Development of iterative optimization technology: Selecting pure component spectra using a small-scale feed frame simulator.

The application of spectroscopic process analytical technology (PAT) for in-line data collection offers advantages to modern pharmaceutical manufacturing. Partial least squares (PLS) models are the preferred approach for predicting API potency from PAT data, particularly near-infrared (NIR) spectra. However, the calibration burden of PLS models is sometimes considered prohibitive.

Adaptive modeling optimized by the data fusion strategy: Real-time dying cell percentage prediction using capacitance spectroscopy.

The previous research showcased a partial least squares (PLS) regression model accurately predicting cell death percentages using in-line capacitance spectra. The current study advances the model accuracy through adaptive modeling employing a data fusion approach. This strategy enhances prediction performance by incorporating variables from the Cole-Cole model, conductivity and its derivatives over time, and Mahalanobis distance into the predictor matrix (X-matrix).

Continuous manufacturing of pharmaceutical products: A density-insensitive near infrared method for the in-line monitoring of continuous powder streams.

Near infrared (NIR) spectroscopy is a valuable analytical technique for monitoring chemical composition of powder blends in continuous pharmaceutical processes. However, the variation in density captured by NIR during spectral collection of dynamic powder streams at different flow rates often reduces the performance and robustness of NIR models. To overcome this challenge, quantitative NIR measurements are commonly collected across all potential manufacturing conditions, including multiple flow rates to account for the physical variations.

Influence of powder stream density on near infrared measurements upon scale-up of a simulated continuous process.

Near-infrared (NIR) spectroscopy is a powerful process analytical tool for monitoring chemical constituents in continuous pharmaceutical processes. However, the density variation introduced when quantitative NIR measurements are performed on powder streams at different flow rates is a potential source of a lack of model robustness. Since different flow rates are often required to meet the production requirements (e.

Application of a wavelength angle mapper for variable selection in iterative optimization technology predictions of drug content in pharmaceutical powder mixtures.

Process analytical technology (PAT) is an essential tool within pharmaceutical manufacturing to ensure consistent quality and maintain process control. Near-infrared (NIR) spectroscopy is one of the most popular PAT techniques, particularly for monitoring active pharmaceutical ingredient (API) concentrations. To interpret the spectral outputs of NIR spectroscopy, advanced multivariate models are required.

Capacitance spectroscopy enables real-time monitoring of early cell death in mammalian cell culture.

Background/aims: Previous work developed a quantitative model using capacitance spectroscopy in an at-line setup to predict the dying cell percentage measured from a flow cytometer. This work aimed to transfer the at-line model to monitor lab-scale bioreactors in real-time, waiving the need for frequent sampling and enabling precise controls.

Methods And Results: Due to the difference between the at-line and in-line capacitance probes, direct application of the at-line model resulted in poor accuracy and high prediction bias.

NIR Spectroscopy as an Online PAT Tool for a Narrow Therapeutic Index Drug: Toward a Platform Approach Across Lab and Pilot Scales for Development of a Powder Blending Monitoring Method and Endpoint Determination.

An online near-infrared (NIR) spectroscopy platform system for real-time powder blending monitoring and blend endpoint determination was tested for a phenytoin sodium formulation. The study utilized robust experimental design and multiple sensors to investigate multivariate data acquisition, model development, and model scale-up from lab to manufacturing. The impact of the selection of various blend endpoint algorithms on predicted blend endpoint (i.

Comparison Between Pure Component Modeling Approaches for Monitoring Pharmaceutical Powder Blends with Near-Infrared Spectroscopy in Continuous Manufacturing Schemes.

Near-infrared (NIR) spectroscopy has become an important process analytical technology (PAT) for monitoring and implementing control in continuous manufacturing (CM) schemes. However, NIR requires complex multivariate models to properly extract the relevant information and the traditional model of choice, partial least squares, can be unfavorable on account of its high material and time investments for generating calibrations. To account for this, pure component-based approaches have been gaining attention due to their higher flexibility and ease of development.

