Process Analytical Technology Approach Research Articles

Pressurized Hot Water Extraction as Green Technology for Natural Products as Key Technology with Regard to Hydrodistillation and Solid-Liquid Extraction.

Hydrodistillation and solid-liquid extraction with organic solvents or supercritical CO2 are standard technologies for natural product manufacturing. Within this technology, portfolio pressurized hot water technology is ranked as a green, sustainable, resilient, kosher and halal manufacturing process. Essential for sustainability is energy integration for heating and cooling the auxiliary water as well as product concentration without evaporation but with the aid of low energy consuming ultra- and nanofiltration membrane technology. The incorporation of modern unit operations, such as pressurized hot water extraction, along with inline measurement devices for Process Analytical Technology approaches, showcases a shift in traditional extraction processes. Traditional equipment and processes still dominate the manufacturing of plant extracts, yet leveraging innovative chemical process engineering methods offers promising avenues for the economic and ecological advancement of botanicals. Techniques such as modeling and process intensification with green technology hold potential in this regard. Digitalization and Industry 4.0 methodologies, including machine learning and artificial intelligence, play pivotal roles in sustaining natural product extraction manufacturing and can profoundly impact the future of human health.

Proof of a LOD prediction model with orthogonal PAT methods in continuous wet granulation and drying

Real-time monitoring of critical quality attributes, such as residual water in granules after drying which can be determined through loss-on-drying (LOD), during wet granulation and drying is essential in continuous manufacturing. Near-infrared (NIR) spectroscopy has been widely used as process analytical technology (PAT) for in-line LOD monitoring. This study aims to develop and apply a model for predicting the LOD based on process parameters. Additionally, the efficacy of an orthogonal PAT approach using NIR and mass balance (MB) for a vibrating fluidized bed dryer (VFBD) is demonstrated. An in-house-built, cost-effective NIR sensor was utilized for measurements and exhibited good correlation compared to standard method via infrared drying. The combination of NIR and MB, as independent methods, has demonstrated their applicability. A good correlation, with a Pearson r above 0.99, was observed for LOD up to 16 % (w/w). The use of an orthogonal PAT method mitigated the risk of false process adaption. In some experiments where the NIR sensor might have been covered by powder and therefore did not measure accurately, LOD monitoring via MB remained feasible. The developed model effectively predicted LOD or process parameters, resulting in an R2 of 0.882 and a RMSE of 0.475 between predicted and measured LOD using the standard method.

Fuzzy Set Qualitative methodology for identifying the Critical Process Parameters and Quality attributes in the manufacturing of Arogyavardhini Rasa

The traditional drug manufacturing process involves numerous qualitative attributes that directly impact product quality. The Process Analytical Technology approach considers that to enhance process control, identifying critical process parameters and critical quality attributes that affect the manufacturing process is very much necessary. The Ayurvedic drug manufacturing process is more driven by fuzzy qualitative attributes. The present study was executed to identify the Critical Process Parameters and Critical Quality Attributes in the manufacturing process of a herbo-mineral formulation, viz. Arogyavardhini Rasa. Fuzzy set Qualitative Comparative Analysis (fsQCA) methodology was adopted to observe and identify the critical parameters. The study was executed in three steps, viz. Data collection, Data arrangement, and Analysis. The raw data collected was arranged and analyzed in the software R studio using the package QCA in four steps, viz. Calibration, Analysis of Necessity and Sufficiency, Truth Table construction, and Minimization. The results obtained show that Size reduction, Mardana, and Drying are the identified Critical Process Parameters that, in combination, lead to the outcome, i.e., good product quality. Thus, this study proves that Fuzzy Set Qualitative Comparative Analysis can be used as an efficient tool for the identification and measurement of the Critical Process Parameters that affect the Critical Quality Attributes and, thereby, the product quality in the manufacturing of Arogyavardhini Rasa.

