Process Analytical Technology Tool Research Articles

Implemention of Innovative Process Analytical Technologies to Characterize Critical Quality Attributes of Co-Formulated Monoclonal Antibody Products.

Characterizing co-formulated monoclonal antibodies (mAbs) poses significant challenges in the pharmaceutical industry. Due to the high structural similarity of the mAbs, traditional analytical methods, compounded by the lengthy method development process, hinder product development and manufacturing efficiency. There is increasing critical need in the pharmaceutical industry to streamline analytical approaches, minimizing time and resources, ensuring a rapid clinical entry and cost-effective manufacturing. This study investigates the application of process analytical technologies (PAT) to address such challenges. Our investigation introduces two complementary technologies, on-line ultra-performance liquid chromatography (online UPLC) and multimode fluorescence spectroscopy (MMFS), as potential PAT tools tailored for characterizing critical quality attributes (CQA) in co-formulated mAb products. Specifically, the CQAs under evaluation include the total protein concentration of the mAbs within the co-formulation and the ratio of mAb A to mAb B. Online UPLC enables direct and automated measurement of the CQAs through physical separation, while MMFS determines them in a non-destructive and more swift manner based on chemometric modeling. We demonstrate these technologies' comparable performance to conventional methods, alongside substantial benefits such as reduced analytical turnaround time and decreased laboratory efforts. Ultimately, integrating them as innovative PAT tools expedites the delivery of therapeutic solutions to patients and enhances manufacturing efficiency, aligning with the imperative for swift translation of scientific discoveries into clinical benefits.

Application of artificial intelligence (AI) as a process analytical technology (PAT) tool in healthcare industry

Process Analytical Technology (PAT) has revolutionized manufacturing by providing real-time insights into process parameters. This guide delves into the synergistic potential of AI and PAT, offering a comprehensive overview of their integration. It explores the way AI algorithms can enhance data analysis, prediction, and control complex manufacturing processes. The document provides a fundamental understanding of AI concepts relevant to PAT, including machine learning, deep learning, and computer vision. Real-world case studies help to illustrate the practical application of AI in diverse industries, such as pharmaceuticals, chemicals, and food processing. By highlighting the benefits of AI-driven PAT, such as improved product quality, increased efficiency, and reduced costs, this guide empowers readers to harness the power of AI for process optimization and innovation. The objective of this review is to provide a base for establishing the regulatory guidelines and adaptation of PAT-controlled applications in the regulations.

Process analytical technology based quality assurance of API concentration and fiber diameter of electrospun amorphous solid dispersions

In this study, a novel quality assurance system was developed utilizing Process analytical technology (PAT) tools and artificial intelligence (AI). Our goal was to monitor the critical quality attributes (CQAs) like drug concentration, morphology and fiber diameter of electrospun amorphous solid dispersion (ASD) formulations with fast at-line techniques. Doxycycline-hyclate (DOX), a tetracycline-type antibiotic was used as a model drug with 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) as the matrix excipient. The water-based formulations were electrospun with high-speed electrospinning (HSES). Raman and NIR sensors and machine vision-based color measurement techniques were employed to accurately determine the drug concentration. Given that morphology can influence the solubility of the drug, a convolutional neural network (CNN)-based AI model was developed to examine this property and detect manufacturing defects. Additionally, the diameter of electrospun fibrous samples was measured using camera images and a trained AI model, enabling rapid analysis of fiber diameter with results similar to that of scanning electron microscopy (SEM). These methods and models demonstrate potential in-line analytical tools, offering rapid, cheap and non-destructive analysis of ASD formulations.

