Process Analytical Technology Research Articles

Progress on the process analysis technology for the pharmaceutical hot melt extrusion

Progress on the process analysis technology for the pharmaceutical hot melt extrusion

PROCESS ANALYTICAL TECHNOLOGY (PAT) IN PHARMACEUTICAL MANUFACTURING: A REVIEW

Process Analytical Technology (PAT) is a key concept in pharmaceutical manufacturing that involves the use of analytical techniques to monitor and control manufacturing processes in real-time. This review aims to provide an overview of PAT in pharmaceutical manufacturing, including its principles, applications, and benefits.

Real-Time Auto Controlling of Viable Cell Density in Perfusion Cultivation Aided by In-Line Dielectric Spectroscopy With Segmented Adaptive PLS Model.

Serving as a dedicated process analytical technology (PAT) tool for biomass monitoring and control, the capacitance probe, or dielectric spectroscopy, is showing great potential in robust pharmaceutical manufacturing, especially with the growing interest in integrated continuous bioprocessing. Despite its potential, challenges still exist in terms of its accuracy and applicability, particularly when it is used to monitor cells during stationary and decline phases. In this study, data pre-processing methods were first evaluated through cross-validation, where the first-order derivative emerged as the most effective method to diminish variability in prediction accuracy across different training datasets. Subsequently, a segmented adaptive partial least squares (SA-PLS) model was developed, and its accuracy and universality were demonstrated through several validation studies using different clones and culture processes. Furthermore, a real-time viable cell density (VCD) auto-control system in perfusion culture was established, where the VCD was maintained around the target with notable precision and robustness. This model enhanced the monitoring capabilities of capacitance-based PAT tools throughout the cultivation, expanded their application in cell-specific automatic control strategies, and contributed vitally to the advancement of continuous manufacturing paradigms.

Challenges in developing a Process Analytical Technology (PAT)‐based verification of UV‐C treatment of milk

Ultraviolet radiation (UV‐C) is building a strong reputation as a non‐thermal processing method in the food industry which inactivates spoilage and pathogenic microbes through DNA damage. Approved under Regulation (EC) No 258/97, UV‐treated milk is deemed safe, with EFSA approving a dose of 1045 J/L post‐pasteurisation, increasing vitamin D3 content and shelf life to 21 days. However, current verification relies solely on reactor process conditions, which may fail. Therefore, a verification method, akin to pasteurisation's alkaline phosphatase test, is essential. A process analytical technology sensor, analysing photooxidation‐induced spectral changes, could ensure treatment efficacy. However, developing such sensors faces challenges from milk's optical properties (low UV transmission) and natural variability. Developing such sensor could pave the way for standalone UV‐C treatment as a future environmentally friendly alternative. The objective of this study is to systematically document the challenges encountered to date in the investigation of this novel verification methodology.

Integrated SegFlow, µSIA, and UPLC for Online Sialic Acid Quantitation of Glycoproteins Directly from Bioreactors.

This study emphasizes the critical importance of closely monitoring and controlling the sialic acid content in therapeutic glycoproteins, including EPO, interferon-γ, Orencia, Enbrel, and others, as the level of sialylation directly impacts their pharmacokinetics (PK), immunogenicity, potency, and overall clinical performance due to its influence on protein clearance via hepatic asialoglycoprotein receptors (ASGPR). The ASGPR recognizes and binds to glycoproteins exposed to terminal galactose or N-acetylgalactosamine residues, leading to receptor-mediated endocytosis. Recent studies have demonstrated that sialylation of O-linked glycan plays a role in protecting against macrophage galactose lectin (MGL)-mediated clearance. In addition to the impact on serum half-life, sialylation can influence other clinical outcomes, including immunogenicity, potency, and cytotoxicity. Therefore, the level of sialic acid is a critical quality attribute (CQA), and monitoring and regulating sialylation has become a regulatory requirement to ensure desired clinical performance. To achieve consistent levels of sialic acid-to-protein ratio, the time of upstream harvest and conductivity of downstream wash buffers must be tightly regulated based on the sialic acid content. Therefore, the utilization of process analytical technology (PAT) tools for generating real-time or near-real-time sialic acid content is a business-critical requirement. This work demonstrates the utility of an integrated PAT system for near real-time online sialic acid measurements. The system consists of a micro-sequential injection analyzer (µSIA) interfaced with SegFlow and an ultra performance liquid chromatography (UPLC). The fully automated architecture exemplifies the execution of online sampling, automatic sample preparation, and subsequent online UPLC analysis. This carefully orchestrated PAT framework effectively supports the requirements of QbD-driven continuous bioprocessing.