Optimization of radial extrusion and pellet coating processes using PAT approaches

FDA's initiative Pharmaceutical CGMPs for the 21st century opened the door for introduction of several risk based approaches in pharmaceutical industry. One significant advancement that has emerged is the implementation of process analytical technology (PAT), which has opened doors for understanding and controlling complex technological processes. Two such processes, radial extrusion and pellet coating, offer a solid foundation for the application of PAT tools due to their numerous critical process parameters. The aim of the first part of the study was to optimize the neutral pellet production to produce the pellets with properties desired for successful film coating using design of experiments (DoE). In the second part the optimized pellets underwent film coating and the coating quantity was predicted in real or near real-time using in-line and at-line NIR probes and the performance of both probes was compared.The desired properties of the pellets, narrow particle size distribution, high sphericity and high process yield, were successfully achieved. Models for film coating quantity prediction using in-line and at-line NIR probe were successfully calibrated and tested by coating two additional batches. Despite the limited sample size for model calibration, at-line NIR exhibited excellent prediction performance and enabled accurate determination of process end-point. The coating quantity determined by UV/VIS spectroscopy in both test batches deviated by less than 2.0 % from the target value. However, the in-line NIR probe, primarily due to its inferior spectral resolution, displayed a slightly lower quality of the calibrated model and notable overprediction for the tested batches.

Green Manufacturing for Herbal Remedies with Advanced Pharmaceutical Technology.

Herbal remedies are in most cases still manufactured with traditional equipment installations and processes. Innovative chemical process engineering methods such as modeling and process intensification with green technology could contribute to the economic and ecologic future of those botanicals. The integration of modern unit operations such as water-based pressurized hot water extraction and inline measurement devices for process analytical technology approaches in traditional extraction processes is exemplified. The regulatory concept is based on the quality-by-design demand for autonomous feed-based recipe operation with the aid of digital twins within advanced process control. This may include real-time release testing to the automatic cleaning of validation issues. Digitalization and Industry 4.0 methods, including machine learning and artificial intelligence, are capable of keeping natural product extraction manufacturing and can contribute significantly to the future of human health.

Process Characterization of the Transesterification of Rapeseed Oil to Biodiesel Using Design of Experiments and Infrared Spectroscopy

For optimization of production processes and product quality, often knowledge of the factors influencing the process outcome is compulsory. Thus, process analytical technology (PAT) that allows deeper insight into the process and results in a mathematical description of the process behavior as a simple function based on the most important process factors can help to achieve higher production efficiency and quality. The present study aims at characterizing a well-known industrial process, the transesterification reaction of rapeseed oil with methanol to produce fatty acid methyl esters (FAME) for usage as biodiesel in a continuous micro reactor set-up. To this end, a design of experiment approach is applied, where the effects of two process factors, the molar ratio and the total flow rate of the reactants, are investigated. The optimized process target response is the FAME mass fraction in the purified nonpolar phase of the product as a measure of reaction yield. The quantification is performed using attenuated total reflection infrared spectroscopy in combination with partial least squares regression. The data retrieved during the conduction of the DoE experimental plan were used for statistical analysis. A non-linear model indicating a synergistic interaction between the studied factors describes the reactor behavior with a high coefficient of determination (R²) of 0.9608. Thus, we applied a PAT approach to generate further insight into this established industrial process.

Process Analytical Technology (PAT) in Quality Assurance: A Detailed Review

Process Analytical Technology (PAT) is a proactive initiative published by the Food and Drug Administration so as to overcome the conventional way of batch testing. As per the documented guideline it can be stated as a system for designing, analyzing, and controlling pharmaceutical manufacturing through the timely measurement of critical quality and performance parameters. PAT is a quality driven approach with innovative, strategic and rapid systems, so as to clearly understand, predict, manipulate, control and refine manufacturing processes. Owing to its multidimensional applications, process analysis can be carried out even in the most critical processes, like crystallization, by the on-line technique.PAT is one of the prime objectives stressed in the Initiative for Pharmaceutical CGMPs for the 21st Century published by the Food and Drug Administration. The chief motive of this dynamic approach is to carry out measurements on raw materials and in the in process materials or process parameters with tight controls, with a prime goal to enhance final product quality and reduce the chances of error or default/defect. The prime inventiveness of the PAT initiative is to focus on building quality inside the product and the entire manufacturing processes, in addition to continuous process improvement. The adoption of PAT approach can provide a plethora of benefits to the pharmaceutical industry by enhancing product quality while providing supercilious asset utilization and niche financial value. PAT bestows better insight of raw materials, by characterizing it physically and chemically, detailed understanding of manufacturing parameters, all of which collectively decide the fate of the quality and appeal of the final product. Unlikely to the traditional approach of testing the product at its terminal stage, PAT is a dynamic approach to keeping an eye on the manufacturing and other related processes on a continuous basis compared to a discrete one, and keeps a strict check at all stages of production. Hence this detailed review will stress on the importance of PAT and its overall conceptualization, which shall be indeed propitious for furnishing an integrated systems approach for quality design, process analyses, understanding and control, continuous improvement, knowledge and risk-based management within the FDA 21st century framework of Good manufacturing initiative and will be a useful guide to the industry and academia personnel for better understanding of this approach. Additionally it also highlights the unique synergy of Quality by Design with PAT for establishing an in depth understanding of the manufacturing process.

