Micro-viscoelastic Characterization of Compressed Oral Solid Dosage Forms with Ultrasonic Wave Dispersion Analysis.

Due to their constituent powders, the materials of advanced compressed oral solid dosage (OSD) forms are micro-composites and strongly visco-elastic at macro- and micro-length scales. The disintegration, drug release, and mechanical strength of OSD forms depend on its micro-texture (such as porosity) and micro-scale physical/mechanical properties. In the current work, an algorithmic ultrasonic characterization framework for extracting the micro-visco-elastic properties of OSD materials is presented, and its applicability is demonstrated with a model material. The proposed approach is based on the effect of visco-elasticity and granularity on the frequency-dependent attenuation of an ultrasonic wave pulse in a composite (granular) and viscous medium. In modeling the material, a two-parameter Zener model for visco-elasticity and a scattering attenuation mechanism based on Rayleigh scattering for long-wave approximation are employed. A novel linear technique for de-coupling the effects of micro-visco-elasticity and scattering on attenuation and dispersion is developed and demonstrated. The apparent Young's modulus, stress, and strain relaxation time constants of the medium at micro-scale are extracted and reported. Based on this modeling and analysis framework, a set of computational algorithms has been developed and demonstrated with experimental data, and its practical utility in pharmaceutical manufacturing and real-time release testing of tablets is discussed.

Machine learning modeling for ultrasonic quality attribute assessment of pharmaceutical tablets for continuous manufacturing and real-time release testing.

In in-process quality monitoring for Continuous Manufacturing (CM) and Critical Quality Attributes (CQA) assessment for Real-time Release (RTR) testing, ultrasonic characterization is a critical technology for its direct, non-invasive, rapid, and cost-effective nature. In quality evaluation with ultrasound, relating a pharmaceutical tablet's ultrasonic response to its defect state and quality parameters is essential. However, ultrasonic CQA characterization requires a robust mathematical model, which cannot be obtained with traditional first principles-based modeling approaches. Machine Learning (ML) using experimental data is emerging as a critical analytical tool for overcoming such modeling challenges. In this work, a novel Deep Neural Network-based ML-driven Non-Destructive Evaluation (ML-NDE) modeling framework is developed, and its effectiveness for extracting and predicting three CQAs, namely defect states, compression force levels, and amounts of disintegrant, is demonstrated. Using a robotic tablet handling experimental rig, each attribute's distinct waveform dataset was acquired and utilized for training, validating, and testing the respective ML models. This study details an advanced algorithmic quality assessment framework for pharmaceutical CM in which automated RTR testing is expected to be critical in developing cost-effective in-process real-time monitoring systems. The presented ML-NDE approach has demonstrated its effectiveness through evaluations with separate (unused) test datasets.

Early detection and assessment of invisible cracks in compressed oral solid dosage forms.

In the pharmaceutical manufacturing industry, real-time in situ quality monitoring for detecting defects at an early stage is a desirable ability, especially in high-rate production, to minimize downstream quality-related issues, financial losses, and timeline risks. In this study, we focus on the early detection of crack formation in compressed oral solid dosage (OSD) forms at its onset before complete delamination and/or capping in downstream processing. The detection of internal tablet cracks related to local micro-stress/strain states, internal granularity (texture), and micro-structure failures is rather unlikely by traditional testing methods, such as the USP reference standards for friability, fracturing, or hardness testing. In addition, these tests do not permit the objective and quantitative evaluation of the influence of formulation and process parameters, which are critical for the development of high-quality drug products manufactured at high rates on a large scale. Internal cracks (potentially resulting in 'capping' and/or 'lamination') under high-strain compaction of highly visco-elastic powder materials are a common failure mode. In the current study, two approaches are introduced and utilized for non-destructively detecting and evaluating hidden cracks in pharmaceutical compacts based on (i) varying axial load-displacement measurements and (ii) ultrasonic reflection ray tracing. The reflection ray tracing technique is a non-destructive, inexpensive, rapid, and material-sparing approach, which makes it advantageous for real-time quality monitoring and defect characterization applications. The varying axial load-displacement technique is more suitable for analytical studies, especially in the design and development phases of compressed OSD products. In this study, as a model application, utilizing these two approaches, it is demonstrated how internal and external cracks can be detected, localized, characterized, and analyzed as a function of disintegrant ratio and main compression force. Various uses of these two techniques in practice, such as in Continuous Manufacturing (CM) and Real-Time Release Testing (RTRT), are also discussed.