Challenges, opportunities and recent advances in near infrared spectroscopy applications for monitoring blend uniformity in the continuous manufacturing of solid oral dosage forms.

Near infrared (NIR) spectroscopy has been widely recognized as a powerful PAT tool for monitoring blend uniformity in continuous manufacturing (CM) processes. However, the dynamic nature of the powder stream and the fast rate at which it moves, compared to batch processes, introduces challenges to NIR quantitative methods for monitoring blend uniformity. For instance, defining the effective sample size interrogated by NIR, selecting the best sampling location for blend monitoring, and ensuring NIR model robustness against influential sources of variability are challenges commonly reported for NIR applications in CM.

Development of calibration-free/minimal calibration wavelength selection for iterative optimization technology algorithms toward process analytical technology application.

As continuous manufacturing (CM) processes are developed, process analytical technology (PAT) via NIR spectroscopy has become an integral tool in process monitoring. NIR spectroscopy requires the deployment of complex multivariate models to extract the relevant information. The model of choice for the pharmaceutical industry is Partial Least Squares (PLS).

NIR spectroscopic methods for monitoring blend potency in a feed frame - calibration transfer between offline and inline using a continuum regression filter.

A material sparing method for near-infrared (NIR) calibration was developed using an offline apparatus coupled with a calibration transfer method to enable a partial least squares (PLS) model to monitor the concentration of active pharmaceutical ingredients (API) in the feed frame of a rotary tablet press. The offline apparatus was designed to simulate the powder flow dynamic and NIRS measurement environment of a tablet-press feed frame. A comprehensive experimental design, including calibration and testing, was employed to determine blend inhomogeneity.

Rapid at-line early cell death quantification using capacitance spectroscopy.

Cell death is one of the failure modes of mammalian cell culture. Apoptosis is a regulated cell death process mainly observed in cell culture. Timely detection of apoptosis onset allows opportunities for preventive controls that ensure high productivity and consistent product quality.

Metabolic trends of Chinese hamster ovary cells in biopharmaceutical production under batch and fed-batch conditions.

Extensive knowledge of Chinese hamster ovary (CHO) cell metabolism is required to improve process productivity and culture performance in biopharmaceutical manufacturing. However, CHO cells show a dynamic metabolism during culturing in batch and fed-batch bioreactors. CHO cell metabolism is generally described as taking place in three stages: exponential growth phase, stationary phase, and death phase.

Quality by Design Methodology Applied to Process Optimization and Scale up of Curcumin Nanoemulsions Produced by Catastrophic Phase Inversion.

In the presented study, we report development of a stable, scalable, and high-quality curcumin-loaded oil/water (o/w) nanoemulsion manufactured by concentration-mediated catastrophic phase inversion as a low energy nanoemulsification strategy. A design of experiments (DoE) was constructed to determine the effects of process parameters on the mechanical input required to facilitate the transition from the gel phase to the final o/w nanoemulsion and the long-term effects of the process parameters on product quality. A multiple linear regression (MLR) model was constructed to predict nanoemulsion diameter as a function of nanoemulsion processing parameters.

Rapid serum-free/suspension adaptation: Medium development using a definitive screening design for Chinese hamster ovary cells.

The biopharmaceutical industry prefers to culture the mammalian cells in suspension with a serum-free media (SFM) due to improved productivity and process consistency. However, mammalian cells preferentially grow as adherent cells in a complete medium (CM) containing serum. Therefore, cells require adaptation from adherence in CM to suspension culture in SFM.

Terahertz Time of Flight Spectroscopy as a Coating Thickness Reference Method for Partial Least Squares Near Infrared Spectroscopy Models.

Near infrared spectroscopy (NIRS) is often used during the tablet coating process to assess coating thickness. As the coating process proceeds, the increase and decrease in NIRS signal from both the coating formulation and tablet core has been related to coating thickness. Partial least-squares models are often generated relating NIRS spectra to reference coating thickness measurements for in-line and/or at-line monitoring of the coating process.