Investigation of near infrared and Raman fibre optic process sensors for protein determination in milk protein concentrate

This study investigated the potential of two fibre optic process sensors based on near infrared (NIR) or Raman spectroscopic technology for protein measurement in milk protein concentrate (MPC). Partial least squares (PLS) models were developed using NIR, Raman, and fusion of NIR and Raman spectra data. Calibration models developed were optimized by selecting different spectral pre-treatment methods and spectral regions. Overall, the three optimal models (NIR, Raman, fused NIR and Raman) yielded R2p values >0.9 and RMSEP values in the range of 0.168–0.185 %. The optimised fusion model outperformed all Raman models and had a similar protein prediction accuracy (R2p = 0.911 and RMSEP = 0.178 %) compared to the optimised NIR model (R2p = 0.917 and RMSEP =0.168 %). Results of the study demonstrated that both NIR and Raman process probes can be used as process analytical technology (PAT) tools for inline protein measurements of MPC post membrane filtration.

Parameter Optimization and Capacitance-Based Monitoring of In Situ Cell Detachment in Microcarrier Cultures

This study delves into the scale-down optimization of the in situ cell detachment process for MA 104 cells cultivated on Cytodex 1 microcarriers (MCs). Through a systematic exploration, critical operational parameters—the agitation speed, incubation time, Trypsin–EDTA volume and corresponding activity, and washing steps—were identified as key factors influencing the efficiency and scalability of in situ cell detachment in microcarrier-based cell culture. Maintaining an appropriate agitation speed (1.25 × Njs, minimum agitation speed at which no microcarriers remain stationary for the signification period of 5 s), optimizing the Trypsinization incubation time (up to 60 min), and implementing multiple washing steps (two times) post-medium removal were found to be crucial for efficient cell detachment and subsequent growth. Our study demonstrates the feasibility of reducing the final Trypsin volume to 50 mL per gram of microcarrier while maintaining a Trypsin activity above 380 USP/mL. These conditions ensure complete cell dissociation and improve the cost effectiveness in large-scale productions. Additionally, we introduced real-time monitoring using a capacitance sensor during in situ cell detachment. This method has proven to be an effective process analytical technology (PAT) tool for tracking the cell detachment progress and efficiency. It allows for the prediction of cell detachment based on signals recorded between 3 and 7 min of Trypsinization, enabling rapid process decisions without the need for offline sampling, thereby enhancing the overall process control. This systematic approach not only optimizes in situ cell detachment processes but also has significant implications for the scalability and efficiency of microcarrier-based cell culture systems.

THz-TDS transflection measurements as a process analyser for tablet mass

Tablet content and content uniformity are essential for the market release of the drug product. For tablets, content and uniformity are determined by the weight ratio of active pharmaceutical ingredient in the tablet and the tablets’ total mass. Novel process analytical technology tools for the control of the ratio of the active pharmaceutical ingredient have been proposed and implemented, but more robust, sensitive, and fast sensors for the control of tablet mass are desirable. In the presented study terahertz time-domain spectroscopy (THz-TDS) is proposed as a potential process analyser for tablet mass. THz-TDS is based on pulsed terahertz signals, which are mapped in the time-domain. Thus, the signal amplitude and arrival time are recorded. THz-TDS measurements of a tablet with a reflection setup result in two signals – a frontside reflection and a backside transflection. The presented study demonstrates that an increase in the tablet mass results in an increase in the time delay of the backside transflection. This is a result of the high refractive index of the solid fraction compared to air. It is suggested that the transflection can be used as an indirect measure of tablet mass for which root mean squared errors of around 1 mg were found. The potential to measure tablets at high acquisition rates (50 Hz) is explored and considered feasible. Additionally, it has been demonstrated in previous work that the time delay of the frontside reflection allows a simultaneous assessment of the tablet height. The presented methodology opens the possibility of in-line monitoring of tablet mass as part of a content and content uniformity strategy at high sampling rates in the production environment. Further, as tablet height and mass can be assessed simultaneously, monitoring and control of the compaction process based on a comprehensive assessment of physical tablet attributes can also be envisioned.

