shell. The amplitude of vibrations increased with particle size due to larger particle momentum before a collision. The fill level and the V-shell scale also influenced the measured vibrations as particle motion was affected which in turn affected momentum. Changes in particle flowability could be detected through variations in the measured acoustic emissions.Conclusion: The measured vibrations from passive acoustic emissions reflected particle motion and interactions within a V-blender demonstrating potential as a monitoring method.

Development of Process Analytical Technology (PAT) methods for controlled release pellet coating

This work focused on the control of the manufacturing process for a controlled release (CR) pellet product, within a Quality by Design (QbD) framework. The manufacturing process was Wurster coating: firstly layering active pharmaceutical ingredient (API) onto sugar pellet cores and secondly a controlled release (CR) coating. For each of these two steps, development of a Process Analytical Technology (PAT) method is discussed and also a novel application of automated microscopy as the reference method.Ultimately, PAT methods should link to product performance and the two key Critical Quality Attributes (CQAs) for this CR product are assay and release rate, linked to the API and CR coating steps respectively. In this work, the link between near infra-red (NIR) spectra and those attributes was explored by chemometrics over the course of the coating process in a pilot scale industrial environment. Correlations were built between the NIR spectra and coating weight (for API amount), CR coating thickness and dissolution performance. These correlations allow the coating process to be monitored at-line and so better control of the product performance in line with QbD requirements.

Real-time monitoring of adherent Vero cell density and apoptosis in bioreactor processes

This study proposes an easy to use in situ device, based on multi-frequency permittivity measurements, to monitor the growth and death of attached Vero cells cultivated on microporous microcarriers, without any cell sampling. Vero cell densities were on-line quantified up to 10(6)cellmL(-1). Some parameters which could potentially impact Vero cell morphological and physiological states were assessed through different culture operating conditions, such as media formulation or medium feed-harvest during cell growth phase. A new method of in situ cell death detection with dielectric spectroscopy was also successfully implemented. Thus, through permittivity frequency scanning, major rises of the apoptotic cell population in bioreactor cultures were detected by monitoring the characteristic frequency of the cell population, f(c), which is one of the culture dielectric parameters. Both cell density quantification and cell apoptosis detection are strategic information in cell-based production processes as they are involved in major events of the process, such as scale-up or choice of the viral infection conditions. This new application of dielectric spectroscopy to adherent cell culture processes makes it a very promising tool for risk-mitigation strategy in industrial processes. Therefore, our results contribute to the development of Process Analytical Technology in cell-based industrial processes.

The Development of PAT (Process Analytical Technology) for Drug Production and the Requirements for Domestic Pharmaceutical Engineering Education

After decades of practice and development, the GMP of drug production has entered the cGMP (Current Good Manufacturing Practice) era. In 21st century, PAT has become one of the new trends in the reform of the United States cGMP. In order to learn from foreign pharmaceutical quality control and production management experience, in this paper, the concept of PAT was introduced, the background of drug production PAT and its significance, the development trends of domestic pharmaceutical production PAT were reviewed. The domestic pharmaceutical engineering education under the new situation of PAT was discussed with emphasis. It was pointed out that to meet the requirements of the development of PAT, China's pharmaceutical engineering education needs constant adjustment and reform.

Monitoring quality attributes for high-shear wet granulation with audible acoustic emissions

Continuing development of process analytical technology (PAT) tools is needed in the pharmaceutical industry to provide more flexible processing and achieve products of consistent quality. For high-shear wet granulation, audible acoustic emissions (AAEs) have shown potential as a PAT tool for monitoring changes in physical properties related to product quality. This article develops the relationship between AAEs and two critical quality attributes, size and density, and investigates the potential for monitoring product quality online. Condenser microphones were placed inside the air exhaust of a PMA-10 high-shear granulator to collect AAEs for a design of experiment (DOE) where particle size and density were varied by changing the grade of Avicel in the formulation. The results showed increases in particle size and density affect the observed decreases in the AAEs at granulation end-point and during over wetting. In addition, the changes in size and density could be represented by different combinations of 10 Hz frequency groups and the trends in the multivariate scores support online monitoring.

New Perspectives for Visual Characterization of Pharmaceutical Solids

The utilization of descriptive image information in pharmaceutical powder technology is rather limited. Consequently, the development of this discipline is a challenge within physical characterization of pharmaceutical solids. The aim of this study was to develop and evaluate an inventive visual characterization approach for monitoring the granule growth in a fluidized‐bed granulation process and to use the generated image information in the prediction of tabletting behavior of granules. Surface images of samples from 34 granulations were continuously captured during the spraying and drying phases of the process and particle size distributions were determined. The gray scale difference matrix (GSDM) was derived from two surface images taken in controlled illumination conditions. The particle size calculation from the surface images was based on a multivariate Partial Least Square (PLS) model between the GSDM and sieve analysis measurements. The image information of the end‐point samples was also evaluated with respect to tabletting behavior of the granules produced. Principal component analysis (PCA) was used for data visualization. The introduced approach was suitable in particle size measurements of granules during all process phases and in the monitoring of different kinds of granule growth behavior. The visual inspection of the granule samples was powerful, enabling representational batch‐to‐batch comparisons. The tabletting behavior of the granules could be predicted directly from particle size information generated from the surface images. PCA as a projection method was efficient in data visualization. Development of process analytical technologies (PAT) aims at improving the efficiency of processes. The presented visual characterization approach can be an effective process analytical tool in particle size analysis also enabling the evaluation of the further product quality in the end of the granulation process. The idea of characterization of bulk surface images opens new perspectives for characterization of pharmaceutical solids. © 2004 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 93:165–176, 2004