A FT-NIR Process Analytical Technology Approach for Milk Renneting Control

The study proposes a process analytical technology (PAT) approach for the control of milk coagulation through near infrared spectroscopy (NIRS), computing multivariate statistical process control (MSPC) charts, based on principal component analysis (PCA). Reconstituted skimmed milk and commercial pasteurized skimmed milk were mixed at two different ratios (60:40 and 40:60). Each mix ratio was prepared in six replicates and used for coagulation trials, monitored by fundamental rheology, as a reference method, and NIRS by inserting a probe directly in the coagulation vat and collecting spectra at two different acquisition times, i.e., 60 s or 10 s. Furthermore, three failure coagulation trials were performed, deliberately changing temperature or rennet and CaCl2 concentration. The comparison with fundamental rheology results confirmed the effectiveness of NIRS to monitor milk renneting. The reduced spectral acquisition time (10 s) showed data highly correlated (r > 0.99) to those acquired with longer acquisition time. The developed decision trees, based on PC1 scores and T2 MSPC charts, confirmed the suitability of the proposed approach for the prediction of coagulation times and for the detection of possible failures. In conclusion, the work provides a robust but simple PAT approach to assist cheesemakers in monitoring the coagulation step in real-time.

Process monitoring of polysaccharide deketalization for vaccine bioconjugation development using in situ analytical methodology

Pneumococcal conjugate vaccines (PCVs) are formed by bioconjugation of a carrier protein to the purified capsular polysaccharide (Ps) from multiple serological strains of Streptococcus pneumoniae. The associated bioconjugation chemistry relies on initial selective modifications to the Ps backbone structure. Among these modifications, removal of a ketal functional group, termed deketalization, is one that is important for pharmaceutical PCV production. Herein, we report a process monitoring investigation into the deketalization of a polysaccharide relevant to PCV process development. We have applied process analytical technology (PAT) for in situ process monitoring to study the deketalization reaction in real time. We find that in situ FTIR spectroscopy elucidates multiple classes of reaction kinetics, one of which correlates strongly with the deketalization reaction of interest. This PAT approach to real time reaction monitoring offers the possibility of improved process monitoring in the pharmaceutical production of PCVs. To our knowledge, this report represents the first PAT investigation into Ps deketalization. Our findings suggest that broader application of PAT to the chemical modifications associated with PCV bioconjugation, as well as other pharmaceutically relevant bioconjugation processes, carries the power to enhance process understanding, control, and efficiency through real time process monitoring.

Fast and Flexible mRNA Vaccine Manufacturing as a Solution to Pandemic Situations by Adopting Chemical Engineering Good Practice—Continuous Autonomous Operation in Stainless Steel Equipment Concepts

SARS-COVID-19 vaccine supply for the total worldwide population has a bottleneck in manufacturing capacity. Assessment of existing messenger ribonucleic acid (mRNA) vaccine processing shows a need for digital twins enabled by process analytical technology approaches in order to improve process transfer for manufacturing capacity multiplication, a reduction in out-of-specification batch failures, qualified personal training for faster validation and efficient operation, optimal utilization of scarce buffers and chemicals and speed-up of product release by continuous manufacturing. In this work, three manufacturing concepts for mRNA-based vaccines are evaluated: Batch, full-continuous and semi-continuous. Technical transfer from batch single-use to semi-continuous stainless-steel, i.e., plasmid deoxyribonucleic acid (pDNA) in batch and mRNA in continuous operation mode, is recommended, in order to gain: faster plant commissioning and start-up times of about 8–12 months and a rise in dose number by a factor of about 30 per year, with almost identical efforts in capital expenditures (CAPEX) and personnel resources, which are the dominant bottlenecks at the moment, at about 25% lower operating expenses (OPEX). Consumables are also reduceable by a factor of 6 as outcome of this study. Further optimization potential is seen at consequent digital twin and PAT (Process Analytical Technology) concept integration as key-enabling technologies towards autonomous operation including real-time release-testing.