In-line indirect concentration measurement of ultralow dose API during twin-screw wet granulation based on NIR and Raman spectroscopy

Twin-screw wet granulation (TWSG) is a promising continuous alternative of pharmaceutical wet granulation. One of its benefits is that the components dissolved in the granulation liquid are distributed homogeneously in the granules. This provides an elegant way to manufacture products with ultralow drug doses. Near-infrared (NIR) and Raman spectroscopy are well-established process analytical technology (PAT) tools that can be used for the in-line monitoring of TSWG. However, their detection limit does not enable the measurement of components in the ultralow (i.e., ppm) range. In this paper, an indirect approach is presented that enables the real-time determination of the concentration of a drug in concentrations between 40 and 100 ppm by using the signal of an excipient, in this case, the polyvinylpyrrolidone (PVP). This component is also dissolved in the granulation liquid; therefore, it is distributed in the same way as the active ingredient. Results of HPLC measurements have proved that the models trained to quantify the concentration of PVP in real-time gave an accurate determination for the active ingredient as well (root mean squared error was 7.07 ppm for Raman and 5.31 ppm for NIR spectroscopy, respectively). These findings imply that it is possible to indirectly predict the concentration of ultralow dose drugs with in-line analytical techniques based on the concentration of an excipient.

THz-TDS as a PAT tool for monitoring blend homogeneity in pharmaceutical manufacturing of solid oral dosage forms: A proof-of-concept study

The process analytical technology (PAT) framework is well established and integral to facilitate process understanding, enable a transition from batch to continuous manufacturing, and improve product quality. Near-infrared (NIR) spectroscopy has been established as a standard PAT tool for many process analytical challenges, including monitoring powder blend homogeneity. However, alternative technologies for monitoring powder blending are of interest due to the importance of the blending step in manufacturing solid oral dosage forms. Terahertz time-domain spectroscopy (THz-TDS) is therefore explored in this study as an alternative tool for monitoring blend homogeneity with the potential for endpoint control in a batch blending process. Powder blends of microcrystalline cellulose (MCC) and dibasic calcium phosphate dihydrate and blends of MCC and granulated α-lactose monohydrate were investigated non-invasively at various compositions using THz-TDS in transmission mode for acquiring spectra from samples enclosed in the blending container. It was found that attenuation- and phase-related parameters acquired with THz-TDS could reliably resolve physical changes related to the homogeneity of the blend. Further evaluations revealed that changes in the bulk density of the blend, in addition to the intrinsic optical properties of the materials, played a critical role in the observed trends for both systems. In contrast, the scattering contribution of the powder was mainly crucial for the attenuation-related parameter in blends with materials of high refractive indices. Finally, THz-TDS measurements were acquired throughout a blending process mimicking a continuous acquisition. The method could follow blending dynamics and resulted in reasonable predictive errors of the content of 0.5 – 2.5 %. Relative standard deviations for high content blends (20 %) were acceptable (3 – 7 %) whereas at low contents (5 %) significantly higher values (9 – 35 %) were found. Based on these findings, THz-TDS is a feasible PAT tool for monitoring blend homogeneity and controlling high content blend processes, although precision and accuracy is considered to improve with a more suitable interface.

Experimental design of a film flow cleaning rig equipped with in-line process analytical technology (PAT) tool for real-time monitoring

The main purpose of this research was to develop an experimental film flow cleaning rig that can be combined with Process analytical technology (PAT) tools to reduce cleaning time and costs. Here, we show that the use of in-line UV–Vis was successful for real-time monitoring of the cleaning process of olanzapine as a challenging residue to clean. The cleaning process was found to be affected by the properties of the olanzapine soil, and the study showed the competing effects of mechanical lift-off and dissolution action with methanol as a solvent. However, The method is limited by the cleaning mechanisms, with the dissolution being the only mechanism that can be accurately quantified using an in-line UV–Vis PAT tool. This experimental approach can be used to optimize cleaning process conditions and solvent choices at the bench scale before deployment. The material of which the cleaning rig was printed limited the solvent that could be used for this study, and future modifications will include a more chemical-resistant material.

