This case study describes how in-line FTIR was used as a PAT tool to monitor and control a continuous multi-step process for producing 6-hydroxybuspirone. Real-time FTIR measurements allowed for precise control of base to substrate ratios, minimizing unwanted side products and waste. The continuous process was successfully developed at lab scale and then transferred to a pilot plant reactor, demonstrating the value of PAT tools for facilitating scale-up and ensuring product quality.
The document discusses Process Analytical Technology (PAT), which uses modern monitoring and process control tools to understand and control manufacturing processes. PAT aims to understand all sources of variability and ensure quality. Its framework involves process understanding through identifying variability sources and using tools like multivariate data analysis, modern process analyzers like UV/Vis probes, and continuous improvement software. The document outlines how PAT can be applied in mixing processes using probes to monitor solid particle size and liquid properties like turbidity and color. PAT allows for real-time monitoring to decrease production time and assure quality.
This document discusses Process Analytical Technology (PAT). It begins with an introduction to PAT, defining it as a system to design, analyze, and control manufacturing through timely measurements of critical quality attributes. It then discusses how PAT works by selecting a suitable PAT system and identifying critical process parameters. It highlights some key benefits of PAT such as improving process understanding and control, enhancing safety, and reducing variation. The document also provides examples of common PAT applications and discusses regulatory guidance around implementing PAT from agencies like the FDA.
The document discusses Process Analytical Technology (PAT) and its implementation in the pharmaceutical industry. PAT uses tools like near infrared (NIR) spectroscopy and Raman spectroscopy to monitor critical quality attributes during manufacturing. The key aspects of PAT include identifying quality attributes through risk analysis, understanding manufacturing processes, and using process analyzers to monitor parameters and detect defects early. Process analyzers provide real-time multivariate data to facilitate continuous process monitoring and control. NIR spectroscopy and Raman spectroscopy allow fast, non-destructive measurement and have been applied to various unit operations in pharmaceutical manufacturing. Successful implementation of PAT and process analyzers can improve quality, reduce costs, and help ensure consistent production of quality products.
1. Process analytical technology (PAT) aims to shift pharmaceutical development and manufacturing from testing quality through sampling to building quality into products using continuous monitoring and control strategies.
2. PAT involves establishing quantitative relationships between raw materials, process parameters, and product quality attributes to decrease variability, contamination, and costs while improving quality.
3. The goals of PAT include encouraging innovation through a risk-based regulatory framework that facilitates new manufacturing technologies and ensures consistent application of regulations.
The document discusses process analytical chemistry, which involves applying analytical chemistry techniques to chemical processes for quality control and production monitoring. It provides an introduction to process analytical chemistry, outlines its importance for obtaining real-time process measurements, and notes some of its applications in industries like pharmaceutical manufacturing. The document also discusses related topics like process analytical technology and on-line monitoring.
The document discusses Process Analytical Technology (PAT), which uses modern monitoring and process control tools to understand and control manufacturing processes. PAT aims to understand all sources of variability and ensure quality. Its framework involves process understanding through identifying variability sources and using tools like multivariate data analysis, modern process analyzers like UV/Vis probes, and continuous improvement software. The document outlines how PAT can be applied in mixing processes using probes to monitor solid particle size and liquid properties like turbidity and color. PAT allows for real-time monitoring to decrease production time and assure quality.
This document discusses Process Analytical Technology (PAT). It begins with an introduction to PAT, defining it as a system to design, analyze, and control manufacturing through timely measurements of critical quality attributes. It then discusses how PAT works by selecting a suitable PAT system and identifying critical process parameters. It highlights some key benefits of PAT such as improving process understanding and control, enhancing safety, and reducing variation. The document also provides examples of common PAT applications and discusses regulatory guidance around implementing PAT from agencies like the FDA.
