Measurements from these sensors do not need complex multivariate models that require developing, validating, and maintaining, explains Jim Holman, process development manager, APC Pharma Solids, at GEA UK. One of the most fascinating spectroscopic methods is the omnipresent near-infrared spectroscopy, which over the past decade has been successfully implemented as a fast at-line/on-line/in-line quality control in almost all facets of food and pharmaceutical manufacturing. 6. Journal Research on the correlation between dissolution results and measured

profiles using principal component analysis." The major advantage of this procedure is that the sample can be conditioned prior to the measurement. Through the use of probes As always, there will be a balance between what is technologically feasible and costs, especially as biogenerics have the potential to reduce profitability of biotechnology therapeutic products. Spectroscopic sensors are able to furnish process engineers with such data.

results, to raw material, process parameters, and in-line readings.

3. cores, and other stages in the process. this could also include accelerated dissolution rate analysis, is that batches are now compared to a substantial compilation

of batches included in a validated model.

These mathematical tools can be perceived as complex without the appropriate training, posing a risk of misinterpretation without a complete understanding of the chemical and physical phenomena at play. Although its implementation as an on-line monitoring tool is severely hampered by the requirement of a strong homogeneous magnetic field, it is foreseen that this technique will also invade the more advanced segments of the food and medical industries for quality control. For potent drugs, for example, the amount of API in the blend is typically low, so there can be a lot of noise in spectroscopy and a longer sample time is required.

The effect of scale ups and post approval changes Hillier will discuss the lessons learned from ongoing industry collaborations in sampling and sensing in a presentation at the IFPAC conference (Feb. 28, 2017). Visual and near-infrared spectrum of three samples of sucrose: amorphous sucrose, fine crystalline sucrose, and coarse crystalline sucrose. While NIR has gotten most of the attention, PAT is not limited Near infrared happens to reside in a region of the electromagnetic spectrum where the wavelengths of the light coincide with particle size and particulates in many samples and thus give rise to strong scatter phenomena. 5. 13, No. level.

Another problem is that some PAT techniques may be too slow for some processes. line testing is better control of the process. PAT has been strongly encouraged by the FDA and the ICH as a means to produce consistently high-quality products through continuous monitoring and control of critical operations. With atline measurements, the sample is withdrawn from the process flow and analyzed with analytical equipment that is located in the immediate environment of the industrial equipment. PAT can provide better process control and result in better process understanding. The PAT framework intends to make effective use of state-of-the-art pharmaceutical science, engineering principles and knowledge throughout the life cycle of a product to improve the efficiency of both manufacturing and regulatory processes, and to achieve this by using an integrated systems approach to regulate product quality. Process analytical technology approach consists to properly design, analyze and control the manufacturing process. manner, with single parameters tracked by control charts. Like sensors built on near-infrared technology, mid-infrared sensors have substantial potential as a quantitative quality control tool for the food industry, but thus far, it has mainly found use in off-line liquid analyses of especially milk, edible oils, and wine. High-resolution nuclear magnetic resonance (NMR) is probably the most successful and versatile spectroscopic technique yet to be developed. The advantages of PAT are many and varied. All rights reserved. in constant contact with drug product.

Recently PAT has been described for monitoring and controlling crystallizations on scale. The costs of quality control are high, but as noted by one prominent biotechnology expert, without analysis, you have nothing [63]. We use cookies to help provide and enhance our service and tailor content and ads. Process sensors include a combination of tools available to manufacturing scientists to design, monitor and control a process. discussions throughout the pharmaceutical industry concerning

The methods are robust to potential variation in incoming raw materials and scalable over throughput ranges.. of chemometrics."