Investigation of the rehydration characteristics of dairy and infant formula powders using focused beam reflectance measurement and electrical resistance tomography

The potential of focused beam reflectance measurement (FBRM) and electrical resistance tomography (ERT) was evaluated as on‐line process analytical technologies (PAT) for monitoring powder rehydration. Skim milk powder (SMP) and stage one infant formulas were evaluated. Among all samples, SMP had the greatest conductivity by ERT (P < 0.05), this was confirmed by off‐line methods, that is, SMP had a higher solubility, whereas infant formulas had lower solubility. Particle counts for fines of all samples reached peak values ~450 s. Results demonstrated PAT tools offer capability for rehydration characterisation of dairy and non‐dairy powders.

Simple and fast one-step FRET assay of therapeutic mAb bevacizumab using anti-idiotype DNA aptamer for process analytical technology

We developed an aptamer-based fluorescence resonance energy transfer (FRET) assay capable of recognizing therapeutic monoclonal antibody bevacizumab and rapidly quantifying its concentration with just one mixing step. In this assay, two fluorescent dyes (fluorescein and tetramethylrhodamine) labeled aptamers bind to two Fab regions on bevacizumab, and FRET fluorescence is observed when both dyes come into close proximity. We optimized this assay in three different formats, catering to a wide range of analytical needs. When applied to hybridoma culture samples in practical settings, this assay exhibited a signal response that was concentration-dependent, falling within the range of 50–2000 μg/mL. The coefficients of determination (r2) ranged from 0.998 to 0.999, and bias and precision results were within ±24.0 % and 20.3 %, respectively. Additionally, during thermal and UV stress testing, this assay demonstrated the ability to detect denatured samples in a manner comparable to conventional Size Exclusion Chromatography. Notably, it offers the added advantage of detecting decreases in binding activity without changes in molecular weight. In contrast to many existing process analytical technology tools, this assay not only identifies bevacizumab but also directly measures the quality attributes related to mAb efficacy, such as the binding activity. As a result, this assay holds great potential as a valuable platform for providing highly reliable quality attribute information in real-time. We consider this will make a significant contribution to the worldwide distribution of high-quality therapeutic mAbs in various aspects of antibody manufacturing, including production monitoring, quality control, commercial lot release, and stability testing.

Raman and NIR spectroscopy-based real-time monitoring of the membrane filtration process of a recombinant protein for the diagnosis of SARS-CoV-2

This research shows the detailed comparison of Raman and near-infrared (NIR) spectroscopy as Process Analytical Technology tools for the real-time monitoring of a protein purification process. A comprehensive investigation of the application and model development of Raman and NIR spectroscopy was carried out for the real-time monitoring of a process-related impurity, imidazole, during the tangential flow filtration of Receptor-Binding Domain (RBD) of the SARS-CoV-2 Spike protein. The fast development of Raman and NIR spectroscopy-based calibration models was achieved using offline calibration data, resulting in low calibration and cross-validation errors. Raman model had an RMSEC of 1.53 mM, and an RMSECV of 1.78 mM, and the NIR model had an RMSEC of 1.87 mM and an RMSECV of 2.97 mM. Furthermore, Raman models had good robustness when applied in an inline measurement system, but on the contrary NIR spectroscopy was sensitive to the changes in the measurement environment. By utilizing the developed models, inline Raman and NIR spectroscopy were successfully applied for the real-time monitoring of a process-related impurity during the membrane filtration of a recombinant protein. The results enhance the importance of implementing real-time monitoring approaches for the broader field of diagnostic and therapeutic protein purification and underscore its potential to revolutionize the rapid development of biological products.