Enhancing Patient-Centric Drug Development: Coupling Hot Melt Extrusion with Fused Deposition Modeling and Pressure-Assisted Microsyringe Additive Manufacturing Platforms with Quality by Design.

In recent years, with the increasing patient population, the need for complex and patient-centric medications has increased enormously. Traditional manufacturing techniques such as direct blending, high shear granulation, and dry granulation can be used to develop simple solid oral medications. However, it is well known that "one size fits all" is not true for pharmaceutical medicines. Depending on the age, sex, and disease state, each patient might need a different dose, combination of medicines, and drug release pattern from the medications. By employing traditional practices, developing patient-centric medications remains challenging and unaddressed. Over the last few years, much research has been conducted exploring various additive manufacturing techniques for developing on-demand, complex, and patient-centric medications. Among all the techniques, nozzle-based additive manufacturing platforms such as pressure-assisted microsyringe (PAM) and fused deposition modeling (FDM) have been investigated thoroughly to develop various medications. Both nozzle-based techniques involve the application of thermal energy. However, PAM can also be operated under ambient conditions to process semi-solid materials. Nozzle-based techniques can also be paired with the hot melt extrusion (HME) process for establishing a continuous manufacturing platform by employing various in-line process analytical technology (PAT) tools for monitoring critical process parameters (CPPs) and critical material attributes (CMAs) for delivering safe, efficacious, and quality medications to the patient population without compromising critical quality attributes (CQAs). This review covers an in-depth discussion of various critical parameters and their influence on product quality, along with a note on the continuous manufacturing process, quality by design, and future perspectives.

Integrated Optics Waveguides and Mesoporous Oxides for the Monitoring of Volatile Organic Compound Traces in the Mid-Infrared.

Volatile organic compounds (VOCs) are an ever-growing hazard for health and environment due to their increased emissions and accumulation in the air. Quantum cascade laser-based infrared (QCL-IR) sensors hold significant promise for gas monitoring, thanks to their compact, rugged design, high laser intensity, and high molecule-specific detection capabilities within the mid-infrared spectrum's fingerprint region. In this work, tunable external cavity QCLs were complemented by an innovative germanium-on-silicon integrated optics waveguide sensing platform with integrated microlenses for efficient backside optical interfacing for the tunable laser spectrometer. The waveguide chip was coated with a mesoporous silica coating, thereby increasing the signal by adsorptive enhancement of VOCs while at the same time limiting water vapor interferences. Different least square fitting methods were explored to deconvolute the resulting spectra, showing subparts-per-million by volume (sub-ppmv) limits of detection and enrichment factors of up to 22 000 while keeping the footprint of the setup small (29 × 23 × 11 cm³). Finally, a use-case simulation for the continuous detection of VOCs in a process analytical technology environment confirmed the high potential of the technique for the monitoring of contaminants. By successfully demonstrating the use of photonic waveguides for the monitoring of VOCs, this work offers a promising avenue for the further development of fully integrated sensors on a chip.

