Pharmaceutical manufacturing is a complex process often utilizing complex scientific and engineering principles. The new FDA initiative considers process analytical technology (PAT) to be a system for designing, analyzing, and controlling manufacturing through timely measurements (i.e., during processing) of critical quality and performance attributes of raw and in-process materials and processes, with the goal of ensuring final product quality. The key to the success of PAT is applying the process monitoring tools needed to carry out on-line analysis of each of the critical product attributes.
Process analysis has advanced significantly during the past several decades, due to an increasing appreciation for the value of collecting process data. Available tools have evolved from those that predominantly take univariate process measurements, such as pH, temperature, and pressure, to those that measure different biological, chemical, and physical attributes. Currently, process monitoring is rapidly moving towards non-destructive methods such as new spectroscopic methods. These measurements may be taken off-line, at-line or on-line, before, during or after the steps of the manufacturing process.
Most spectroscopic techniques utilize electromagnetic waves propagating through materials such as optical spectroscopy and its related derivations, such as FTIR, NIR and fluorescence methods. These methods play an essential role in the analysis of chemical attributes of the material (e.g., identity and purity) and in defining parametric end-points for utilized chemical processes. However, despite these obvious advantages the applications of traditional ‘electromagnetic’ spectroscopy methods are limited, in particular for process analysis in opaque samples and concentrated dispersions as well as samples without required optical activity (absorption spectrum). Therefore, certain physical and mechanical attributes of pharmaceutical ingredients that are critical to product quality are not easily achievable with standard spectroscopy methods. Consequently, the inherent, undetected variability of raw materials may be manifested in the final product. Such attributes (e.g. particle size, concentration and their variations within a sample) of raw and in-process materials may pose a significant challenge because of their complexities and difficulties related to collecting representative samples. For example, it is well known that powder sampling procedures can be erroneous.
Several new technologies are now available that can acquire information on multiple attributes non-destructively with minimal or no sample preparation. High-Resolution Ultrasonic Spectroscopy (HR-US) is a novel technique with enormous potential for analysis of a wide range of samples and processes in PAT. This technique is based on precision measurements of the parameters of acoustical waves propagating through materials. It allows fast at-/on-line analysis of formulation consistency of raw materials, ingredients and intermediates, process impurity analysis, particle sizing, batch-to-batch variation, stability assessment, etc. Unlike traditional analytical spectroscopy, optical transparency is not required as ultrasonic waves propagate through most types of samples. Moreover, in opaque samples it allows analysis of the interior (bulk properties) of the samples in contrary to many optical techniques, which collect the signal reflected at the surface.
HR-US generates product quality information in real process time and for a wide range of samples and dynamic processes. It is possible to monitor the manufacturing stages continuously and make adjustments to ensure that the finished product will meet the desired quality and specification.
This abridged article briefly describes some key features of the HR-US technique, which are beneficial for PAT installation, as well as specific advantages of the method in comparison to more traditional spectroscopy methods. Details for the full version are at the end of this article.
HR-US is a non-destructive analytical tool based on precision measurements of the velocity and attenuation of acoustical waves at high frequencies propagating through materials. It allows the analysis of composition, aggregation, gelation, micelle formation, crystallization, dissolution, sedimentation, enzyme activity, conformational transitions in polymers, ligand binding, antigen-antibody interactions, and many other processes that play a key role in drug production. Capable of dealing with a wide range of samples and dynamic processes, HR-US provides real time product quality information.
Two independent parameters, ultrasonic attenuation and ultrasonic velocity are measured in HR-US. Ultrasonic attenuation is determined by the energy losses in ultrasonic waves and can be expressed in terms of the high-frequency viscosity of the medium or its longitudinal loss modulus. This allows analysis of kinetics of fast chemical reactions and microstructure of materials including particle sizing, aggregation, gelation, crystallization and other processes and characteristics. Ultrasonic velocity is determined by the density and the elastic response of the sample to the oscillating pressure in the ultrasonic wave and thus can be expressed in terms of compressibility or storage modulus. This parameter is extremely sensitive to the molecular organization, composition and intermolecular interactions in the analyzed medium and is responsible for the major portion of applications of HR-US for analysis of chemical properties of materials.
