Questions and Answers
Which of the following are critical attributes that affect blend uniformity? (Select all that apply)
PAT stands for Process Analytical Technology.
True
What is the main technology used in PAT?
Near Infrared (NIR) spectroscopy
PAT allows investigation into a process to find the causes of __________.
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Match the following PAT solutions with their correct descriptions:
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What does PAT require in terms of mindset?
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What does Process Analytical Technology (PAT) aim to ensure during the manufacturing process?
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Which of the following are advantages of implementing PAT? (Select all that apply)
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PAT is primarily a product-centric approach.
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What are Critical Process Parameters (CPP)?
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PAT is often associated with in-process control testing during __________.
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What is the role of near-infrared (NIR) spectroscopy in PAT?
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When implementing PAT, sufficient knowledge of the process needs to be gathered only in the late stages of development.
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Which of the following is NOT a benefit of using PAT?
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What is the typical integration time for the Linear Variable Filter System?
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NIR and Raman spectroscopy both require sample preparation.
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What kind of housing does the Real-time process monitoring NIR solution have?
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The _____ should be constructed from materials deemed acceptable according to registered or compendia testing regimes.
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Which of the following attributes are critical for production processes?
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Thief sampling is considered representative for sampling powders.
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What does the Spectral Match Value (SMV) method correlate to?
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_____ is when the same chemical structure but different physical characteristics may lead to production issues.
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What type of NIR spectrometer uses a 10 ms typical integration time?
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What is a key requirement for raw material qualification using NIR?
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Raman spectroscopy is known to be sensitive to moisture levels in samples.
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Which technique can detect color without issues?
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Study Notes
Process Analytical Technology (PAT)
- PAT is a system for designing, analyzing, and controlling manufacturing through timely measurements of critical quality and performance attributes of raw and in-process materials and processes.
- The goal of PAT is to ensure final product quality, and quality cannot be tested into products; it should be built-in or designed.
PAT: A Paradigm Shift in Pharma Industry
- PAT is process-centric, not product-centric.
- PAT aims to design and develop well-understood processes that consistently ensure pre-defined quality at the end of the manufacturing process.
Traditional Approach vs PAT Approach
- Traditional approach: process is developed, frozen, and validated using 3 commercial batches, with subsequent quality control via off-line investigation in the laboratory.
- PAT approach: at-line, on-line, and in-line analysis for identifying critical sources of variability and establishing process understanding, enabling continuous process verification.
Key Advantages of PAT
- Better process understanding, leading to faster product development/scale-up, robust and reliable processes, and product quality assurance at lower costs.
- Generating cost savings through reduced production cycle times, energy consumption, and reagent consumption.
- Improving safety through process automation.
- Enabling continuous processing and real-time release to shorten production cycle time and achieve process efficiency.
- Facilitating continuous improvement and being eco-friendly by reducing waste and energy consumption.
PAT Implementation in Product Life Cycle
- PAT implementation spans the entire product life cycle, from early development to commercial manufacture.
- PAT is often associated with in-process control testing in commercial manufacturing, but it's essential to gain sufficient knowledge of the process/product in early development stages.
PAT Application in Solid Dosage Manufacturing Line
- PAT is used to monitor and control powder flow, particle size, and moisture levels to ensure consistent tablet compression.
- NIR and in-line Particle Size Analyzer (PSA) are used to monitor and control the process.
- PAT ensures that powder blends are not segregating during compression and potency is consistent over the entire process.
PAT Application in Liquid Dosage Manufacturing Line
- PAT is used to monitor and control process parameters such as purity, identity, and conformity to predict how to process material in a QbD environment.
- NIR is used to monitor and control the filling process to ensure content uniformity/assay is consistent over the entire process.
- In-line Viscometer and Headspace Gas Analyzer are used to monitor and control process parameters.
Critical Process Parameter (CPP)
- CPP is a process parameter whose variability has an impact on a critical quality attribute.
- PAT is used to monitor and control CPPs to ensure the process produces the desired quality.
- Risk assessment and experimentation are used to establish the linkage between potential CPPs and CQAs.### PAT: Major Techniques
- Near-Infrared (NIR) Spectroscopy and Raman Spectroscopy are two major techniques in Process Analytical Technology (PAT)
NIR Spectroscopy
- Uses short wave region (700-1100nm) for transmission measurements and long wave region (1100-2500nm) for diffuse reflectance measurements
- Components: light source, slit, mirror, diffraction grating (prism), order sorter, detector
- Setup and calibration: slit opening, mirror distance, grating position
- Fourier Transform IR (FTIR) and Linear Variable Filter (LVF) are two types of NIR spectrometers
Overtones and Combinations in NIR Spectra
- Each overtone describes the information of the previous one, but one order of magnitude less in intensity
- Spectrum of biscuit dough with main areas of absorption identified
NIRS Applications
- Identification, qualification, and assay of starting materials, intermediates, and finished products
- Verification of physicochemical properties
- Gaining process understanding
- Monitoring and controlling processes (off-line, at-line, on-line, in-line)
- Continuous improvement and life cycle management
- Enables enhanced assessment of quality of materials and processes by extensive and more representative sampling
NIRS in PAT Analysis
- Not all NIR spectrometers are suitable for PAT analysis
- Requirements for PAT analysis: capturing critical material and process information within a very short time frame
- Considerations: stability, reliability, robustness, ruggedness, mobility, ease of installation and operation
LVF NIR PAT Solutions
- Real-time process monitoring
- Field, at-line, in-line analysis
- Rugged, IP65 housing, internal rechargeable battery
- USB powered, Bluetooth or USB connection
- Weight: 318g (portable device), 250g (handheld device)
MicroNIR Cloud-Based and On-Device Analysis
- Cloud-based and on-device analysis capabilities
- Real-time process monitoring and analysis
PAT for Raw Material Quality Monitoring
- Raw material quality test: current facts
- Physical and mechanical attributes are critical for production process
- Minor differences in physical attributes can affect process robustness
- PAT principles and tools can provide relevant information relating to physical, chemical, and biological attributes
NIR and Raman Spectroscopy in Raw Material Application
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Similarities: non-destructive, handheld devices, no sample preparation, user-friendly, work through plastic
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Differences: required multiple standards for defining statistical threshold### NIR and Raman Spectroscopy in Raw Material Application
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Dipole moment variation is active in all kinds of pharma ingredients in NIR spectroscopy, while polarizability variation is active in limited pharma ingredients in Raman spectroscopy.
