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101ADVANCING PHARMACEUTICAL MANUFACTURING WITH PROCESS ANALYTICAL TECHNOLOGY: A COMPREHENSIVE REVIEW
Golla Lavanya
Asst. Professor, Department of Pharmaceutical Chemistry, Princeton College of Pharmacy, Hyderabad, Telangana, India
B Venkatesham
Asst. Professor, Department of Pharmaceutical Chemistry, Princeton College of Pharmacy, Hyderabad, Telangana, India
Abstract - To incorporate quality into products, process analytical technology (PAT) makes use of various technologies and tools. Science-based knowledge of the proposed drug product's physical, chemical, and mechanical properties are necessary for effective PAT implementation. An integrated systems approach to quality design, process analysis, understanding and control, continuous improvement, knowledge, and risk-based management looks promising for the PAT project as a whole. By acting on data in real time and eliminating sampling, early PAT devices increased process efficiency and safety. The more in-depth process knowledge gained by PAT applications leads to increased processing opportunities and robustness. For all kinds of chemical reactions and process monitoring, including drying, distillations, crystallizations, hydrogenations, and others, modern advancements in analytical technologies provide chemical and analytical insights.
Keywords: Process Analytical Technology, ICHQ10, cost control.
1 INTRODUCTION
The FDA defines Process Analytical Technology as a system for designing, analyzing, and controlling manufacturing processes by promptly measuring critical quality and performance attributes of raw materials, in-process materials, and processes with the intention of guaranteeing the quality of the finished product. PAT was introduced in 2001 by the Food and Drug Administration (FDA) to lessen the likelihood of producing a subpar product. Pharmaceutical companies now have the tools they need to design high-quality products and improve process efficiencies thanks to PAT. It looks at raw and in-process materials to make sure the final product is good. Utilizing conventional process sensors like pressure and analyzer technologies, PAT incorporates measurement science. PAT emphasizes in-line testing with near infrared, Raman, or other methods. The retrieved data would reveal the properties of blends, cores, and other process stages. Using tests all the while, consistency, drying,
and blending endpoints, and other designated stages can be pinpointed to a serious level of conviction. In-line probes would be strategically placed throughout the production process to reduce sampling error. PAT is not a service or product. It's a concept, a principle, or a way of doing things that you have to put into action. As pharmaceutical companies strive to implement the framework established by regulators1, the PAT market is rapidly developing and evolving.
It uses real-time information to reduce process variation and manufacturing capability. In industries like the chemical and pharmaceutical industries, the PAT improves quality while simultaneously cutting costs.
1.1 When to Introduce Process Analytical Technology (PAT):
A pharmaceutical product's quality must be taken into consideration from the very beginning. The equal participation of research and development and seamless communication between manufacturing
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102 are essential preconditions. Theintroduction of quality into a product from the beginning is one goal of PAT.
Therefore, its participation in the R&D phase is crucial. It will be much simpler to conduct root-cause analysis of quality or process failures from scale-up to commercial manufacturing if product quality requirements are understood and implemented from the beginning. To this end PAT could assume a considerably more significant part in the plan and examination of assembling processes, empowering execution control to be founded on ideal estimation of well - depicted basic handling information. To meet emerging requirements for the speed and volume of data collection, data processing requirements should also be taken into consideration in the context of the overall strategy for process analysis.
Knowledge management and real-time analysis necessitate the collection of all production batch data, such as through
data warehousing. As a result, large sets of measurement data can be generated long before a PAT data management strategy based on online process analysis or data mining can be established.
1.2 Basis for Process Analytical Technology:
It is common knowledge that several of the core concepts were pioneered decades ago by other manufacturing industries such as fine chemicals, semiconductors, petroleum, and consumer products. This is the case despite the fact that the FDA's PAT framework began to take shape just prior to the creation of the twenty-first century cGMPs initiative in 2001. Process analytical chemistry (PAC) and advanced manufacturing science are the primary concepts that set PAT apart from the traditional industrial pharmacy skill set (which also includes pharmaceutical and materials science, chemistry, and engineering).
Figure 1 PAT
The science and technology of displacing laboratory-based measurements with sensors and instruments closer to the operation site is typically referred to as process analytical chemistry. The more recent initiative ―Quality by Design‖ (QbD) is also aligned with the PAT concepts.5 The ICH Q8 guideline defines Quality by Design as ―a systematic approach to development that begins with predefined objectives and emphasizes product and process understanding and process control, based on sound science and
quality risk management.‖6 The objective of PAC is to ―supply quantitative and qualitative information about a chemical process for monitoring, control, and optimization.‖
2 DEVELOPMENT OF PAT
Process/method/equipment validation, process controls in accordance with standard operating procedures (SOPs), process instructions/master recipes, and off-line sampling at the conclusion of each batch are all examples of traditional
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103 pharmaceutical quality systems.Manufacturing process enhancements are not innately encouraged by this kind of system. Process logical science (PAC) has been acted in the petrochemical business for quite a long time. This method, which makes use of analytical and process chemistry in addition to multivariate tools, has recently been referred to as process analytical technology (PAT). PAT tools are used to make sure that products have quality built in, understand processes better, work more efficiently, and cost less. In 2002, the Food and Medication Organization (FDA) declared another drive, Drug Current Great Assembling Practices (cGMPs) for the 21st 100 years, to improve and modernize the guideline of drug assembling and item quality. The pharmaceutical industry's early adoption of new technological advancements was part of this initiative.
