After discovery by Herschel in the 1800s, NIRS has been applied as a useful spectral analysis technology in many studies. NIRS is a qualitative and quantitative analysis based on the transmittance and reflectance generated by molecular vibrational motion using light in the near-infrared range of 780–2800 nm. It is most often used in the pharmaceutical industry as a real-time process-monitoring tool for product quality control and quality assurance during processing [11,19,20,21,22,23,24]. The NIRS is connected to a fiber optic probe, and the QA of the product in the process is non-destructively measured by the transmission and reflection of the NIRS by the sample, and quality control through real-time monitoring is possible [19]. The inside of the probe is composed of an optical fiber, a lens, mirror, and signal channel, and the outside of the probe is made of a corrosion-resistant material. It is connected through a sapphire window, so it can be effectively used even in poor process conditions. When the probe is connected to the NIR spectrometer, the light emitted from the light source is focused by the focusing lens. The light reflected by the mirror located at the tip of the probe is transmitted to the NIR spectrum by reflecting a sample. The transmitted signal forms a spectrum through computer software connected to the NIR spectrometer. However, a disadvantage of NIRS is that it is more difficult to interpret a signal than by using conventional analysis methods, such as chromatography, ultraviolet/visible (UV-VIS) light, and others, because the absorption bands overlap due to spectral complexity. In addition, because this is a relative approach, it is necessary to form and verify an accurate correction model using a reference method to utilize it effectively [20]. Nevertheless, NIRS can non-destructively measure the IQAs of a product in a short time during the process, and it can be used as a tool for RTRT in the pharmaceutical industry by enabling the process control and quality assurance of finished products through real-time monitoring [7,21,72,134,135,136,137,138,139,140,141,142,143,144,145,146,147,148,149,150,151,152,153,154,155,156]. Some literature, which shows that PAT is highly applicable to CPV through RTRT, conducted to monitor and evaluate product quality by applying NIRS as a PAT tool, are presented below in various pharmaceutical industries.

Similar to NIRS, Raman spectroscopy is a noncontact analysis technology that uses optical fibers [157]. Raman spectroscopy is a type of vibration spectroscopy. Various Raman laser sources offer a range of wavelengths (generally 785 nm), from the UV-VIS to near-infrared regions; the most common are visible light lasers [158]. In general, vibrations occur in chemical bonds that are not rigid, and materials can be characterized based on their molecular-vibration frequencies. Raman spectroscopy is widely used in pharmaceutical manufacturing because it enables the rapid characterization of the chemical composition and structure of a solid, liquid, gas, gel, or powder sample by providing the detailed characteristics of their vibrational transitions [1]. Raman spectroscopy is used to determine the molecule in the sample, and their intensity enables the calculation of the drug content of a particular sample. One of the main reasons for using PAT is to build and qualitatively analyze the specificity library of the raw material spectrum, including impurities in the sample [158]. Raman spectroscopy is ideally suited for PAT systems because it has the flexibility to operate on-line or in-line. Moreover, it provides both quantitative and qualitative data, enabling accurate and consistent monitoring and control during real-time processes. Depending on the compound, the Raman spectrum for a specific molecule differs for each movement of the scattered photon energy, and because it has a unique fingerprint, it enables the monitoring of qualitative information [8,159]. Furthermore, it can be used for analyzing liquid products without moisture interference, similar to Fourier-transform infrared spectroscopy (FTIR) or NIRS, and has a high measurement speed.

Similar to other spectroscopy methods, Raman spectroscopy is commonly used as a real-time monitoring tool for CPV in various pharmaceutical unit processes, including blending, granulation, coating, and tableting. It can analyze the IQAs and CQAs of drug content [160,161,162] during the blending process, moisture content [8,9] during the drying and granulation process, and coating thickness and content [157,163,164] during the coating process, as well as enable polymorph identification in API preparation [165,166,167], granule-formulation analysis [8], blending uniformity [27,168], particle-size analysis [16,159,169], and others.