The document discusses Process Analytical Technology (PAT) and its implementation in the pharmaceutical industry. PAT uses tools like near infrared (NIR) spectroscopy and Raman spectroscopy to monitor critical quality attributes during manufacturing. The key aspects of PAT include identifying quality attributes through risk analysis, understanding manufacturing processes, and using process analyzers to monitor parameters and detect defects early. Process analyzers provide real-time multivariate data to facilitate continuous process monitoring and control. NIR spectroscopy and Raman spectroscopy allow fast, non-destructive measurement and have been applied to various unit operations in pharmaceutical manufacturing. Successful implementation of PAT and process analyzers can improve quality, reduce costs, and help ensure consistent production of quality products.
1. Process analytical technology (PAT) aims to shift pharmaceutical development and manufacturing from testing quality through sampling to building quality into products using continuous monitoring and control strategies.
2. PAT involves establishing quantitative relationships between raw materials, process parameters, and product quality attributes to decrease variability, contamination, and costs while improving quality.
3. The goals of PAT include encouraging innovation through a risk-based regulatory framework that facilitates new manufacturing technologies and ensures consistent application of regulations.
The document discusses process analytical chemistry, which involves applying analytical chemistry techniques to chemical processes for quality control and production monitoring. It provides an introduction to process analytical chemistry, outlines its importance for obtaining real-time process measurements, and notes some of its applications in industries like pharmaceutical manufacturing. The document also discusses related topics like process analytical technology and on-line monitoring.
An audit of a microbiology laboratory involves independently reviewing the laboratory's records, operations, and procedures to evaluate efficiency, effectiveness, compliance, and risk mitigation. The objectives are to determine the quality systems in place, the knowledge and capabilities of audited staff, and whether continuous improvement is part of the culture. Principles of efficient auditing include proper preparation, documentation, adherence to methods and standard operating procedures, and staff proficiency demonstrations. Types of audits include those of contract manufacturers, contract laboratories, ingredient suppliers, and internal audits. A micro audit works backwards or forwards from samples to comprehensively evaluate microbiological control. The auditing process consists of planning, on-site information gathering, report preparation, exit meeting,
The document discusses Scale-Up and Post Approval Changes (SUPAC) guidelines established by the FDA. It defines SUPAC as changes made to the manufacturing process, equipment, batch size, or site after a drug has received FDA approval. The guidelines establish three levels of changes with varying documentation and reporting requirements depending on the level of change. Level 1 changes have the least requirements while level 3 changes require extensive testing data and may need pre-approval before implementation.
TGA presentation: PICS Guide for GMP and Data Integrity relating to microbiol...TGA Australia
An overview of regulatory requirements introduced as part of the new PIC/s PE009-13 Guide to Good Manufacturing Practice, specifically outlining impact on micro laboratories. Also, a summary of the new PI041-1 Data Integrity Guidance will be provided with a particular focus of Data Integrity in the laboratory
This document summarizes guidelines for analytical method validation from a presentation by the non-profit organization "Drug Regulations". Key points include: analytical methods must be validated for their intended use; validation should demonstrate accuracy, precision, specificity, linearity, range and robustness; changes may require revalidation; and transfer between labs requires verification to ensure equivalent performance.
This presentation describes the principles of qualification and validation which are applicable to the facilities, equipment, utilities and processes used for the manufacture of medicinal products. It is a GMP requirement that manufacturer’s control the critical aspects of their particular operations through qualification and validation over the life cycle of the product and process. Any planned changes to the facilities, equipment, utilities and processes, which may affect the quality of the product, should be formally documented and the impact on the validated status or control strategy assessed.
Analytical Method & Technology Transfer Ispe GuideCrown Cork & Seal
This document provides guidance on effectively transferring analytical methods between laboratories. It recommends a standardized process for transferring technology with minimum documentation. This includes establishing acceptance criteria before transfer, executing training at the receiving unit, and issuing a transfer report confirming the receiving unit's qualification. The guidance outlines experimental designs and acceptance criteria for transferring various analytical methods like assay, content uniformity, impurities testing, and dissolution testing. Acceptance criteria are generally based on statistical analyses showing equivalence between laboratory results.