Among the PAT tools that are largely being used in the pharmaceutical industry are near-infrared spectroscopy, Raman spectroscopy, and terahertz pulsed spectroscopy technologies. Process analytical technology (PAT) is defined by the FDA as a mechanism to design, analyze, and control pharmaceutical manufacturing processes through the measurement of critical process parameters that affect critical quality attributes of an active pharmaceutical ingredient (API). Trace substance sensitivity can be obtained by fluorescence sensors, as most substances do not fluoresce, and emission spectra can therefore be measured against a black background. The advantage of on/in Important fluorophores include proteins (containing the amino acids tryptophan, tyrosine, and phenylalanine), coenzymes, vitamins, caffeine, chlorophyll, polyphenols, flavanoids, and aflatoxins. Chemometrics are Principal Component Analysis (PCA) and Partial Least Squares This chapter includes a description of general strategies by development phase as well as the primary drivers for deployment of PAT. of Pharmaceutical and Biomedical Analysis, 13, 1273-1281, 1995. Process Analytical Technologies involve the use of raw material Raman spectroscopy, based on weak, inelastic scattered side bands arising, when illuminating a sample with a strong monochromatic laser light, appears to be an attractive alternative to the practically impossible on-line implementation of mid-infrared sensors. Institute These spectroscopic methods are based on different regions of the electromagnetic spectrum and on different physical principles, and have naturally different sensing capabilities. The potential advantages of implementing spectroscopic sensors for quality control directly in food and pharmaceutical processes will create a continuous quest for still more informative and multivariate sensors to be developed. use of PLS to determine which underlying variables contributed But they share the ability to provide rapid multivariate information on the sample being monitored, which in turn makes it possible to simultaneously determine several quality parameters. As these signals are repeated throughout the region, the near-infrared spectrum can be regarded as a holographic signature of the mid-infrared spectrum. The objective of PAT is to provide more frequent and automated measurements. On-line near infrared (NIR) spectroscopy, for example, is being used to measure critical quality attributes (CQAs) such as blend uniformity and moisture content of tablets.

Copyright 2022 Elsevier B.V. or its licensors or contributors. These analytical methods determine the oligomeric state of the antigen, which is critical for its immunogenic properties [62]. Data from UPLC is used in R&D, process development, and manufacturing, notes Hillier. Eli Lilly and Companys continuous direct compression process for oral solid dosage drug manufacturing won the International Society for Pharmaceutical Engineering (ISPE) Facility of the Year Awards category award for Process Innovation, in part, for a control scheme anchored by advanced automation and PAT (1). elements." Variables which affect the dissolution rate can be better understood One of the challenges is that using PAT commercially, over a long time period, requires a significant amount of personnel hours for maintenance-checking equipment and keeping calibrations up to date, notes Hausner. Hubert Cdric, Hubert Philippe, in Encyclopedia of Analytical Science (Third Edition), 2019. Journal of Pharmaceutics, 212, 41-53, 2001. and NIR tablet analyzers. with subtle interactions of variables. the desired specifications. This will result in a more robust process, better In the case of online measurements, samples are not necessarily removed from the process flow but temporarily separated for example via a by-pass system which transports the sample directly through the online measurement device. Topics will include RTR and soft sensors in continuous manufacturing and advances in PAT technologies such as LIF. In this fashion quality is built into the processing (QbD), not tested into the products [2,5,38,39]. from the production plant), would be at-line testing. Chemometrics is the intersection

Product quality and performance are ensured through the design of effective and efficient manufacturing processes. Process Analytical Technology Over the years, PAT based on various spectroscopic techniques has been developed and proved to be versatile in applications to the understanding of chemical reactions including asymmetric transformations. These correlations must be performed with the & Biomedical Analysis, Vol. Process analytical technologies (PAT) have played an important role in process development and scale-up of asymmetric syntheses of chiral molecules including active pharmaceutical ingredients in the pharmaceutical industry. A more thorough understanding of the chemistry and process via PAT on a molecular level creates more process robustness, uses more efficiently resources and creates thus a more sustainable environment. of chemistry and the mathematics of large matrices of data.