Optimizing Industrial Solid-Phase Peptide Synthesis: Integration of Raman Spectroscopy as Process Analytical Technology

Optimizing Industrial Solid-Phase Peptide Synthesis: Integration of Raman Spectroscopy as Process Analytical Technology

Research on manufacturing process control and analysis technology of civil aircraft

Abstract The manufacturing stage is the core link of product reliability, and the manufacturing process control is the bridge between design reliability and product reliability. In the manufacturing process, the influence of various factors on the formation of product reliability is considered and controlled. Meanwhile, the process failure mode and impact analysis (PEMEA) method is introduced to clarify its principle and method. The key processes of the manufacturing and assembly process are identified by taking the RAT system of certain aircraft as an example. Effective measures are proposed to improve the manufacturing and assembly process, ensure the manufacturing reliability of products, and provide strong support for improving the quality and reliability of civil aircraft.

Design of a Pharmaceutical 3D Printer Using Quality-by-Design Approach

PurposePharmaceutical three-dimensional (3D) printing is an innovative production technique which enables the manufacturing of personalized medicine at the point-of-care. A reliable 3D printer is paramount for the successful implementation in clinical practice. In this paper, the design strategy of a pharmaceutical semi-solid extrusion 3D printer is described, where the concept of quality-by-design is applied.MethodsThe technical design stages are divided in the conceptual design and detailed design stage. The minimal viable product, critical process parameters and implemented control strategies were defined.ResultsThe critical process parameter with the highest impact is the temperature of the cartridge during preheating, i.e. prior to the production process. The temperature is controlled with an accurate thermistor, closed feedback loop and thermal isolation. The temperature can be monitored at all times using the graphical user interface and there is an audit trail using the logging system. Software was developed conforming to GAMP5.ConclusionsBuild-in control strategies in the design of the pharmaceutical 3D printer can mitigate risks during the production process of personalized medicine. The regulatory landscape surrounding 3D-printed drug products remains challenging. By using this design approach, relevant guidelines were taken into account during the design of a pharmaceutical 3D printer. Future development of the 3D printer should include the incorporation of process analytical technology tools and upscaling of feedstock production to further support the implementation of personalized medicine 3D-printed at the point-of-care.

Quantification of Amlodipine Maleate Content in Amorphous Solid Dispersions Produced by Fluidized Bed Granulation Using Process Analytical Technology Tools

Background: Active pharmaceutical ingredient (API) content is a critical quality attribute (CQA) of amorphous solid dispersions (ASDs) prepared by spraying a solution of APIs and polymers onto the excipients in fluid bed granulator. This study presents four methods for quantifying API content during ASD preparation. Methods: Raman and three near-infrared (NIR) process analysers were utilized to develop methods for API quantification. Four partial least squares (PLS) models were developed using measurements from three granulation batches, with an additional batch used to evaluate model predictability. Models performance was assessed using metrics such as root mean square error of prediction (RMSEP), root mean square error of cross-validation (RMSECV), residual prediction deviation (RPD), and others. Results: Off-line and at-line NIR models were identified as suitable for process control applications. Additionally, at-line Raman measurements effectively predicted the endpoint of the spraying phase. Conclusions: To the best of authors’ knowledge, this is the first study focused on monitoring API content during fluidized bed granulation (FBG) used for ASD preparation. The findings provide novel insights into the application of Raman and NIR process analysers with PLS modelling for monitoring and controlling ASD preparation processes.

Using in-line measurement and statistical analyses to predict tablet properties compressed using a Styl'One compaction simulator: A high shear wet granulation study.

High shear wet granulation (HSWG) is widely used in tablet manufacturing mainly because of its advantages in improving flowability, powder handling, process run time, size distribution, and preventing segregation. In-line process analytical technology measurements are essential in capturing detailed particle dynamics and presenting real-time data to uncover the complexity of the HSWG process and ultimately for process control. This study is to find relationships between Lenterra in-line measurements and granule properties and tablet properties. The Styl'One Evolution compaction simulator was used to produce tablets that mimic an industrial rotary tablet press, which is different from the Gamlen used in our previous study. Furthermore, this research provided an understanding of the granule growth mechanisms during the granulation process, revealing that an induction granule growth mechanism occurs. This is specific to the material and process conditions studied. The model developed using data from a Gamlen tabletting press demonstrated high predictability for data generated using the Styl'One Evolution compaction simulator, with an R2 value of 0.9535 and a RMSE of 0.4040 MPa. This finding highlights the ability of the model to predict tablet tensile strength independently of the compaction machine used, suggesting industrial-scale applications. The findings of this research provide substantial advances in understanding and monitoring the granulation process, with promising implications for scalable industrial processes.