HSI is well known for chemical or spectral imaging. It is a nondestructive PAT tool that can extract both spatial and spectral information from an object by integrating existing imaging and spectroscopy techniques. HSI can be applied to various wavelength ranges, including visual, near-infrared, and short-wave infrared (1000–2500 nm). Each pixel of the image acquired by the HSI tool, which contains a spectrum of a specific location, comprises hundreds of consecutive wavelength bands in each space. This generates a large amount of information because the spectrum is constantly acquired from a wide range. Similar to other spectroscopy methods, the preprocessing of the acquired data cube must be performed on qualitative and quantitative images by extracting information in an easy-to-understand image format [170]. HSI provides dependable chemical and spatial imaging data on the content and distribution of API and excipients during the processes of blending, granulation, and tableting [170]. The acquired images are combined and processed in three dimensions (3D) to form the data cube. The x and y dimensions of the formed cube are shown as the two space dimensions, whereas λ is the spectral dimension. There are four basic techniques (spatial scanning, spectral scanning, nonscan, and spatiotemporal scanning) for acquiring 3D (x, y, λ) data in a hyperspectral cube, and the choice of technology depends on the specific application. HIS as an on-line PAT tool has been used to monitor blending uniformity and analyze tablet variability [171]. Moreover, it can analyze the sample to be measured faster than spectroscopy, and it is also used for package monitoring to ensure products are correctly placed in the package, identify defective tablets, or detect empty slots in a package [172]. Kandpal et al. studied an in-line HIS system for monitoring drug content in microtablets’ surface. The collected multivariate data were evaluated by applying the PLSR and PCR chemometric model. The authors showed a high predictive ability and proposed a quick in-line determination of product quality using HIS.

TPI, a widely used PAT tool for real-time imaging, is applied for monitoring tablet surface and coating analysis [173]. The terahertz absorption spectrum is related to the 3D arrangement and covers the spectral range of 0.1–4.0 THz, which corresponds to the range between the infrared and microwave frequencies. For this reason, the terahertz region is known as far-infrared radiation. Compared with infrared radiation, it has the advantage of causing little scattering because of its longer wavelength, and lower radiation energy interacting with drugs is less likely to damage the sample [173]. Furthermore, TPI is widely used as a noninvasive method because it uses nonionizing radiation and is safe to use. As mentioned previously, TPI is mainly used in the pharmaceutical coating process. In particular, it is used for predicting the degree of coating thickness in sustained-release tablets, in which the coating thickness is directly related to drug release [164,174,175,176]. If drug release is via the coating instead of through the dissolution of the tablet, then it can be predicted by analyzing the coating formulation using TPI.

MS is an extremely useful PAT tool for the qualitative analysis of drug, compound, and related substances. Because it has a high resolution and mass accuracy, it is also used in the qualitative analysis of small molecules and is often selected and used in biological processes, such as in analyzing heterogeneous biomolecules [177,178,179]. In addition, it provides quick analysis when high throughput sample preparation and automated data processing are possible [8]. The mass spectrum is commonly employed to obtain the identity of two compounds or to establish the structure of a new compound and provides the accurate molecular weight or molecular formula to indicate the existence of a specific structural unit in a molecule. The main advantage of MS is its ability to measure several types of compounds with excellent discrimination over a very short analysis time. Moreover, it is used to quantitatively analyze known substances or identify unknown compounds in a sample and to reveal the structure and chemical properties of other molecules. To perform MS, a vacuum must be maintained, and the sample needs to be vaporized and ionized. Thus, the disadvantage of MS is that a sample cannot be analyzed if it cannot be decomposed and evaporated. The typical applications of MS include the real-time control of the drying process, particularly the monitoring of the trace amounts of organic solvents used in the production of intermediate and finished products.

ARS as a PAT tool detects and analyzes the sound generated during the pharmaceutical process. The sound detected by ARS is much higher than the frequencies detectable by the human ear [180,181]. It is usually applied to processes that cause acoustic emission and is applied to the chemical reaction checking or blending, pulverization, and fluidized-bed granulation of the drugs. For example, during the granulation process, particles emit various sounds when they collide with each other and cause friction in the equipment. As with most PAT tools, ARS is noninvasive, does not require sample preparation, and has the advantage of being an inexpensive and convenient application method. Using acoustic emission, quantitative information, such as particle characteristics and moisture content, can be obtained. Changes in the physical properties of the powder, such as compression characteristics and distribution characteristics, can be monitored. Tsujimoto et al. used ARS to monitor and characterize particle motion due to friction occurring during the fluidized-bed granulation process; they also monitored the behavior of particles via the correlation between ARS and particle motion. ARS was installed at the bottom of the fluidized-bed granulator, and the collected sound was amplified and the sensitivity optimized to analyze the frequency. The impact of particles hitting the chamber wall increased with the increasing rotational speed of the fluidized-bed granulator, resulting in the subsequent increase of the AE amplitude. In addition, the instability due to the increased amount of spray solution, i.e., increased moisture content, could be detected during the fluidized-bed granulation process by ARS [180].