Expediting online liquid chromatography for real-time monitoring of product attributes to advance process analytical technology in downstream processing of biopharmaceuticals

The application of Process Analytical Technology (PAT) principles for manufacturing of biotherapeutics proffers the prospect of ensuring consistent product quality along with increased productivity as well as substantial cost and time savings. Although this paradigm shift from a traditional, rather rigid manufacturing model to a more scientific, risk-based approach has been advocated by health authorities for almost two decades, the practical implementation of PAT in the biopharmaceutical industry is still limited by the lack of fit-for-purpose analytical methods. In this regard, most of the proposed spectroscopic techniques are sufficiently fast but exhibit deficiencies in terms of selectivity and sensitivity, while well-established offline methods, such as (ultra-)high-performance liquid chromatography, are generally considered as too slow for this task. To address these reservations, we introduce here a novel online Liquid Chromatography (LC) setup that was specifically designed to enable real-time monitoring of critical product quality attributes during time-sensitive purification operations in downstream processing. Using this online LC solution in combination with fast, purpose-built analytical methods, sampling cycle times between 1.30 and 2.35 min were achieved, without compromising on the ability to resolve and quantify the product variants of interest. The capabilities of our approach are ultimately assessed in three case studies, involving various biotherapeutic modalities, downstream processes and analytical chromatographic separation modes. Altogether, our results highlight the expansive opportunities of online LC based applications to serve as a PAT tool for biopharmaceutical manufacturing.

Bioprocess in-line monitoring and control using Raman spectroscopy and Indirect Hard Modeling (IHM).

Process in-line monitoring and control are crucial to optimize the productivity of bioprocesses. A frequently applied Process Analytical Technology (PAT) tool for bioprocess in-line monitoring is Raman spectroscopy. However, evaluating bioprocess Raman spectra is complex and calibrating state-of-the-art statistical evaluation models is effortful. To overcome this challenge, we developed an Indirect Hard Modeling (IHM) prediction model in a previous study. The combination of Raman spectroscopy and the IHM prediction model enables non-invasive in-line monitoring of glucose and ethanol mass fractions during yeast fermentations with significantly less calibration effort than comparable approaches based on statistical models. In this study, we advance this IHM-based approach and successfully demonstrate that the combination of Raman spectroscopy and IHM is capable of not only bioprocess monitoring but also bioprocess control. For this purpose, we used this combination's in-line information as input of a simple on-off glucose controller to control the glucose mass fraction in Saccharomyces cerevisiae fermentations. When we performed two of these fermentations with different predefined glucose set points, we achieved similar process control quality as approaches using statistical models, despite considerably smaller calibration effort. Therefore, this study reaffirms that the combination of Raman spectroscopy and IHM is a powerful PAT tool for bioprocesses.

Development of novel portable NIR spectroscopy process analytical technology (PAT) tool for monitoring the transition of ibuprofen to ibuprofen sodium during wet granulation process

The aim of this research was to develop a process analytical technology (PAT) tool for monitoring the transformation of the active ingredient ibuprofen into the fast-dissolving salt ibuprofen sodium during the wet granulation process. Two near-infrared (NIR) spectrophotometers, portable and benchtop spectrophotometer, were compared. During the analysis with the built models, both demonstrated comparable accuracy and precision (R2X = 0.995, R2Y = 0.927, Q2 = 0.995, and R2X = 0.990, R2Y = 0.948, Q2 = 0.992, respectively). Considering the applicability, a model based on the portable NIR spectroscopic data was chosen for further development and application as a PAT tool for monitoring different steps during the wet granulation process. The evaluation of the model's predictive capability involved analyzing laboratory trial batches with varying amounts of sodium carbonate, resulting in different concentrations of ibuprofen sodium at the end of the wet granulation process. Subsequently, tablets were manufactured from each trial batch, followed by dissolution analysis. The dissolution rate assays were in good agreement with the NIR-predicted concentrations of ibuprofen sodium at the end of the wet granulation process. Based on the results, the proposed model provides an excellent tool to monitor the ibuprofen acid-salt transformation, to determine the end-point of the reaction, and to efficiently control the wet granulation process.