Non-destructive detection of disintegrant levels in compressed oral solid dosage forms.

Quality issues related to compressed oral solid dosage (OSD) forms, such as tablets, arise during the design, development, and production stages, despite established processes and robust production tools. One of the primary quality concerns is the disintegration properties and drug release profile of immediate-release OSD products, which depend on their micro-texture and micro-viscoelastic properties at the grain level. These properties are influenced by the composition of the formulation, particularly the disintegrant level in the tablet matrix and the porosity of the matrix. In this study, a novel, rapid, non-destructive ultrasonic characterization technique was proposed to correlate the sensitivity of propagating elastic wave speeds, physical/mechanical properties, and the dispersion profile of the OSD material with the disintegrant level (% w/w) in the formulation and the compression force applied during tableting. The proposed characterization framework involves transmitting pressure (longitudinal) and shear (transverse) waves through the OSDs to calculate the speed of sound, which in turn provides information on the apparent Young's and shear moduli. In addition, the attenuation profile of the propagating wave is obtained through dispersion analysis. To investigate the impact of disintegrants and compression force on ultrasonic wave propagation in OSDs, we incorporated seven levels of a frequently used disintegrant. In each formulation, OSDs are compacted in five compaction forces. The sensitivity of wave speeds, physical/mechanical properties, and attenuation profile was observed with each disintegrant and compression force level. The utilization of ultrasonic techniques may present a viable solution for rapid, non-destructive, non-invasive, and cost-effective testing methods required in continuous manufacturing (CM) and real-time release testing (RTRT), and its practical utility in pharmaceutical manufacturing is also discussed.

Machine learning framework for extracting micro-viscoelastic and micro-structural properties of compressed oral solid dosage forms.

A compressed pharmaceutical oral solid dosage (OSD) form is a strongly micro-viscoelastic material composite arranged as a network of agglomerated particles due to its constituent powders and their bonding and fractural mechanical properties. An OSD product's Critical Quality Attributes, such as disintegration, drug release (dissolution) profile, and structural strength ("hardness"), are influenced by its micro-scale properties. Ultrasonic evaluation is direct, non-destructive, rapid, and cost-effective. However, for practical process control applications, the simultaneous extraction of the micro-viscoelastic and scattering properties from a tablet's ultrasonic response requires a unique solution to a challenging inverse mathematical wave propagation problem. While the spatial progression of a pulse traveling in a composite medium with known micro-scale properties is a straightforward computational task when its dispersion relation is known, extracting such properties from the experimentally acquired waveforms is often non-trivial. In this work, a novel Machine Learning (ML)-based micro-property extraction technique directly from waveforms, based on Multi-Output Regression models and Neural Networks, is introduced and demonstrated. Synthetic waveforms with a given set of micro-properties of virtual tablets are computationally generated to train, validate, and test the developed ML models for their effectiveness in the inverse problem of recovering specified micro-scale properties. The effectiveness of these ML models is then tested and demonstrated for a set of physical OSD tablets. The micro-viscoelastic and micro-structural properties of physical tablets with known properties have been extracted through experimentally acquired waveforms to exhibit their consistency with the generated ML-based attenuation results.

Ultrasonic characterization of complete anisotropic elasticity coefficients of compressed oral solid dosage forms.

In compacted materials, elastic anisotropy coupled with residual stresses could play a determining role in the manifestation of various types of defects such as capping and lamination, as it creates shear planes/bands and temporal relaxation. This internal micro-structure leads to time-delayed flaw initiation/formation, crack tip propagation under residual stresses, and ultimately product quality failures. Thus, their accurate characterization and variations are useful for understanding underlying failure mechanisms and to monitor variations in materials, processes and product quality during production prior to onset of failure. The extraction of tablet anisotropic elasticity properties is a challenging task, especially for commercial tablets with complex shapes, as shape often prevents the use of traditional destructive techniques (e.g., diametric compression testers) to produce accurate measurements. This study introduces and applies an ultrasonic approach to extracting the complete transverse isotropic elastic properties of compressed oral solid dosage forms to a commercial tablet product. A complete set of waveforms and the constitutive matrix for the compacted materials are reported. In addition, a perturbation analysis is carried out to analytically relate propagation speeds in various directions to the elastic coefficients. The proposed characterization approach is non-destructive, rapid, easy, and reliable in evaluating tablet anisotropy.