Comminution technologies in the pharmaceutical industry: a comprehensive review with recent advances

Abstract Comminution processes play a pivotal role in diverse applications, ranging from food processing, to mining and materials engineering. The pharmaceutical industry is no exception, with an increased focus on particle engineering to overcome the growing challenges related to the complexity of new drug molecules such as poor water solubility or stability issues. Additionally, the preparation of powders for pulmonary, transdermal, topical, ophthalmic, oral or parenteral administration often requires specific particle size requirements. Thus, milling technologies offer an excellent option for controlling particle size, improving the stability, dissolution, absorption rate, and bioavailability of poorly water-soluble drugs. They also contribute to enhancing pharmaceutical forms and overall product performance. This review highlights the different types of technologies used for comminution, the respective advantages and drawbacks, as well as connected topics including feed material properties, analytical techniques, process analytical technology, process safety, new top-down technologies and key information to consider when selecting a technology. Thus, an in-depth approach of comminution in the pharmaceutical industry is presented. This compilation serves as a source of comprehensive information for those who decide to initiate research projects in this field, or to update their existing literature knowledge and understanding.

Modern Approaches to Quality Assurance of Drug Formulation

Development of the pharmaceutical science have gone through amazing change over the past two decades, and modern technologies continue to transform QA process in drug formulation. considering the importance of ensuring the quality, safety, and efficacy of pharmaceutical products, it is now essential that the evolution of QA methodologies and techniques, especially these accelerate through automation analytics and regulatory frameworks, become important to this end. This review highlight the convince in QA of drug formulation, with more focus on latest trends such as "quality by design", process analytical technology and advance analytical techniques like spectroscopy, chemometrics, and artificial intelligence.

(Invited) Integrating Molecular Recognition Nanosensors with Bioprocesses for Real-Time, Non-Destructive, and Multivariate Process Analytics

As biological and chemical production processes become more sophisticated and evolve in various forms, there is a critical need for the development of new biochemical analysis systems capable of qualifying the versatile synthesis variables and product quality at each site. Despite traditional instrumental analyses including spectroscopy, mass spectrometry, or chromatography, being utilized as the gold standard providing precision, they are not suitable for smart process analytical technology (PAT) for future chemical and biological manufacturing, which should enable real-time, non-destructive, and on-site multivariate process monitoring without complicated sample preparations. Many optoelectronic sensors based on nanotechnology have been showing potential for this with very high sensitivity and selectivity, yet they have not been integrated into actual PAT systems due to abscence of a form factor design, sensor materials integration, and data processing techniques.In this talk, we will introduce our recent approach on a label-free and multivariate real-time sensor system based on a unique molecular recognition array for smart biological process monitoring. We designed a wide library of 3D corona interfaces of near-Infrared (nIR) fluorescent single-walled carbon nanotube (SWCNT) transducers for the multivariate biochemical molecules as process quality attributes. We integrated this nIR fluorescent sensor array with a new mobile form factor based on microfluidics and fiber optics, and developed a remote nano-biophotonic signal transducing technique. With this, we can analyze biological production samples online, allowing for the simultaneous extraction of rich molecular data in real-time wihtout any sample preparation and labeling steps. We will introduce two representative molecular recognition based PAT systems: i) physicochemical heterogeneity analysis of therapeutic cells production for reliable treatment efficacy, and ii) Chinese hamster ovary (CHO) cell based bioreactor for a high-performance antibody production.