References: When out of specification results PLS is used to correlate data, such as finished product dissolution Communication between PAT sensors and systems enables visibility of information about a reaction in real time and can eventually allow movement to automated, closed-loop control of a small or large-molecule reaction using PAT, says Ernie Hillier, principal systems manager at Waters Corporation. Chemometrics plays an important role in the PAT toolbox. Implementing visual analyzers in manufacturing industries is therefore rather common from simple LAB (lightness and a and b color-opponent dimensions in color model) color measurements of meat to advanced multichannel grading of furs. techniques as a primary means of process monitoring. Some views on the past, present and future of Chemistry, Umea University, Umea, Sweden. However, some drawbacks may arise if the chemometric tools are not used properly.

creating high quality drug product, less level/stage 2 testing,

The first step away from off-line testing (laboratory separated 4/5, 377-383, 1995. Emergence in the analytical QbD approaches helps in establishing proper control strategy for the analytical method to control variability and improve robustness in method performance with high quality. Along with traditional Process Analytical Technology provides better knowledge of raw and its application to the pharmaceutical industry.

Another advantage of PCA is that it can handle the large can be quantified. A process is considered well understood when (1) all critical sources of variability are identified and explained, (2) variability is managed by the process, and (3) product quality can be accurately and reliably predicted over the design space established for materials used, process parameters, and manufacturing conditions.4 Well-understood processes consistently ensure predefined final product quality and could, consequently, reduce regulatory concerns while at the same time increase process efficiency. However, for the industry to realize the potential for such indirect methods based on trace amount of indicator substances, a new paradigm shift may be required. An improper selection or design of the instrument or even an inadequate installation could lead to extensive maintenances or inoperable instrument. With increased use, however, some of the limitations of current technology are becoming evident. One of the key techniques is focused beam reflectance monitoring (FBRM), which monitors the number, size, and shape of particles through chord length distribution.

Although it is not likely to eliminate validation, the effort spent to incorporate PAT, especially for a new product or for a process change, can enhance manufacturing consistency and reduce failed batchesproviding an economic advantage. in the process, uniformity, drying, and mixing endpoints, and

Product and process specifications are based on a mechanistic understanding of how formulation and process factors affect product performance. As even more improvements are made in areas such as tertiary structure analysis and feedback mechanisms, even better control may be possible. quality. could be accurately predicted well before the product is analyzed. This strategy has been able to ensure a high level of product quality but at the expense of extremely high production costs (e.g., hours to days of process-stops owing to time-consuming analysis, batches not right first time, losses of high-value products). Figure 5 shows how three samples of exactly the same compound differ tremendously depending on the particle size of the sample being measured: amorphous sucrose, fine crystalline sucrose, and coarse crystalline sucrose. Equipment and Processing Report-02-15-2017, www.facilityoftheyear.org/winners/2017-process-innovation, ISPE, Category Winner for Process Innovation,. This article will briefly mention a few relevant spectroscopic sensors for PAT and discuss the advantages and disadvantages (Table 2). "Principal component analysis of dissolution data with missing Another mode is known as in-line testing, which places probes Adams, E., Walczak, B., Vervaet, C., Risha, P., Massart, D., of data into a few recognizable components without any loss of other targeted stages can be pinpointed to a high degree of certainty. Alves, in Comprehensive Chemometrics, 2009. and terminology common to these methods will be described to provide Improved process analytical technology and new ways of thinking seek to enhance measurement and control for next-generation pharmaceutical manufacturing. would be under such high control that the dissolution results Near-infrared sensors have the additional advantage that the instrumentation is relatively simple and that the radiation may be transmitted through quartz, making the use of optical fibers feasible.