Development of a Robust Control Strategy for Fixed-Dose Combination Bilayer Tablets with Integrated Quality by Design, Statistical, and Process Analytical Technology Approach.

Control strategy and quality by design (QbD) are widely used to develop pharmaceutical products and improve drug quality; however, studies on fixed-dose combination (FDC) bilayer tablets are limited. In this study, the bilayer tablet consisted of high-dose metformin HCl in a sustained-release layer and low-dose dapagliflozin l-proline in an immediate-release layer. The formulation and process of each layer were optimized using the QbD approach. A d-optimal mixture design and response surface design were applied to optimize critical material attributes and critical process parameters, respectively. The robust design space was developed using Monte Carlo simulations by evaluating the risk of uncertainty in the model predictions. Multivariate analysis showed that there were significant correlations among impeller speed, massing time, granule bulk density, and dissolution in the metformin HCl layer, and among roller pressure, ribbon density, and dissolution in the dapagliflozin l-proline layer. Process analytical technology (PAT) was used with in–line transmittance near-infrared spectroscopy to confirm the bulk and ribbon densities of the optimized bilayer tablet. Moreover, the in vitro drug release and in vivo pharmacokinetic studies showed that the optimized test drug was bioequivalent to the reference drug. This study suggested that integrated QbD, statistical, and PAT approaches can develop a robust control strategy for FDC bilayer tablets by implementing real-time release testing based on the relationships among various variables.

Advanced Process Analytical Technology in Combination with Process Modeling for Endpoint and Model Parameter Determination in Lyophilization Process Design and Optimization

Lyophilization is widely used in the preservation of thermolabile products. The main shortcoming is the long processing time. Lyophilization processes are mostly based on a recipe that is not changed, but, with the Quality by Design (QbD) approach and use of Process Analytical Technology (PAT), the process duration can be optimized for maximum productivity while ensuring product safety. In this work, an advanced PAT approach is used for the endpoint determination of primary drying. Manometric temperature measurement (MTM) and comparative pressure measurement are used to determine the endpoint of the batch while a modeling approach is outlined that is able to calculate the endpoint of every vial in the batch. This approach can be used for process development, control and optimization.

Digital Twin of mRNA-Based SARS-COVID-19 Vaccine Manufacturing towards Autonomous Operation for Improvements in Speed, Scale, Robustness, Flexibility and Real-Time Release Testing

Supplying SARS-COVID-19 vaccines in quantities to meet global demand has a bottleneck in manufacturing capacity. Assessment of existing mRNA (messenger ribonucleic acid) vaccine processing shows the need for digital twins enabled by process analytical technology approaches to improve process transfers for manufacturing capacity multiplication, reduction of out-of-specification batch failures, qualified personnel training for faster validation and efficient operation, optimal utilization of scarce buffers and chemicals, and faster product release. A digital twin of the total pDNA (plasmid deoxyribonucleic acid) to mRNA process is proposed. In addition, a first feasibility of multisensory process analytical technology (PAT) is shown. Process performance characteristics are derived as results and evaluated regarding manufacturing technology bottlenecks. Potential improvements could be pointed out such as dilution reduction in lysis, and potential reduction of necessary chromatography steps. 1 g pDNA may lead to about 30 g mRNA. This shifts the bottleneck towards the mRNA processing step, which points out co-transcriptional capping as a preferred option to reduce the number of purification steps. Purity demands are fulfilled by a combination of mixed-mode and reversed-phase chromatography as established unit operations on a higher industrial readiness level than e.g., precipitation and ethanol-chloroform extraction. As a final step, lyophilization was chosen for stability, storage and transportation logistics. Alternative process units like UF/DF (ultra-/diafiltration) integration would allow the adjustment of final concentration and buffer composition before lipid-nano particle (LNP) formulation. The complete digital twin is proposed for further validation in manufacturing scale and utilization in process optimization and manufacturing operations. The first PAT results should be followed by detailed investigation of different batches and processing steps in order to implement this strategy for process control and reliable, efficient operation.