Determining the effect of photodegradation on film coated nifedipine tablets with terahertz based coating thickness measurements.

Film coating of nifedipine tablets is commonly performed to reduce photo-degradation. The coating thickness of these tablets is a primary dictating factor of photo-stability. Terahertz spectroscopy enables accurate measurement of coating thickness.

Refractive Index Measurement of Pharmaceutical Solids: A Review of Measurement Methods and Pharmaceutical Applications.

Refractive index is an important optical parameter that can be used to characterize the physicochemical properties of pharmaceutical solids. The complexity of most drugs and solid oral dosage systems introduces challenges for refractive index measurement methods. These challenges are highlighted, and different types of measurement methods are discussed in this review article.

Quality by Design Approach Using Multiple Linear and Logistic Regression Modeling Enables Microemulsion Scale Up.

The development of pharmaceutical nanoformulations has accelerated over the past decade. However, the nano-sized drug carriers continue to meet substantial regulatory and clinical translation challenges. In order to address some of these key challenges in early development, we adopted a quality by design approach to develop robust predictive mathematical models for microemulsion formulation, manufacturing, and scale-up.

Development of an In-Line Near-Infrared Method for Blend Content Uniformity Assessment in a Tablet Feed Frame.

Process analytical technology (PAT) has shown great potential for in-line tableting process monitoring. The study focuses on the development and validation of an in-line near-infrared (NIR) spectroscopic method for the determination of content uniformity of blends in a tablet feed frame. An in-line NIR method was developed after careful evaluation of the impact of potential experimental factors on the robustness and model accuracy and precision.

Feedforward and Feedback Control of a Pharmaceutical Coating Process.

This work demonstrates the use of a combination of feedforward and feedback loops to control the controlled release coating of theophylline granules. Feedforward models are based on the size distribution of incoming granules and are used to set values for the airflow in the fluid bed processor and the target coat weight to be applied to the granules. The target coat weight of the granules is controlled by a feedback loop using NIR spectroscopy to monitor the progress of the process.

Prediction of Dissolution Profiles From Process Parameters, Formulation, and Spectroscopic Measurements.

This study utilized multiple modeling approaches to predict immediate release tablet dissolution profiles of 2 model drugs: theophylline and carbamazepine. Two sets of designs of experiments were applied based on individual drug characteristics to build in adequate dissolution variability. The tablets were scanned using a near-infrared (NIR) spectrometer and then subjected to in vitro dissolution test at critical time points.

Influence of moisture variation on the performance of Raman spectroscopy in quantitative pharmaceutical analyses.

To develop a robust quantitative calibration model for spectroscopy, different sources of variability that are not directly related to the components of interest should be included in the calibration samples; this variability should be similar to that which is anticipated during validation and routine operation. Moisture content of pharmaceutical samples can vary as a function of supplier, storage conditions, geographic origin or seasonal variation. Additionally, some pharmaceutical operations (e.

A "Large-N" Content Uniformity Process Analytical Technology (PAT) Method for Phenytoin Sodium Tablets.

Accurate assessment of tablet content uniformity is critical for narrow therapeutic index drugs such as phenytoin sodium. This work presents a near-infrared (NIR)-based analytical method for rapid prediction of content uniformity based on a large number of phenytoin sodium formulation tablets. Calibration tablets were generated through an integrated experimental design by varying formulation and process parameters, and scale of manufacturing.

Method Development and Validation of an Inline Process Analytical Technology Method for Blend Monitoring in the Tablet Feed Frame Using Raman Spectroscopy.

Inline process analytical technology sensors are the key elements to enable continuous manufacturing. They facilitate real-time monitoring of critical quality attributes of both intermediate materials and finished products. The aim of this study was to demonstrate method development and validation for inline and offline calibration strategies to determine the blend content during tablet compression via Raman spectroscopy.