In some cases, PAT measurements can be used qualitatively to build models such as process trajectories or process signatures which can be used to characterize process variability and highlight unusual process behaviors. The set of methods and techniques for data analysis enclosed in this scientific field are essential to extract information from measurements performed during process operation. Whether for laboratory equipment or instrument used for process analysis, installation, qualification, analysis or maintenance operations should be staffed with properly trained personnel. flows, pH and other physical parameters, PAT focusses on the use as blending, or drying, the FDA has proposed creating on/at-line A thorough discussion of PAT and its FDA and ICH guidances is beyond the scope of this chapter. be identified earlier than with an f2 comparison. PAT is defined as Systems for analysis and control of manufacturing processes based on timely measurements of critical quality parameters and performance attributes of raw and in-process materials [59, 60]. the necessary computations. PAT has been reviewed [40]. As can be seen in the above discussion, the use of PAT techniques The industry is starting to take a serious look at where current PAT is reaching its limit and what the alternatives are, notes Doug Hausner, Associate Director for Industrial Relations and Business Development at the Engineering Research Center for Structured Organic Particulate Systems (C-SOPS), an academicindustry consortium based at Rutgers University. This region of the electromagnetic spectrum contains overtones and combination tones of the fundamental vibrations normally found in the mid-infrared region. measuring constant purity instead of yield. All of the four approaches have certain advantages and drawbacks and there is hardly ever a clearly right or wrong approach to sampling. The central point of PAT is to generate product quality Hausner notes that continuous manufacturing allows process engineers to run experiments more quickly, with less material compared to batch, so that collecting more data is not as costly. and minimal product failure. PCA is a technique of creating data models of previously produced to eliminate noise, identify latent variables, and extrapolate 1. The conventional approach to assess product quality in the pharmaceutical industry has been, for about a century, to test samples collected at the end of each batch. without the need to reduce data points. Moreover, they have in common that they are absolutely nondestructive, as they contain energies from approximately 40kcalmol1 to approximately 1kcalmol1, not enough to break covalent bonds (50130kcalmol1) and, for example, to initiate autoxidation (Figure 4). disadvantages associated with this approach are continual process

RTR for drug tablets, for example, would need PAT to confirm the chemical identity of the API at the correct concentration in finished tablets exiting the tablet press, as well as to predict hardness and weight or thickness. The vibrational spectroscopies near-infrared, mid-infrared, and Raman have in common that practically all substances will give rise to substantial absorption/scattering effects, for which information on trace substances or detailed conformational information is normally hidden in spectra of complex samples such as food. PAT has brought together different disciplines, which was presumably one of the intentions of the Food and Drug Administration guidance PAT- A Framework for Innovative Pharmaceutical, Development, Manufacturing and Quality Assurance. PAT has different connotations within different industries, companies, and health authorities. properties, manufacturing parameters, process monitoring, and information in real-time. One advantage is elimination of Trends could potentially One advantage this technique has over the commonly used f2 metric Adams, E., Maesschalck, R., De Spiegeleer, B., Vander Heyden, While process monitoring traditionally involved temperature, pressure,

The answer will depend not only on the quality parameter to be measured but also on the possible sample presentation, the need for nondestructiveness, robustness, and, last but not least, possible spin-off in terms of other relevant quality parameters to be measured. Regression (PLS).

ScienceDirect is a registered trademark of Elsevier B.V. ScienceDirect is a registered trademark of Elsevier B.V. Specification of Drug Substances and Products (Second Edition), Industrial Applications of Asymmetric Synthesis, In-Process Assays, In-Process Controls, and Specifications, Practical Process Research and Development (Second Edition), Quality by design-based development of nondestructive analytical techniques, Handbook of Process Chromatography (Second Edition), Comprehensive Chemometrics (Second Edition), describing a regulatory framework aimed at encouraging development and innovation in the pharmaceutical industry. can be a huge benefit to those who choose to use the technology. The pharmaceutical manufacturing industry has a lot to gain from the use of chemometrics in any PAT effort, both in terms of increased process understanding and consequently in economic, efficacy, and safety terms through better process operation. This is The near-infrared light does not destroy or react with This could help Like mid-infrared spectroscopy, Raman scatter measures the fundamental molecular vibrations, and like near-infrared radiation, Raman scattering can be transmitted in optical quartz fibers.

materials, manufacturing parameters and their impact on finished Y., Smeyers-Verbeke, J., Massart, D., "Evaluation of dissolution In another application, on-line HPSEC with differential refractometry and multi-angle laser light scattering is being applied to control manufacturing of an HIV viral vaccine. Critical parameters can be controlled, thereby Each company selects tools, vendors, integration with hardware and software, and how (or if) to communicate to Health Authorities. The manufacturing process could be continuously monitored and Rudolf W. Kessler, Waltraud Kessler, in Comprehensive Chemometrics (Second Edition), 2020, PAT is defined by the US Food and Drug Administration as a system for designing, analyzing, and controlling manufacturing through timely measurements (i.e., during processing) of critical quality and performance attributes of raw and in-process materials and processes with the goal of ensuring final product quality.7. Figure 5. This chapter aims to give a glimpse of the present state of QbD and PAT tools in the pharmaceutical industry. is highly complex.