Control and Monitoring of Milk Renneting Using FT-NIR Spectroscopy as a Process Analytical Technology Tool.

Failures in milk coagulation during cheese manufacturing can lead to decreased yield, anomalous behaviour of cheese during storage, significant impact on cheese quality and process wastes. This study proposes a Process Analytical Technology approach based on FT-NIR spectroscopy for milk renneting control during cheese manufacturing. Multivariate Curve Resolution optimized by Alternating Least Squares (MCR-ALS) was used for data analysis and development of Multivariate Statistical Process Control (MSPC) charts. Fifteen renneting batches were set up varying temperature (30, 35, 40 °C), milk pH (6.3, 6.5, 6.7), and fat content (0.1, 2.55, 5 g/100 mL). Three failure batches were also considered. The MCR-ALS models well described the coagulation processes (explained variance ≥99.93%; lack of fit <0.63%; standard deviation of the residuals <0.0067). The three identified MCR-ALS profiles described the main renneting phases. Different shapes and timing of concentration profiles were related to changes in temperature, milk pH, and fat content. The innovative implementation of MSPC charts based on T2 and Q statistics allowed the detection of coagulation failures from the initial phases of the process.

Development of a PAT tool for monitoring the Wurster coater performance

Real-time process analytical technology (PAT) is proposed as an effective approach for monitoring the performance of a Wurster coater. The coater was used for coating of 0.78 mm pharmaceutical pellets. The coating solution consisted of Hydroxypropyl methylcellulose/Poly ethylene glycol. During the coating process, small amounts of pellets (∼2 g) were sampled at 10 min. intervals and the pressure fluctuations were recorded at the same time. The signals were analyzed using the wavelet transform (WT) and decomposed into different sub-signals. Principal component analysis (PCA) was employed to the energies of these sub-signals, whose outliers were eliminated using the Mahalanobis distance method. The reference coating thickness data were obtained via spectrophotometry during the coating process. The partial least squares (PLS) regression was incorporated with the PCA for the development of a model for prediction of the coating thickness. The PLS regression revealed that the pressure fluctuations can be used to evaluate the thickness with a good precision. This study demonstrated the applicability of pressure fluctuations for the prediction of the coating thickness. This method can be regarded as a new robust, fast and non-intrusive PAT approach for monitoring the coating process which can be easily used by engineers and practitioners.

Accelerating Biologics Manufacturing by Modeling or: Is Approval under the QbD and PAT Approaches Demanded by Authorities Acceptable without a Digital-Twin?

Innovative biologics, including cell therapeutics, virus-like particles, exosomes, recombinant proteins, and peptides, seem likely to substitute monoclonal antibodies as the main therapeutic entities in manufacturing over the next decades. This molecular variety causes a growing need for a general change of methods as well as mindset in the process development stage, as there are no platform processes available such as those for monoclonal antibodies. Moreover, market competitiveness demands hyper-intensified processes, including accelerated decisions toward batch or continuous operation of dedicated modular plant concepts. This indicates gaps in process comprehension, when operation windows need to be run at the edges of optimization. In this editorial, the authors review and assess potential methods and begin discussing possible solutions throughout the workflow, from process development through piloting to manufacturing operation from their point of view and experience. Especially, the state-of-the-art for modeling in red biotechnology is assessed, clarifying differences and applications of statistical, rigorous physical-chemical based models as well as cost modeling. “Digital-twins” are described and efforts vs. benefits for new applications exemplified, including the regulation-demanded QbD (quality by design) and PAT (process analytical technology) approaches towards digitalization or industry 4.0 based on advanced process control strategies. Finally, an analysis of the obstacles and possible solutions for any successful and efficient industrialization of innovative methods from process development, through piloting to manufacturing, results in some recommendations. A central question therefore requires attention: Considering that QbD and PAT have been required by authorities since 2004, can any biologic manufacturing process be approved by the regulatory agencies without being modeled by a “digital-twin” as part of the filing documentation?