Effect of shape on the physical properties of pharmaceutical tablets.

Despite a well-established process understanding, quality issues for compressed oral solid dosage forms are frequently encountered during various drug product development and production stages. In the current work, a non-destructive contact ultrasonic experimental rig integrated with a collaborative robot arm and an advanced vision system is presented and employed to quantify the effect of the shape of a compressed tablet on its mechanical properties. It is observed that these properties are affected by the tablet geometric shapes and found to be linearly sensitive to the compaction pressures. It is demonstrated that the presented approach significantly improves the repeatability of the experimental waveform acquisition. In addition, with the increased confidence levels in waveform acquisition accuracy and corresponding pressure and shear wave speeds due to improved measurement repeatability, we conclude that pharmaceutical compact materials can indeed have a negative Poisson's ratio, therefore can be auxetic. The presented technique and instrument could find critical applications in continuous tablet manufacturing, and its real-time quality monitoring as measurement repeatability has been significantly improved, minimizing product quality variations.

Mechanical property characterization of bilayered tablets using nondestructive air-coupled acoustics.

A noncontact/nondestructive air-coupled acoustic technique to be potentially used in mechanical property determination of bilayer tablets is presented. In the reported experiments, a bilayer tablet is vibrated via an acoustic field of an air-coupled transducer in a frequency range sufficiently high to excite several vibrational modes (harmonics) of the tablet. The tablet vibrational transient responses at a number of measurement points on the tablet are acquired by a laser vibrometer in a noncontact manner. An iterative computational procedure based on the finite element method is utilized to extract the Young's modulus, the Poisson's ratio, and the mass density values of each layer material of a bilayer tablet from a subset of the measured resonance frequencies. For verification purposes, a contact ultrasonic technique based on the time-of-flight data of the longitudinal (pressure) and transverse (shear) acoustic waves in each layer of a bilayer tablet is also utilized. The extracted mechanical properties from the air-coupled acoustic data agree well with those determined from the contact ultrasonic measurements. The mechanical properties of solid oral dosage forms have been shown to impact its mechanical integrity, disintegration profile and the release rate of the drug in the digestive tract, thus potentially affecting its therapeutic response. The presented nondestructive technique provides greater insight into the mechanical properties of the bilayer tablets and has the potential to identify quality and performance problems related to the mechanical properties of the bilayer tablets early on the production process and, consequently, reduce associated cost and material waste.

Effects of compaction pressure, speed and punch head profile on the ultrasonically-extracted physical properties of pharmaceutical compacts.

Despite a well-established manufacturing-process understanding, tablet quality issues are frequently encountered during various stages of drug-product development. Compact breaking force (tensile strength), capping and friability are among the commonly observed characteristics that determine the integrity, quality and manufacturability of tablets. In current study, a design space of the compaction pressure, compaction speed and head flat types is introduced for solid dosage compacts prepared from pure silicified microcrystalline cellulose, a popular tableting excipient. In the reported experiments, five types of head flat types at six compaction pressure levels and two compaction speeds were employed and their effects on compact mechanical properties evaluated. The mechanical properties of the tablets were obtained non-destructively. It is demonstrated these properties correlate well with compact porosity and tensile strength, thus their availability is of practical value. The reported mechanical properties are observed to be linearly sensitive to the tableting speed and compaction pressure, and their dependency on the head-flat profile, while clearly visible in the presented waveforms, was found to be nonlinear in the range of the parameter space. In this study, we detail a non-destructive, easy-to-use approach for characterizing the porosity and tensile strength of pharmaceutical tablets.

Mechanical properties of P-selectin PSGL-1 bonds.