HR-US ultrasonic spectrometers with their outstanding resolution, down to 0.00001% (thus providing the measurements in samples at concentration level down to 0.3 ppm) are the first commercial instruments that allow the user to enjoy the full potential of ultrasonic analysis.
A variety of ultrasonic detection cells are available for different types of the analysis: standard sample cells of 1ml in capacity, flow-through cells that allow the carrying out of the analysis in-flow, cells with automatic sampling, cells with small volume capacities (as low as 0.03ml) and cells that allow semi-solid samples to be analyzed.
Measurements are computer controlled and the data can be transformed into the concentration of the components during the processes, rate of the reaction, change in molecular weight, particle size and their volume fraction. The analysis can be made in various environment conditions: at temperatures between -60 to 120°C, and under pressure up to 15 bars. This dynamic flexibility of the analysis is critical for on-line process monitoring in drug production.
Some advantages of the HR-US technique in comparison with standard spectroscopy methods include:
Analysis of the sedimentation and aggregation in the suspensions of drug prepared using different polymer coatings
Control particle size in dispersed phase is a critical issue in stability of pharmaceutical formulations. Particle characteristics can affect many different areas including inhalation delivery systems, tablet dissolution characteristics, formulation quality and solubility or absorption. Batch to batch variation in particle size can lead to unpredictable variations in the life span and shelf life and heat stability of a product. Traditionally, the characterization of the particles in dispersion is made by optical methods such as light scattering. This means that the sample must be collected from the production line and diluted to reach optical transparency and avoid multiple scattering effects. On the other hand, the application of new HR-US ultrasonic measurements allows direct analysis of the particle size and their volume fraction in the dispersions even concentrated samples (e.g. 40%), thus avoiding the problems associated with dilution (which often affects the particle size and the aggregation rate).
In the current example, HR-US technique was used for real-time analysis of the effect of different polymer coatings on the sedimentation rate and the evolution of the particle size in 20% drug suspension. The samples of drug suspensions were prepared using hydroxypropyl cellulose as the drug carrier system. The drug particles in one sample were coated with polymer, which had higher molecular weight (approximately twice) in comparison with the polymer used in the preparation of another sample. Fresh samples were collected using the HR-US Colloid Stability Analyzer, and sedimentation and aggregation processes were monitored continuously.
Sedimentation is reflected in ultrasonic measurements as a change in velocity and attenuation with time. Aggregation (change in the particle size) also affects the attenuation. HR-US software allows deconvolution of these changes and provides real time change in the particle size and the volume fraction.
Initial particle size in the first sample is 0.8 m, which is 25% larger than the size in the second sample. However, the particle size in sample two increases faster with time due to the aggregation. The growth of particles is accompanied by a decrease in volume fraction that can be attributed to the sedimentation by about 0.7% of original volume concentration in sample one and 1.4% of original volume concentration in the sample two within 20 minutes. Both processes (sedimentation and aggregation) are more evident in sample two, thus indicating lower stability of this sample compared with sample one. One of the possible factors responsible for higher stability of suspension one can be a “thicker” polymer layer on drug particles in the sample, which protects the particles against aggregation.
Effect of dilution on the evolution of drug particles size was analyzed by the measurements of the sedimentation profile in diluted suspensions. Two tendencies, an increase in the particles size with time and decrease in the particle fraction (sedimentation) observed in diluted suspensions are similar to those found in undiluted samples, however the intensity of these processes is different. In the case of the suspension two, the aggregation and sedimentation decrease significantly with the sample dilution. The relative loss of volume fraction within 20 min in diluted suspension two is 0.7% of the original volume concentration in comparison with 1.4% in undiluted suspension. Particle size in the diluted sample two increases by 1.3 times within 20 min, which is significantly smaller that in the undiluted sample, 1.7. The effect of the dilution on the aggregation and sedimentation rates is less evident for the sample one. This observation is in the agreement with higher stability of suspension one discussed above.
HR-US provides a powerful tool for the development of new products and optimization of existing products as well as for quality control and process control in PAT installation. It provides real time information on chemical and microstructural characteristics across a broad range of materials. The arrival of a new generation of ultrasonic spectrometers, HR-US analyzers, will have a profound impact on the efficiency and profitability of pharmaceutical processes.