A study on the applicability of multiple process analysers in the production of coated pellets

Process analytical technology (PAT) has become an important factor in design, analysis and control of complex technological processes. In the present study, pellet coating process was monitored using four different PAT approaches, i.e. near-infrared (NIR) spectroscopy, Raman spectroscopy, in-line image analysis, and spatial filtering technique (SFT). Robustness and accuracy of a novel in-line image analyser was studied during the active ingredient coating process on the pilot scale in the first part of the study. In the second part, multivariate model for in-line monitoring of critical quality attributes, such as moisture content and coating thickness, was calibrated with off-line NIR measurements of laboratory scale samples. The quality of the model was evaluated during the pilot scale batches. In the last part of the study, applicability of two different Raman process analysers for real time moisture content and coating quantity determination was investigated extensively. In addition, Raman spectral data was correlated with the in-line SFT measurements. The results and their interpretations present novel aspects of multiple process analysing techniques, which could help improve pellet coating process monitoring and control. Moreover, presented multivariate model calibration approaches could significantly reduce time, costs, and effort needed to implement PAT into the pharmaceutical industry.

Process analytical technology for cheese manufacture

SummaryRecent research on the development and application of process analytical technology (PAT) for cheese manufacture is reviewed in this article. PAT is a framework for innovative process manufacturing and quality assurance, which has been widely investigated for dairy processing applications, where particular processing challenges arise due to the variations in the physiochemical properties of milk. Cheese manufacturers are increasingly considering the adoption of a PAT approach to facilitate manufacture of cheese with enhanced product quality, safety and process efficiency. However, to date adoption of PAT in the dairy industry has been limited due to challenges associated with development and validation of calibration models, instrument variability, sanitary design and compatibility with processing environments. New technical developments in PAT tools, advances in chemometric modelling, robust data management tools and improved understanding of critical product and process parameters will facilitate further adoption of a PAT approach in cheese manufacture.

At-line validation of a process analytical technology approach for quality control of melamine-urea-formaldehyde resin in composite wood-panel production using near infrared spectroscopy.

The reactivity of melamine-urea-formaldehyde resins is of key importance in the manufacture of engineered wood products such as medium density fibreboard (MDF) and other wood composite products. Often the MDF manufacturing plant has little available information on the resin reactivity other than details of the resin specification at the time of batch manufacture, which often occurs off-site at a third-party resin plant. Often too, fresh resin on delivery at the MDF plant is mixed with variable volume of aged resin in storage tanks, thereby rendering any specification of the fresh resin batch obsolete. It is therefore highly desirable to develop a real-time, at-line or on-line, process analytical technology to monitor the quality of the resin prior to MDF panel manufacture. Near infrared (NIR) spectroscopy has been calibrated against standard quality methods and against 13C nuclear magnetic resonance (NMR) measures of molecular composition in order to provide at-line process analytical technology (PAT), to monitor the resin quality, particularly the formaldehyde content of the resin. At-line determination of formaldehyde content in the resin was made possible using a six-factor calibration with an R 2(cal) value of 0.973, and R 2(CV) value of 0.929 and a root-mean-square error of cross-validation of 0.01. This calibration was then used to generate control charts of formaldehyde content at regular four-hourly periods during MDF panel manufacture in a commercial MDF manufacturing plant.

Quality by design (QbD), Process Analytical Technology (PAT), and design of experiment applied to the development of multifunctional sunscreens

Multifunctional formulations are of great importance to ensure better skin protection from harm caused by ultraviolet radiation (UV). Despite the advantages of Quality by Design and Process Analytical Technology approaches to the development and optimization of new products, we found in the literature only a few studies concerning their applications in cosmetic product industry. Thus, in this research work, we applied the QbD and PAT approaches to the development of multifunctional sunscreens containing bemotrizinol, ethylhexyl triazone, and ferulic acid. In addition, UV transmittance method was applied to assess qualitative and quantitative critical quality attributes of sunscreens using chemometrics analyses. Linear discriminant analysis allowed classifying unknown formulations, which is useful for investigation of counterfeit and adulteration. Simultaneous quantification of ethylhexyl triazone, bemotrizinol, and ferulic acid presented at the formulations was performed using PLS regression. This design allowed us to verify the compounds in isolation and in combination and to prove that the antioxidant action of ferulic acid as well as the sunscreen actions, since the presence of this component increased 90% of antioxidant activity in vitro.