The accurate determination of the mechanical properties of P-selectin and PSGL-1 is crucial for design and optimization of applications utilizing such bonds, e.g. biosensors and targeted drug delivery systems, as adhesion and mechanical interactions play a critical role in several key functions of biological cells. In current work, the spring constant and rupture force of a single P-selectin PSGL-1 ligand receptor bond and the Young's modulus of a layer made of these ligand receptors are reported. The work-of-adhesion of the P-selectin PSGL-1 interface is also characterized. In the reported experiments, PSGL-1 coated particles are deposited on a P-selectin coated substrate and their transient nanometer scale out-of-plane displacements are acquired employing a laser Doppler vibrometer as they are excited by an ultrasonic field. From the spectral response of a single particle, the resonance frequencies of its vibrational motion are identified, and with help of a particle adhesion model, the average rupture force and stiffness of a single P-selectin PSGL-1 ligand receptor are determined as Frupt = 171 ± 56 pN and kb = 0.56 ± 0.04 mN/m, respectively. Furthermore, the Young's modulus and work-of-adhesion of a layer of P-selectin PSGL-1 ligand receptors are extracted as E = 28.74 ± 3.96 MPa and WA = 70.0 ± 8.0 mJ/m2, respectively. Unlike Atomic Force Microscopy (AFM) and other probe-based techniques, the reported approach eliminates the need for direct contact with the sample, which could compromise the accuracy of the results by imposing unspecified additional contact interactions. Further, the current technique can be employed for measurements under various fluid flow conditions.

Air-coupled non-contact mechanical property determination of drug tablets.

A non-contact/non-destructive technique for determining the mechanical properties of coated drug tablets is presented. In the current measurement approach, air-coupled excitation and laser interferometric detection are utilized and their effectiveness in characterizing the mechanical properties of a drug tablet by examining its vibrational resonance frequencies is demonstrated. The drug tablet is vibrated via an acoustic field of an air-coupled transducer in a frequency range sufficiently high to excite its several vibrational modes (harmonics). The tablet surface vibrational responses at measurement points are acquired by a laser vibrometer in a non-contact manner. An iterative computational procedure based on the finite element method is developed to extract the mechanical properties of the coated tablet from a subset of its measured resonance frequencies. The mechanical properties measured by this technique are compared to those obtained by a standard contact ultrasonic measurement method and a good agreement is found. Sensitivities of the resonance frequencies to the changes in the tablet mechanical properties are also obtained and discussed. The presented non-destructive technique requires no physical contact with the tablet and operates in the microsecond time-scale. Therefore, it could be employed for rapid monitoring and characterization applications.

Drug tablet thickness estimations using air-coupled acoustics.

A non-contact/non-destructive acoustic technique for predicting the coating layer thickness of a drug tablet is presented. Quality of tablet coatings can play a major role in the effectiveness of drug delivery. Many pharmaceutical tablets consist of a tablet core and a coated outer cover. Variations in the tablet coating can be indicative of various process problems and, therefore, is of a concern for quality assurance. In the current non-contact measurement system, an air-coupled excitation and laser interferometric detection for predicting the coating layer thickness of a drug tablet is introduced. Drug tablets with different coating thicknesses are vibrated via an acoustic field generated by an air-coupled transducer in a frequency range sufficiently high to excite their several vibrational modes. The tablet surface vibrational responses are acquired at a number of measurement points by a laser interferometer in a non-contact manner. An iterative computational procedure, based on the FE method and Newton's method, was developed and demonstrated to extract the coating layer thicknesses of the tablets from a subset of the measured resonance frequencies.

Non-destructive acoustic defect detection in drug tablets.

For physical defect detection in drug tablets, a non-destructive and non-contact technique based on air coupled excitation and interferometric detection is presented. Physical properties and mechanical integrity of drug tablets can often affect their therapeutic and structural functions. The monitoring for defects and the characterization of tablet mechanical properties therefore have been of practical interest for solid oral dosage forms. The presented monitoring approach is based on the analysis of the transient vibrational responses of an acoustically excited tablet in both in temporal and spectral domains. The pulsed acoustic field exciting the tablet is generated by an air-coupled transducer. Using a laser vibrometer, the out-of-plane vibrational transient response of the tablet is detected and acquired in a non-contact manner. The physical state of the tablet is evaluated based on the spectral properties of these transient responses. In the current study, the effectiveness of three types of simple similarity measures is evaluated for their potential uses as defect detection norms, and for their potential use in quantifying the extent of tablet defect is discussed. It is found that these quantities can not only be used for identification of defective tablets, but could also provide a measure for the extent of the damage.

Adhesion and stiffness of biotin-superavidin bonds.