MXene-Graphene Oxide Heterostructured Films for Enhanced Metasurface Plasmonic Biosensing in Continuous Glucose Monitoring.

Non-invasive biosensors have attracted attention for their potential to obtain continuous, real-time physiological information through measurements of biochemical markers, such as one of the most important-glucose, in biological fluids. Although some optical sensing materials are used in non-invasivedevices for continuous glucose monitoring (CGM), surface or localized plasmon sensing material are seldom applied in CGM owing to modest sensitivity and bulk sensing apparatus. Herein, a metasurface (MGMSPR) biosensor based on the metasurface plasmon resonance chip modified with heterostructured Ti3C2 MXene-Graphene oxide (MG) is reported, which potentially enables ultra-sensitive glucose detection. The sensor consists of a dual-channel microfluidic device integrated with silver mirror enhanced MGMSPR chips. Not only does it promote the entry of glucose oxidase (GOD) into the internal pores and enhance the stable fixation of GOD in the membrane, but also the integration of MG material provides a high specific surface area and unique electronic properties, thereby significantly enhancing the sensitivity of the MGMSPR sensor. The detection limit of MGMSPR biosensor is 106.8µM. This pioneering approach opens new avenues for monitoring physiological parameters and process analytical technology on an optical platform, providing continuous health monitoring and production process control through optical sensors.

Optimising 3D printed medications for rare diseases: In-line mass uniformity testing in direct powder extrusion 3D printing

Biotinidase deficiency is a rare inherited disorder characterized by biotin metabolism issues, leading to neurological and cutaneous symptoms that can be alleviated through biotin administration. Three-dimensional (3D) printing (3DP) offers potential for personalized medicine production for rare diseases, due to its flexibility in designing dosage forms and controlling release profiles. For such point-of-care applications, rigorous quality control (QC) measures are essential to ensure precise dosing, optimal performance, and product safety, especially for low personalized doses in preclinical and clinical studies. In this work, we addressed QC challenges by integrating a precision balance into a direct powder extrusion pharmaceutical 3D printer (M3DIMAKER™) for real-time, in-line mass uniformity testing, a critical quality control step. Small and large capsule-shaped biotin printlets (3D printed tablets) for immediate- and extended-release were printed. The integrated balance monitored and registered each printlet’s weight, identifying any deviations from acceptable limits. While all large printlet batches met mass uniformity criteria, some small printlet batches exhibited weight deviations. In vitro release studies showed large immediate-release printlets releasing 82% of biotin within 45 min, compared to 100% for small immediate-release printlets. For extended-release formulations, 35% of the drug was released from small printlets, whereas 24% was released from large printlets at the same time point. The integration of process analytical technology tools in 3DP shows promise in enhancing QC and scalability of personalized dosing at the point-of-care, demonstrating successful integration of a balance into a direct powder extrusion 3D printer for in-line mass uniformity testing across different sizes of capsule-shaped printlets.

Implementation 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.

Light-emitting diode-based absorbance detectors for flow-through analysis in analytical chemistry: A tutorial

The development of light-emitting diodes (LEDs) has played a significant role supporting many recent advances made in chemical analysis. Their small size, low power consumption, and semi-monochromaticity make them ideal light sources for portable photometric devices used in field and on-site analysis, environmental monitoring, and industrial applications, such as process analytical technology (PAT) and continuous real-time analysis. This tutorial provides an overview and critical comparison of the key components in LED-based absorbance detectors, including light sources, optical fibres, flow cells, and photodetectors. Fundamental aspects of LEDs relating to their use in such simple detectors are discussed in detail, along with the development of multi-wavelength detectors that incorporate multiple LEDs. The tutorial also details the different methodologies for assessing and characterising the LED-based absorbance detectors. Finally, this tutorial presents some selected applications of LED based photometric detectors in gas sensing, flow injection analysis (FIA), and coupled with separation techniques such as ion chromatography, liquid chromatography, and capillary zone electrophoresis (CZE).

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.