Online monitoring of protein refolding in inclusion body processing using intrinsic fluorescence

Inclusion bodies (IBs) are protein aggregates formed as a result of overexpression of recombinant protein in E. coli. The formation of IBs is a valuable strategy of recombinant protein production despite the need for additional processing steps, i.e., isolation, solubilization and refolding. Industrial process development of protein refolding is a labor-intensive task based largely on empirical approaches rather than knowledge-driven strategies. A prerequisite for knowledge-driven process development is a reliable monitoring strategy. This work explores the potential of intrinsic tryptophan and tyrosine fluorescence for real-time and in situ monitoring of protein refolding. In contrast to commonly established process analytical technology (PAT), this technique showed high sensitivity with reproducible measurements for protein concentrations down to 0.01 g L-1\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$^{-1}$$\\end{document}. The change of protein conformation during refolding is reflected as a shift in the position of the maxima of the tryptophan and tyrosine fluorescence spectra as well as change in the signal intensity. The shift in the peak position, expressed as average emission wavelength of a spectrum, was correlated to the amount of folding intermediates whereas the intensity integral correlates to the extent of aggregation. These correlations were implemented as an observation function into a mechanistic model. The versatility and transferability of the technique were demonstrated on the refolding of three different proteins with varying structural complexity. The technique was also successfully applied to detect the effect of additives and process mode on the refolding process efficiency. Thus, the methodology presented poses a generic and reliable PAT tool enabling real-time process monitoring of protein refolding.Graphical abstractReal-time intrinsic fluorescence monitoring in protein refolding

Multi-dimensional technology - Recent advances and applications for biotherapeutic characterization.

This review provides an overview of the latest advancements and applications in multi-dimensional liquid chromatography coupled with mass spectrometry (mD-LC-MS), covering aspects such as inter-laboratory studies, digestion strategy, trapping column, and multi-level analysis. The shift from an offline to an online workflow reduces sample processing artifacts, analytical variability, analysis time, and the labor required for data acquisition. Over the past few years, this technique has demonstrated sufficient maturity for application across a diverse range of complex products. Moreover, there is potential for this strategy to evolve into an integrated process analytical technology tool for the real-time monitoring of monoclonal antibody quality. This review also identifies emerging trends, including its application to new modalities, the possibility of evaluating biological activity within the mD-LC set-up, and the consideration of multi-dimensional capillary electrophoresis as an alternative to mD-LC. As mD-LC-MS continues to evolve and integrate emerging trends, it holds the potential to shape the next generation of analytical tools, offering exciting possibilities for enhanced characterization and monitoring of complex biopharmaceutical products.

Cryogen-free 400-MHz nuclear magnetic resonance spectrometer as a versatile tool for pharmaceutical process analytical technology.

The discovery of new ceramic materials containing Ba-La-Cu oxides in 1986 that exhibited superconducting properties at high temperatures in the range of 35 K or higher, recognized with the Nobel Prize in Physics in 1987, opened a new world of opportunities for nuclear magnetic resonance (NMRs) and magnetic resonance imaging (MRIs) to move away from liquid cryogens. This discovery expands the application of high temperature superconducting (HTS) materials to fields beyond the chemical and medical industries, including electrical power grids, energy, and aerospace. The prototype 400-MHz cryofree HTS NMR spectrometer installed at Amgen's chemistry laboratory has been vital for a variety of applications such as structure analysis, reaction monitoring, and CASE-3D studies with RDCs. The spectrometer has been integrated with Amgen's chemistry and analytical workflows, providing pipeline project support in tandem with other Kinetic Analysis Platform technologies. The 400-MHz cryofree HTS NMR spectrometer, as the name implies, does not require liquid cryogens refills and has smaller footprint that facilitates installation into a chemistry laboratory fume hood, sharing the hood with a process chemistry reactor. Our evaluation of its performance for structural analysis with CASE-3D protocol and for reaction monitoring of Amgen's pipeline chemistry was successful. We envision that the HTS magnets would become part of the standard NMR and MRI spectrometers in the future. We believe that while the technology is being developed, there is room for all magnet options, including HTS, low temperature superconducting (LTS) magnets, and low field benchtop NMRs with permanent magnets, where utilization will be dependent on application type and costs.