These techniques were used to reliably crystallize an API from EtOH/H2O; previous attempts had been thwarted because the mixture tended to oil out [45]. Sophisticated analytical methods have enabled the biotechnology industry to produce safe and efficacious products. The, Process Analysis | Maintenance, Reliability, and Training, Encyclopedia of Analytical Science (Third Edition), ). PATs use is primarily in batch manufacturing, which still makes up the majority of processes, but also in continuous manufacturing. 2, 2017, Washington DC) is dedicated to advances in PAT, quality by design, and process control for the pharmaceutical, biotechnology, and other industries. assurance of dissolution rates using analytical data correlations. 2002.

The Food and Drug Administration (FDA) is inviting

the reader to PAT.

In particular, the authors will discuss the applications of PAT to the understanding of reaction profiling of asymmetric transformations including asymmetric hydrogenation and hydroformylation processes as well as other asymmetric syntheses, and scaling-up processes involving hazardous species. adjustments made to ensure that the finished product would meet The monitoring, preferably in-line or on-line, of these parameters helps to understand manufacturing processes and therefore to be more effective in testing and making decisions about product quality as well as reduce waste and overall costs.13 Consequently, the definition of user requirements for a specific equipment used for measuring selected CPPs is the core of the analytical instrument lifecycle.

Application of PAT to biotechnological process. The definition of CPPs that affect product-specific CQAs is a key feature of this dynamic approach. It, however, is a wide-ranging subject, which All carried actions must be deeply documented with a high consideration given to the integrity of both raw and processed data.

The desired state of pharmaceutical manufacturing as defined in the PAT guidance is as follows:4. Previously, manufacturing processes have been treated in a univariate Dissolution is the current primary method for evaluating solid The advantage of offline analytics is that expert knowledge is available. Zackrisson, G., Ostling, G., Skagerberg, B., Anflt, T., Offline analysis always exerts significant lag times between recognizing and counteracting against irregularities. Real-time release (RTR) is often discussed as a goal for more efficient manufacturing that applies to both batch and CM processes.

Measurements from these techniques raw materials, and finished product variables would be understood. Lars Hagel, Gail Sofer, in Handbook of Process Chromatography (Second Edition), 2008. samples and is able to penetrate into and through solid samples.

2. for the manufacturer. The greatest challenge is related to presenting interpretable and understandable results so that the benefits are evident to stakeholders. It may also alter the approach to setting in-process specifications, e.g. The upcoming IFPAC conference (Feb. 27Mar. Raman, Mid-IR, acoustic emission signals, and other imaging techniques. product quality.

email for correspondence: [emailprotected]. do occur, drug products can be better investigated through the Engelsen, in Encyclopedia of Spectroscopy and Spectrometry (Third Edition), 2017. PAT operates through in-line or on-line analysis, without the need for samples to be withdrawn, manipulated or diluted. a new mode of operation, which will address these concerns. Then, based on the results obtained through lengthy procedures in a QC laboratory, away from the process, decide about the acceptance, rejection, or sometimes reprocessing of the material produced. Process analytical technology (PAT) is an umbrella term that covers a range of tools and is often cited as being an important component of other innovative initiatives, such as quality by design, real-time release, and continuous manufacturing. When a spectroscopic method is introduced in an industry, the key question What would be the appropriate choice of our new spectroscopic process analyzer? arises. In manufacturing, the application of PAT can prevent processing at risk while waiting for the results from a remote laboratory. is on-line testing, which either draws samples or monitors periodically. line to provide rapid results. we mean with it, and what do we want from it?" This article provides an overview of Process Analytical Technology

Such precaution also allows to reduce the risk of generating inaccurate results due to instrument faulty. By continuing you agree to the use of cookies.

Different approaches to PAT can be used to achieve the same objective and depend on company internal factors, which have led to diversity of approach across the industry. the movement of process dedicated testing equipment to the production PAT is of little value without high-quality data.