A non-invasive vibrational spectroscopy technique is introduced and utilized to characterize the average spring constant of a single Superavidin (SAv)-Biotin (Bi).polyethylene glycol (PEG) ligand receptor complex as well as the effective Young's modulus and adhesion of a layer formed by the SAv-Bi.PEG ligand-receptors. In the reported experiments, SAv coated Polystyrene (PS) particles are deposited on a layer of Bi.PEG receptors, bound to a silicon (Si) substrate by silanization. The substrate and the bonded particles are subjected to a pulsed ultrasonic excitation field and their nanometer scale out-of-plane dynamic responses are acquired using a laser vibrometer. The acquired waveforms are processed to obtain the resonance frequencies of the particle motion. Employing a particle adhesion model, the average spring constant of the single ligand-receptor complex and the effective Young's modulus and work-of-adhesion of the SAv-Bi.PEG ligand-receptor layer are extracted from the resonance frequencies. The average spring constant of an individual SAv-Bi.PEG bond is approximated as 0.1-0.4 mN/m. The work-of-adhesion and effective Young's modulus of the SAv-Bi.PEG layer are determined to be 0.54-2.62 J/m2 and 0.15-2.80 MPa, respectively. The compressive Young's modulus of the SAv-Bi.PEG layer is estimated as 31.0-58.0 MPa. The current approach provides a direct non-contact measurement technique for the stiffness of single ligand receptor complexes and the adhesion of their interfaces. SAv-Bi bonds and PEG polymers are among the most widely utilized complexes in the pharmaceutical and biological applications. Understanding the mechanical properties of PEG and SAv-Bi is an important step towards optimization of their utilization in practical applications such as biosensors and targeted drug delivery.

Early detection of capping risk in pharmaceutical compacts.

Capping is a common mechanical defect in tablet manufacturing, exhibited during or after the compression process. Predicting tablet capping in terms of process variables (e.g. compaction pressure and speed) and formulation properties is essential in pharmaceutical industry. In current work, a non-destructive contact ultrasonic approach for detecting capping risk in the pharmaceutical compacts prepared under various compression forces and speeds is presented. It is shown that the extracted mechanical properties can be used as early indicators for invisible capping (prior to visible damage). Based on the analysis of X-ray cross-section images and a large set of waveform data, it is demonstrated that the mechanical properties and acoustic wave propagation characteristics is significantly modulated by the tablet's internal cracks and capping at higher compaction speeds and pressures. In addition, the experimentally extracted properties were correlated to the directly-measured porosity and tensile strength of compacts of Pearlitol®, Anhydrous Mannitol and LubriTose® Mannitol, produced at two compaction speeds and at three pressure levels. The effect compaction speed and pressure on the porosity and tensile strength of the resulting compacts is quantified, and related to the compact acoustic characteristics and mechanical properties. The detailed experimental approach and reported wave propagation data could find key applications in determining the bounds of manufacturing design spaces in the development phase, predicting capping during (continuous) tablet manufacturing, as well as online monitoring of tablet mechanical integrity and reducing batch-to-batch end-product quality variations.

Correlation of solid dosage porosity and tensile strength with acoustically extracted mechanical properties.

Currently, the compressed tablet and its oral administration is the most popular drug delivery modality in medicine. The accurate porosity and tensile strength characterization of a tablet design is vital for predicting its performance such as disintegration, dissolution, and drug-release efficiency upon administration as well as ensuring its mechanical integrity. In current work, a non-destructive contact ultrasonic approach and an associated testing procedure are presented and employed to quantify and relate the acoustically extracted mechanical properties of pharmaceutical compacts to direct porosity and tensile strength measurements. Based on a comprehensive set of experimental data, it is demonstrated how strongly the acoustic wave propagation is modulated and correlated to the tablet porosity and tensile strength of a compact made using spray-dried lactose and microcrystalline cellulose with varying mixture ratios. The effect of mixing ratio on the porosity and tensile strength on the resulting compacts is quantified and, with the acoustic experimental data, mixing ratio is related to the compact ultrasonic characteristics. The ultrasonic techniques provide a rapid, non-destructive means for evaluating compacts in formulation development and manufacturing. The presented approach and data could find critical applications in continuous tablet manufacturing, its real-time quality monitoring, as well as minimizing batch-to-batch quality variations.

Noncontact photo-acoustic defect detection in drug tablets.