Convolutional Neural Networks Guided Raman Spectroscopy as a Process Analytical Technology (PAT) Tool for Monitoring and Simultaneous Prediction of Monoclonal Antibody Charge Variants.

Charge related heterogeneities of monoclonal antibody (mAb) based therapeutic products are increasingly being considered as a critical quality attribute (CQA). They are typically estimated using analytical cation exchange chromatography (CEX), which is time consuming and not suitable for real time control. Raman spectroscopy coupled with artificial intelligence (AI) tools offers an opportunity for real time monitoring and control of charge variants. We present a process analytical technology (PAT) tool for on-line and real-time charge variant determination during process scale CEX based on Raman spectroscopy employing machine learning techniques. Raman spectra are collected from a reference library of samples with distribution of acidic, main, and basic species from 0-100% in a mAb concentration range of 0-20g/L generated from process-scale CEX. The performance of different machine learning techniques for spectral processing is compared for predicting different charge variant species. A convolutional neural network (CNN) based model was successfully calibrated for quantification of acidic species, main species, basic species, and total protein concentration with R2 values of 0.94, 0.99, 0.96 and 0.99, respectively, and the Root Mean Squared Error (RMSE) of 0.1846, 0.1627, and 0.1029g/L, respectively, and 0.2483g/L for the total protein concentration. We demonstrate that Raman spectroscopy combined with AI-ML frameworks can deliver rapid and accurate determination of product related impurities. This approach can be used for real time CEX pooling decisions in mAb production processes, thus enabling consistent charge variant profiles to be achieved.

Overview: flexible and versatile approach of quality by design & process analytical technology in industries

Quality by Design (QbD) is crucial to the creation of contemporary in pharmaceuticals, microbiology, biotechnology, product management etc. In order to build proactive, scientific, and risk-based processes and products, QbD helps and supports both the industry and the FDA. Instead of waiting until the final quality check of the finished product, it is founded on the idea of establishing quality from the very beginning of the process. A successful plan that lowers batch failures and recalls is finally provided by an efficient QbD approach, which offers insights and crucial upstream information throughout the development process. The purpose of this review is to provide an overview of the implementation of Quality by Design (QbD), its tools, elements, and techniques, the relevancy with various guidelines, and the use in present-day pharmaceutical. The IQ Consortium provides information on the current situation of process analytical technology (PAT) as it relates to the creation of active pharmaceutical ingredients (API) in branded pharmaceutical firms. The article gives concrete examples of why and how the pharmaceutical industry uses PAT tools in API development by using an API process pipeline. PAT can reduce personnel risks involved with sampling dangerous compounds for in-process testing and increase R&D efficiency. Although not all chemical processes or stages are easily suited to applying the features of the PAT toolbox, PAT permits accurate and speedy (real or near time) evaluations of processes that might involve compounds that are highly dangerous, transitory, or heterogeneous when necessary. The major regulatory agencies and the biotech sector have worked hard to assist the application of the ideas of Quality by Design (QbD) and Process Analytical Technology (PAT) over the past ten years, with varying degrees of success. Despite the fact that just one biotech therapy has received approval under the QbD paradigm thus far, the tools and methods associated with these two ideas are deeply ingrained in the work procedures of the majority of international pharmaceutical firms. This overview is mainly focused on the QbD and PAT's development in the first place. Second, give an overview of QbD and PAT implementation and point out any places where more contributions are possible.