Exploring Process Analytical Technology: Applications and Benefits in Pharma Operations A Comprehensive Review

Figure No. 01 Process Analytical Technology

Different Measurement Modes in PAT: -

1. At-line Measurement: It can be defined as the samples are removed and analyzed in close proximity to the production process, either manually or by using automated sampling devices.
2. In-line Measurement: Inline measurement refers to the continuous or real-time monitoring of physical, chemical, or biological parameters during the manufacturing process of pharmaceuticals.
3. On-line Measurement: Online measurement refers to the real-time monitoring of critical process parameters during the pharmaceutical manufacturing process.

US FDA View on Process Analytical Technology: -

Guideline Title: "PAT – A Framework for Innovative Pharmaceutical Development, Manufacturing, and Quality Assurance" (2004). The FDA guidelines for Process Analytical Technology (PAT) are designed to enhance the efficiency and quality of pharmaceutical manufacturing processes. PAT focuses on using analytical tools to monitor and control the manufacturing process in real-time, ensuring that the final product meets the desired quality attributes. Here’s an overview of the key elements of these guidelines:

1. Overview of PAT
   • Purpose: PAT aims to improve the understanding and control of pharmaceutical manufacturing processes. By integrating analytical techniques into the manufacturing process, PAT helps ensure product quality and consistency.
   • Scope: PAT guidelines are applicable to all stages of pharmaceutical manufacturing, including raw material testing, in-process monitoring, and final product testing.
2. Key Components
   • Design and Development Tools: PAT encourages the design of processes that are well-understood and controlled. This involves the development of a robust process model that can be used to predict and control the quality of the final product.
   • Analytical: Various analytical techniques are used, such as spectroscopy, chromatography, and sensors. These tools help monitor critical process parameters and quality attributes in real-time.
   • Process Control: PAT emphasizes the need for continuous process monitoring and control. This involves using real-time data to make adjustments to the process as needed to maintain product quality.
3. Implementation Strategy
   • Risk-Based Approach: The implementation of PAT should be based on a risk assessment. This involves identifying critical quality attributes and critical process parameters that impact product quality.
   • Integration: PAT should be integrated into the overall Quality by Design (QbD) approach, which focuses on designing and controlling processes to ensure the desired product quality.
   • Data Management: Effective data management systems are essential for PAT. This includes data collection, analysis, and interpretation to ensure that process changes are based on reliable information.
4. Implementation Strategy
   • Risk-Based Approach: The implementation of PAT should be based on a risk assessment. This involves identifying critical quality attributes and critical process parameters that impact product quality.
   • Integration: PAT should be integrated into the overall Quality by Design (QbD) approach, which focuses on designing and controlling processes to ensure the desired product quality.
   • Data Management: Effective data management systems are essential for PAT. This includes data collection, analysis, and interpretation to ensure that process changes are based on reliable information.
5. Regulatory Considerations
   • Guidance Documents: The FDA has issued several guidance documents related to PAT, such as the "PAT – A Framework for Innovative Pharmaceutical Development, Manufacturing, and Quality Assurance" (2004). These documents provide detailed recommendations for implementing PAT in a compliant manner.
   • Validation: PAT systems must be validated to ensure they consistently perform as intended. This includes validating the analytical methods, the process controls, and the overall system integration.
6. Benefits of PAT
   • Improved Quality: By monitoring and controlling the process in real-time, PAT helps ensure that the final product consistently meets quality specifications.
   • Increased Efficiency: PAT can lead to more efficient manufacturing processes, reduced production costs, and faster time-to-market for new products.
   • Regulatory Compliance: Implementing PAT can help pharmaceutical companies meet regulatory requirements and standards more effectively.
7. Challenges and Considerations

• • Complexity: Implementing PAT can be complex and may require significant changes to existing processes and systems.
  • Training and Expertise: Proper training and expertise are required to effectively use PAT tools and interpret the data they generate.
  • Cost: Initial setup and ongoing maintenance of PAT systems can be costly. ^[24]

Figure No. 02 US Food and Drug Administration Department

History: -

The history of Process Analytical Technology (PAT) in the pharmaceutical industry is a story of evolving standards and technological advancements aimed at enhancing process control, quality, and efficiency.