Quality assurance monitoring is of great importance in the pharmaceutical industry for the reason that if defects such as coating layer irregularities, internal cracks, and delamination are present in a drug tablet, the desired dose delivery and bioavailability can be compromised. The U.S. Food and Drug Administration (FDA) established the Process Analytical Technology (PAT) initiative, in order to ensure efficient quality monitoring at each stage of the manufacturing process by the integration of analysis systems into the evaluation procedure. Improving consistency and predictability of tablet action by improving quality and uniformity of tablet coatings as well as ensuring core integrity is required. An ideal technique for quality monitoring would be noninvasive, nondestructive, have a short measurement time, intrinsically safe, and relatively inexpensive. In the proposed acoustic system, a pulsed laser is utilized to generate noncontact mechanical excitations and interferometric detection of transient vibrations of the drug tablets is employed for sensing. Two novel methods to excite vibrational modes in drug tablets are developed and employed: (i) a vibration plate excited by a pulsed-laser and (ii) pulsed laser-induced plasma generated shockwave expansion. Damage in coat and/or core of a tablet weakens its mechanical stiffness and, consequently, affects its acoustic response to an external dynamic force field. From the analysis of frequency spectra and the time-frequency spectrograms obtained under both mechanisms, it can be concluded that defective tablets can be effectively differentiated from the defect-free ones and the proposed proof-of-concept techniques have potential to provide a technology platform to be used in the greater PAT effort.

Air-coupled acoustic method for testing and evaluation of microscale structures.

A noncontact testing and characterization approach for microscale structures based on air-coupled acoustic excitation and optical sensing is proposed and demonstrated. Using an air-coupled transducer to externally excite and a laser Doppler vibrometer/interferometer to capture transient displacement wave forms, the experimental approach results in a technique to determine mechanical properties of microscale structural elements. The effectiveness of this method has been demonstrated on commercially available microcantilever beams and microscale rotational oscillators fabricated for this study. The resonance frequencies and mechanical properties (Young's modulus and stiffness) extracted from the transient displacement wave forms have been compared, with good agreement, to computational and simplified analytical models for each case. It is also shown that the technique could serve to diagnose stiction problems of microscale structures. Some potential advantages of the approach described include the simplicity of the test setup, functionality at room conditions, noncontact and nondestructive operations, and repeatability and rapid turn-around time for the evaluation of modal parameters and mechanical properties of microscale structures.

Non-contact microsphere--surface adhesion measurement via acoustic base excitations.

A non-contact adhesion measurement technique based on acoustic base excitation and laser interferometery has been introduced and demonstrated. The vibrational motion of 21.4-microm polystyrene latex particles (PSL) microspheres on surfaces were excited in the frequency range of 0-3.5 MHz, and their axial displacement responses were measured by an interferometer. It is shown that the rolling motion is dominant compared to the axial displacement of the bond. Using a formula for the rotational moment resistance of the particle-surface adhesion bond and the equation of rotational motion, the natural frequency of the rotational motion is related to the work of adhesion of the particle and substrate materials. The substrate materials used in the experiments include copper, aluminum, tantalum, and silicon. Measured work of adhesion values are compared to the data reported in the literature and good agreement is found.

Ultrasonic real-time in-die monitoring of the tablet compaction process-a proof of concept study.

The mechanical properties of a drug tablet can affect its performance (e.g., dissolution profile and its physical robustness. An ultrasonic system for real-time in-die tablet mechanical property monitoring during compaction has been demonstrated. The reported set-up is a proof of concept compaction monitoring system which includes an ultrasonic transducer mounted inside the upper punch of the compaction apparatus. This upper punch is utilized to acquire ultrasonic pressure wave phase velocity waveforms and extract the time-of-flight of pressure waves travelling within the compact at a number of compaction force levels during compaction. The reflection coefficients for the waves reflecting from punch tip-powder bed interface are extracted from the acquired waveforms. The reflection coefficient decreases with an increase in compaction force, indicating solidification. The data acquisition methods give an average apparent Young's moduli in the range of 8-20 GPa extracted during the compaction and release/decompression phases in real-time. A monitoring system employing such methods is capable of determining material properties and the integrity of the tablet during compaction. As compared to the millisecond time-scale dwell time of a typical commercial compaction press, the micro-second pulse duration and ToF of an acoustic pulse are sufficiently fast for real-time monitoring.