Following the cGMPs initiative, the industry received more in-depth PAT guidance (FDA, 2004). The International Conference on Harmonization's guidelines later included similar components of risk analysis, real-time quality control, and continuous improvement (ICH Q8, 2005;
ICH Q9, 2005). The most recent initiative, ICH Q10 "Quality Systems," completed the harmonization process on June 5, 2008. The outcome was that the US, Europe, and Japan were all parties to the ICH, and they agreed to fully implement the guideline through their respective regulatory bodies. The ideas behind ICH Q8 and "Pharmaceutical Development"7 are incorporated into ICH Q10.
2.1 Types of Process Measurement:
1] Off-line testing 2] On-line testing 3] At-line testing 4] In-line testing
3 EXAMPLES OF APPLICATION OF PROCESS ANALYTICAL TECHNOLOGY 3.1 Particle Size
Since active pharmaceutical ingredients (APIs) and excipients have a significant impact on the majority of solid dosage products, theft sampling and laboratory analysis are typically used to monitor their particle sizes. This method of control has a few drawbacks for systems where particle size is important. It's possible that a small sample isn't as accurate as the whole thing. To sample, transport, measure, and report results takes time.
There is probability of openness to administrators and lab faculty. Lots that are rejected can be expensive. Traditional control strategies are impractical for real- time quality assurance due to all of these limitations. PAT methods for measuring particle size take samples of larger, more accurate portions of the bulk product and provide quick analysis with immediate feedback to the control system. Personnel are not exposed because PAT is a closed system.
3.2 Content Uniformity
The production of a uniform mixture of API and excipients in the final dosage form is a primary objective of blending.
Due to the fact that measurements of component identity and concentration are frequently not specific to distribution, it is difficult to identify incomplete mixing in the final dosage form. Blend uniformity is typically assumed by blending for a predetermined amount of time, which is actually monitored by release testing.
There are a few drawbacks to this strategy: It's possible that release testing on small samples doesn't accurately reflect the bulk. Cycle time is shortened when you blend for longer than necessary. Blend time can be affected by feed material variations from batch to batch. "Demixing" may occur when there is too much mixing. Bombed discharge tests risk the whole bunch. In order to control blending more precisely, a PAT strategy provides process comprehension and feedback.
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104 3.3 DryingProduct drying is a necessary step that can have a significant impact on the final product's solid form, either after synthesis or during processing. A drying step can be made to just get rid of too much solvent for later processing, or it can be an essential part of manipulating the solid- state form through dehydration or desolvation. Under most situations, drying is completed temporarily, which can prompt exorbitant process duration as well as unwanted structure change if drying go on past the endpoint.
Uncompensated variations in drying time may result from variations in feed materials from batch to batch; The entire batch may be in danger if release tests fail.
3.4 Crystallization
The molecule spectroscopic method of Raman, NIR, ATR, and FT-IR spectroscopy is used as the sensor in a recent review of the study of the crystallization process using Process analytical technology.
Ranitidine HCL Tablet's various polymorphic forms were identified and quantified with the help of Raman spectroscopy and chemometric data analysis. Due to the rise in structure- based drug design fueled by recent advances in genomics and proteomics, protein crystallization has also been of some interest for PAT applications.
3.5 Pellet Manufacturing by Extrusion- Spheronization
To gain a better understanding of the solid-state behavior of the active pharmaceutical ingredients (APIs) during pelletization, an at-line process analytical technology (PAT) approach was utilized.
During the process, the characterization of polymorphic changes was carried out using X-ray powder diffraction (XRPD), near-infrared (NIR), and Raman spectroscopy. At the conclusion of each stage of processing—blending, granulation, extrusion, spheronization,
and drying—samples were collected.
Batches were dried at 60°C, 100°C, and 135°C temperatures. During processing, water caused both model formulations to form hydrates. Due to saturation of the water signal, NIR spectroscopy was unable to detect hydrate formation in theophylline and nitrofurantoin formulations during the granulation, extrusion, and spheronization stages.
However, it did provide valuable real-time information about the system's water state. The expected pseudopolymorphic changes of the APIs during the wet process stages were confirmed by Raman and XRPD measurements.
4 CONCLUSION
PAT can be thought of as a constellation that places more or less emphasis on a particular activity depending on the problem or situation at hand. There is no written rule or clear path through PAT. In addition to having a solid understanding of the pharmaceutical industry, experience and expertise are essential.
Continuous management support for the development and maintenance of PAT- related activities is essential once a pharmaceutical company decides to implement PAT. For PAT's future success, encouraging, stimulating, and initiating scientific collaboration and interaction, as well as the necessary education and training, is a strategic and necessary step.
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