• Pre-20th Century: In the early days of pharmaceutical manufacturing, quality control was largely reactive, involving post-production testing of final products. Processes were not well understood, and quality was assured through extensive testing of finished goods rather than through process control.
• 1950s-1960s: The introduction of automated control systems such as Distributed Control Systems (DCS) and Programmable Logic Controllers (PLC) marked the beginning of more sophisticated process monitoring and control in pharmaceutical manufacturing. However, the focus remained primarily on mechanical control rather than real-time analysis.
• 1970s-1980s: As analytical technology advanced, techniques like chromatography, spectroscopy, and various sensor technologies became available. These tools provided more detailed insights into the quality of raw materials and finished products but were mostly used in offline quality control rather than for real-time process monitoring.
• 1997: The FDA’s publication of "Pharmaceutical cGMPs for the 21st Century: A Risk-Based Approach " was pivotal. This document emphasized the need to modernize the pharmaceutical manufacturing process and encouraged the adoption of advanced analytical technologies to improve process understanding and control.
• 2000s: The pharmaceutical industry began to adopt PAT more broadly. The use of real-time monitoring technologies, such as near-infrared spectroscopy (NIR), Raman spectroscopy, and in-line sensors, became more common. PAT tools allowed for better process understanding and control, leading to improved product quality and reduced production cost.
• 2004: The FDA issued the "PAT – A Framework for Innovative Pharmaceutical Development, Manufacturing, and Quality Assurance" guidance document. This was a landmark in formalizing PAT principles, defining PAT as a system for designing, analyzing, and controlling manufacturing through timely measurements of critical quality and performance attributes.
•  2010s: The adoption of PAT continued to grow, supported by advances in digital technologies. The integration of PAT with process modeling, data analytics, and control systems improved the ability to predict and manage process outcomes. PAT began to be seen not just as a regulatory requirement but as a valuable tool for achieving operational excellence.
• 2020s: The focus has expanded to include the integration of PAT with Industry 4.0 principles, including the use of digital twins, advanced machine learning algorithms, and the Internet of Things (IoT). These technologies enable even more precise control and optimization of manufacturing processes. PAT systems are increasingly used to support continuous manufacturing, a modern approach that replaces traditional batch production with a continuous flow process. ^[26]

Different Modern Techniques Integrated in PAT Tools: -

The following technique is covered based on the maximum utilization of tools/devices:

1. Near-Infrared Spectroscopy:

IRS has been applied as a useful spectral analysis technology in many studies. NIRS is a qualitative and quantitative analysis based on the transmittance and reflectance generated by molecular vibrational motion using light in the near-infrared range of 780– 2800 nm. It is most often used in the pharmaceutical industry as a real-time process- monitoring tool for product quality control and quality assurance during processing. The NIRS is connected to a fiber optic probe, and the QA of the product in the process is non-destructively measured by the transmission and reflection of the NIRS by the sample, and quality control through real-time monitoring is possible. The inside of the probe is composed of an optical fiber, a lens, mirror, and signal channel, and the outside of the probe is made of a corrosion-resistant material. It is connected through a sapphire window, so it can be effectively used even in poor process conditions. When the probe is connected to the NIR spectrometer, the light emitted from the light source is focused by the focusing lens. The light reflected by the mirror located at the tip of the probe is transmitted to the NIR spectrum by reflecting a sample. The transmitted signal forms a spectrum through computer software connected to the NIR spectrometer. However, a disadvantage of NIRS is that it is more difficult to interpret a signal than by using conventional analysis methods, such as chromatography, ultraviolet/visible (UV-VIS) light, and others, because the absorption bands overlap due to spectral complexity. In addition, because this is a relative approach, it is necessary to form and verify an accurate correction model using a reference method to utilize it effectively. Nevertheless, NIRS can non-destructively measure the IQAs of a product in a short time during the process, and it can be used as a tool for RTRT in the pharmaceutical industry by enabling the process control and quality assurance of finished products through real-time monitoring. ^[1]

2. Raman Spectroscopy:

Raman spectroscopy is a noncontact analysis technology that uses optical fibers. Raman spectroscopy is a type of vibration spectroscopy. Various Raman laser sources offer a range of wavelengths (generally 785 nm), from the UV-VIS to near-infrared regions; the most common are visible light lasers. In general, vibrations occur in chemical bonds that are not rigid, and materials can be characterized based on their molecular-vibration frequencies. Raman spectroscopy is widely used in pharmaceutical manufacturing because it enables the rapid characterization of the chemical composition and structure of a solid, liquid, gas, gel, or powder sample by providing the detailed characteristics of their vibrational transitions. Raman spectroscopy is used to determine the molecule in the sample, and their intensity enables the calculation of the drug content of a particular sample. One of the main reasons for using PAT is to build and qualitatively analyze the specificity library of the raw material spectrum, including impurities in the sample. Raman spectroscopy is ideally suited for PAT systems because it has the flexibility to operate on-line or in-line. Moreover, it provides both quantitative and qualitative data, enabling accurate and consistent monitoring and control during real- time processes. Depending on the compound, the Raman spectrum for a specific molecule differs for each movement of the scattered photon energy, and because it has a unique fingerprint, it enables the monitoring of qualitative information. Furthermore, it can be used for analyzing liquid products without moisture interference, similar to Fourier-transform infrared spectroscopy (FTIR) or NIRS, and has a high measurement speed. Similar to other spectroscopy methods, Raman spectroscopy is commonly used as a real-time monitoring tool for CPV in various pharmaceutical unit processes, including blending, granulation, coating, and tableting. ^[1]

3. UV Spectrophotometer:

Analyzing pharmaceutical active compounds with spectrophotometers requires a small sample quantity to obtain accurate results. UV spectrophotometry for the pharmaceutical industry ensures patient health and safety through applications such as:

• • Dissolution testing: Spectrophotometers can analyze dissolution testing results for oral medication dosages.
  • Chemical quantification and identification: Spectrophotometers can confirm the chemical makeup, purity, and ingredients of drugs.
  • Quality control: Spectrophotometers can obtain the highly accurate color measurements needed to ensure the purity and quality of the product. A high degree of quality control is critical for pharmaceuticals.
  • Regulatory adherence: Spectrophotometers can generate data proving compliance and any risks involved, validating the company's processes. Regulatory bodies require pharmaceutical companies to provide proof of their quality control efforts. ^[29]

Application of PAT Tools to Continuous Manufacturing:

Definition: Continuous Manufacturing can be defined as a seamless supply of input materials, transformation of materials in-process, and simultaneous removal of output materials. ^[27] The ICH guideline aims to establish standardized scientific and technical requirements for implementing and assessing continuous manufacturing (CM) in pharmaceutical production. By harmonizing these requirements, the guideline seeks to ensure consistency in regulatory expectations across different regions and regulatory authorities. The adoption of continuous manufacturing technology has the potential to improve access to medicines by enhancing efficiency, reducing production costs, and accelerating the availability of pharmaceutical products to patients. The guideline aims to support this goal by providing a framework for the effective implementation and assessment of CM technology. By providing a common set of guidelines and standards, the new ICH guideline facilitates international harmonization

in the adoption of continuous manufacturing practices.

Different PAT Tools Applicable in Continuous Manufacturing: -

1. Tool: NIRS XDS Smart Probe Analyzer 2m Fiber
2. Tool: Thermo Scientific Antaris 2 FT-NIR Analyzer.
3. Tool: inLux^TM SEM Raman Interface.
4. Tool: Viasala HMT 120/130.
5. Tool: Sirius SDI Surface Dissolution Imaging.

• Tool: NIRS XDS Smart Probe Analyzer 2m Fiber.

Model: XDS(2m) Fiber.

Make: Metrohm AG.

Scientific and Technical Requirement Passed: Drug uniformity, blending/mixing time.

Mechanism: The NIRS XDS Smart Probe Analyzer uses near-infrared spectroscopy (NIRS) to perform rapid, nondestructive analyses of solid and liquid substances directly in their original containers. The device is designed for both warehouse and laboratory settings, offering an ergonomic and robust solution for quality control.

• • Sample Interaction: The probe is placed in contact with the sample through the container, allowing it to penetrate the material without requiring any alteration to the packaging.
  • Spectral Analysis: The analyzer emits near-infrared light that interacts with the sample. This light is absorbed or reflected differently based on the chemical composition of the substance.
  • Data Acquisition: The probe captures the reflected light and converts it into a spectral data set, representing the sample's unique fingerprint.
  • Analysis and Interpretation: The spectral data is then analyzed using pre-calibrated models to determine the identity and quality of the substance. This can include assessing purity, concentration, and other critical quality parameter.
  • Immediate Results: Users receive immediate pass/fail results on the handle after the measurement, facilitating quick decision-making. ^[28]

Figure No. 03 NIRS XDS Smartprobe Analyzer-2m fiber

• Tool: Sirius SDI Surface Dissolution Imaging.

Model: SDI Surface Dissolution Imaging.

Make: Sirius Analytical.

Scientific and Technical Requirement Passed: Compression/ejection force, compression speed, coating solution, coating weight, tablet flow, granulation end point.

Mechanism: The Sirius SDI (Surface Dissolution Imager) operates on advanced imaging technology to provide real-time visualization of the dissolution process at the solid-liquid interface.

Key Mechanisms of Sirius SDI: -

1. Mechanism for Actipix^TM UV Area Imaging: In this tool, the design of a parallel array detector is there means UV absorbance is placed in parallel to the cell near the tablet placed in the cell.
   • Absorbance Measurement by UV camera: UV camera place near tablet continuously takes the images of tablet during dissolution run and software precisely measure the pixel intensities of different portion of the image. Darker the pixel of the image stronger is the absorbance and vice-versa.
2. Laminar Flow-through System:
   • Flow Cell Design: In flow cell design sample is kept inside the cell and dissolution media is passed through the cell at constant flow rate. As the medium pass through the cell drug dissolve in the medium.
   • Syringe Pump: Syringe pump are used to maintain the constant flow rate.
3. Real Time Imaging and Analysis:
   • As the software collects the image and analysis the intensity of pixel on the image, software generates a 2-dimensional graph. On X-axis time and Y-axis absorbance this shows how the absorbance changes during the time.
4. The images collected are compiled to produce high resolution, 2D movie that shows dynamic changes at the solid-liquid interface which in turn tells how the solid is dissolved in dissolution media and how the concentration level is increased.
5. Data Analysis: From the data collected we can predict the dissolution kinetics, also an analyte can observe from images the dissolution rate and physical changes that occur. ^[30]

Figure No. 04 Sirius SDI Surface Dissolution Imaging