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Measurement principle: NIR spectroscopy measures the absorbed, reflected, or transmitted radiation, whereas Raman spectroscopy measures the inelastically scattered radiation.
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Duration per analysis: NIR spectroscopy takes a maximum of 2 seconds, while Raman spectroscopy takes 5 seconds to minutes.
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Signal output: NIR spectroscopy produces a fingerprint signal, while Raman spectroscopy produces sharp peaks.
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Fluorescence issue: There is no issue with fluorescence in NIR spectroscopy, but fluorescence interference may occur in Raman spectroscopy.
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Analysis of color samples: NIR spectroscopy has no issue, while Raman spectroscopy may damage or burn the sample.
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Parameters that can be detected:
- Moisture level: Yes in NIR spectroscopy, not sensitive in Raman spectroscopy.
- Particle size difference: Yes in NIR spectroscopy, not sensitive in Raman spectroscopy, and affects processability.
- Crystallinity: Yes in NIR spectroscopy, not sensitive in Raman spectroscopy.
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Liquid analysis: NIR spectroscopy requires sampling, while Raman spectroscopy does not.
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Safety for operators: NIR spectroscopy is eye-safe, while Raman spectroscopy poses an eye injury risk and requires safety goggles.
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PAT suitability: NIR spectroscopy is suitable, while Raman spectroscopy is not.
Handheld NIR and Raman Spectroscopy: Performance Comparison
- Raman spectroscopy is active for 99.5% of API and excipients, while NIR spectroscopy is active for 100% of chemicals.
- Total performance: Raman spectroscopy performs well for 53% of samples, moderately for 34%, and poorly for 13%, while NIR spectroscopy performs well for all samples.
- Fluorescence interference occurs in Raman spectroscopy, leading to weak signals and longer analysis times.
Raw Material Identification is Not PAT
- Raw material identification confirms the chemical structure of a molecule, while PAT (Process Analytical Technology) confirms physical characteristics.
- Different physical characteristics of the same substance may have different processability and/or efficacy, leading to production and/or bioavailability issues.
- Raman and NIR spectroscopy are used in raw material identification.
NIRS in Incoming Raw Material Identification and Qualification
- NIRS (Near-Infrared Spectroscopy) is based on the comparison of spectral data with a spectral reference library.
- Qualification is often performed after sample identification, with the qualification spectral library derived from samples representing different grades of the same substance.
- If identification and/or qualification are based on more than one analytical method, it should be clear which reference method(s) will be replaced by the proposed NIR procedures.
- NIRS may be supplemented by other analytical procedures to ensure specificity.
NIR Library Development Recommendation
- The spectral reference library should be established from several batches of different substances.
- The library should be constructed from materials deemed acceptable according to registered or compendia testing regimes.
- Samples from all relevant suppliers should be incorporated into the library.
- Samples should exhibit the variation typical for the substance to be analyzed (e.g., variation in solid-state form, particle size, crystallinity, synthesis route, storage time).
Spectral Match Value (SMV)
- SMV is a simple, flexible, and powerful RM qualification method based on correlation to a mean spectrum.
- SMV performs a pairwise wavelength correlation across a defined spectral region.
Raw Material Qualification: Source Difference
- NIR spectroscopy can differentiate between two different sources of riboflavin sodium phosphate, despite both meeting compendial specifications.
- Source difference is detected using SMV method.
Raw Material Qualification: Particle Size Difference
- SMV model can differentiate between Cefixime powder and Cefixime micronized based on particle size difference.
- Spectra shift is observed due to different particle size.
Raw Material Qualification: Batch Consistency
- NIR spectroscopy can evaluate different batches of Citicoline, a highly hygroscopic powder.
- Batches meeting compendial specifications may still have differences in solubility and moisture content, affecting production.
PAT For Process Monitoring
- PAT is used for process monitoring and control in pharmaceutical manufacturing.
Drying Monitoring
- NIR spectroscopy is used for in-line process monitoring of fluid bed drying.
- Quantitative calibration model: PLS for LOD determination.
Blending Monitoring
- Thief sampling is considered non-representative due to disturbance of local composition and non-homogenous sampling.
- PAT instruments lead to 'grab' samples, but are a better approach than thief sampling.
- The latest US FDA process validation guidance of 2011 states that all sources of variability should be understood.
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Description
This quiz is about the implementation of Process Analytical Technology (PAT) in the pharmaceutical industry, focusing on quality assurance and production efficiency. It is based on a seminar presentation by Noviani Rustanto at the Seminar Farmasi Nasional Pharmanexa 2024.