Similar to FBRM, SFV is a technique that measures the chord length of a moving particle in real time. Therefore, it is used as a PAT tool for the real-time monitoring of particle size, size distribution, and shape in various solid dosage manufacturing processes, including fluidized-bed granulation/coating, grinding, and spray-drying [147,153,182,183,184]. However, unlike FBRM, which uses backscattered laser light, SFV applies a shadow to calculate the particle code length. When the particles pass through a parallel laser beam, a shadow is created in the linear fiber-optic array, and a secondary pulse signal is generated by a single fiber. Hence, it is possible to measure the size and velocity of individual particles simultaneously and calculate the chord length of the particle by using the time of the pulse signal and velocity of the moving particle [77]. Therefore, monitoring using SFV allows quality control to be performed by evaluating the properties of intermediate and finished products in a non-invasive method without special sampling procedures. Due to these characteristics, SFV can be used as a monitoring tool in CPV through RTRT.

FBRM is a technique that provides information on the code length distribution of a population of dispersed particles based on the backscattering of laser light. In the pharmaceutical industry, it is suitable for studying particle properties in suspension [185,186,187,188], emulsion [189,190,191,192], and crystallization [193,194]. Therefore, FBRM is used as a tool to evaluate IQAs including particle size, size distribution, shape, and particle-growth behavior in granulation and crystallization processes, which can have a great influence on the quality of the finished product due to particle properties, and to perform real time monitoring [195]. In the case of FBRM, a laser beam connected to the probe via a fiber is inserted into the process equipment through a sapphire window at the end of the probe. At this time, some of the light scattering generated by the laser beam crossing the particles by high-speed rotational motion is transmitted to the detector to generate the code length. Thousands of code lengths are measured simultaneously, and based on this, a code-length distribution can be generated to measure particle properties such as particle size and size distribution in real-time [92,93,95].

XRF is an atomic analysis technique used to determine the component of a variety of sample types, including solids, liquids, slurries, and powders, similar to inductively coupled plasma light atomic emission spectroscopy (ICP-AES) and atomic absorption spectroscopy (AAS). AAS and ICP-AES are widely used in the pharmaceutical industry for atomic high-sensitivity analysis because they can measure >70 different elements. However, only a specific analyte can be measured by the cathode lamp, and sample preparation takes longer because of the acid-decomposition procedure. Moreover, there are obvious disadvantages because of the large space requirement and high maintenance cost. As an alternative, XRF was developed [196]. XRF is a chemical analysis method based on the transfer of internal electrons and the interaction of X-ray radiation and atoms. High-energy X-rays attack electrons in high-energy atoms, leading to their release [16]. Hence, a vacancy is created in the inner shell, and electrons in the outer orbit are moved to cover the vacancy, thereby generating fluorescent X-rays because of the energy difference between the two orbits. Because each element has an electron of its own energy level, elemental analysis is possible as a result of the unique energy difference resulting from the characteristic X-ray irradiation [197]. Therefore, XRF has the advantage of high selectivity, a small number of collected spectra, and a lack of overlap [198]. The obtained spectrum of XRF indicates the properties of each element, and the intensity of the spectrum indicates the content of the element present in the sample [196]. XRF is unaffected by the matrix effect because it reduces the absorption and scattering of the X-ray beam between the sample and the matrix. Moreover, the sample preparation time is short, and the method is relatively simple because of its high sensitivity [199]. XRF is highly applicable to CPV in the pharmaceutical industry as it allows simpler data analysis because of its lesser influence on the non-overlapping spectrum and matrix effect, as well as its ability to nondestructively quantify multiple elements at the same time. This is explained through research cases in which the quality evaluation of intermediate and finished products was performed through the real-time monitoring of various manufacturing processes in the pharmaceutical industry.

OCT (optical coherence tomography) is a high-resolution imaging method that can non-destructively measure the depth of translucent or cloudy materials. In the pharmaceutical industry, it is used to measure coating thickness and uniformity during the coating process by applying the same principles as TPI. OCT can compensate for the shortcomings of TPI’s low resolution and long measurement time and enables high resolution due to its relatively short wavelength [200,201]. However, imaging the thickness of the coating can be difficult due to strong scattering that limits the depth of penetration into the coating matrix and does not produce a clear refractive index difference. Nevertheless, it can measure not only the coating thickness but also the coating homogeneity within the tablet and has the advantage of being less affected by probe contamination and measurement location during the process compared to NIRS or Raman spectroscopy. Therefore, in the pharmaceutical industry, OCT is widely used as a real-time monitoring tool for the quality control of intermediate and finished products, and several studies have applied this tool to RTRT to prove the possibility of CPV [200]. Eyecon is a direct imaging analyzer of particle size. It does not require sampling and automatically captures data regarding the particle size and shape of the powder or variations to analyze the process. Another PAT tool is microwave resonance technology (MRT). MRT can measure moisture during the granulation process by noting the interaction between water molecules and the changing electromagnetic field. Unlike spectroscopy, such as NIRS and Raman spectroscopy, MRT does not require any mathematical preprocessing of the collected data.