Continuous Flow Chemistry And The Manufacture Of Active Pharmaceutical Ingr...Stuart Silverman
Continuous Flow Chemistry And The Manufacture Of Active Pharmaceutical Ingredients: A Series Of Informative Disquisitions About Continuous Flow Chemistry - Part Four - Quality Assurance and Control Safety
Presentation on the examination of microbiological data for assessment and trending.
Includes: normalizing data, graphs, and assessment of alert and action levels.
Webinar: How to Develop a Regulatory-compliant Continued Process Verificatio...MilliporeSigma
Participate in the interactive webinar now: http://bit.ly/CPVWebinar
Product life cycle consists of 3 phases: Process Design, Process Performance Qualification and the last and the lengthiest Continued Process Verification (CPV). As more and more biomanufacturing processes enter commercial phases, the critical need to understand how to efficiently perform CPV programs arises.
Explore our webinar library: www.emdmillipore.com/webinars
This presentation discusses approaches for determining the number of process performance qualification (PPQ) batches needed based on a risk-based assessment of product and process knowledge and the control strategy. It describes evaluating the risks associated with product attributes, process parameters, and controls. Factors that influence risk, such as raw material variability, equipment capabilities, and process performance history are reviewed. The goal is to justify the minimum number of PPQ batches required based on the level of process understanding and control.
The document discusses Good Laboratory Practices (GLP). It provides definitions and history of GLP. GLP refers to a quality management system for laboratories conducting non-clinical safety studies. It aims to ensure reliability and integrity of test data. Key aspects of GLP include organization, SOPs, facilities, equipment, test systems, study planning and reporting, archiving. Non-compliance can result in disqualification and rejection of study data by regulatory agencies.
This presentation summarizes recommendations from an ISPE working group for assessing blend and content uniformity. The group proposed modifications to address issues with the withdrawn 2002 FDA guidance. Key recommendations include a two-stage blend testing approach using statistical analysis and flexibility in selecting sampling plans, acceptance criteria, and confidence/coverage levels using a risk-based approach.
This document provides information from an online resource called Drug Regulations for pharmaceutical professionals. It discusses concepts related to cleaning validation for active pharmaceutical ingredient plants. The presentation covers topics like acceptance criteria, levels of cleaning, control of cleaning processes, bracketing and worst case scenarios, determination of residue amounts, and cleaning validation protocols. It provides examples and guidelines for calculating acceptance limits for cleaning validation.
This document discusses analytical method transfer between laboratories. It defines analytical method transfer as qualifying a receiving laboratory to use a test procedure that originated in another laboratory. There are different types of method transfers, including comparative testing between laboratories, covalidation where both laboratories participate in validation, and complete or partial revalidation of methods in the receiving laboratory. Successful method transfers require several key elements, such as a pre-approved transfer plan, detailed description of test methods and procedures, description of test requirements, rationale for test parameters, acceptance criteria, and documentation of results. The goal is to verify that analytical methods produce equivalent results in different laboratories.
ANALYTICAL METHOD VALIDATION BY P.RAVISANKAR Dr. Ravi Sankar
This document discusses analytical method validation. It begins with an introduction that defines validation and discusses its importance and regulatory requirements. The document then covers specific validation parameters such as specificity, linearity, accuracy, precision, limit of detection, limit of quantification and more. For each parameter, the document provides definitions, procedures for evaluation, and acceptance criteria. It emphasizes that validation demonstrates a method is suitable for its intended purpose and supports the identity, quality, purity and potency of drug substances and products. The overall summary is that analytical method validation is critical to ensure quality and compliance in the pharmaceutical industry.
FDA Process Validation Guidance (Guidance for Industry: Process Validation- General Principles and Practices, Jan. 2011) outlines process validation activities in three stages - Stage 1: Process Design, Stage 2: Process Qualification and Stage 3: Continued Process Verification. Completion of Stage 2 subsequent to Stage 1 is a major milestone in the Process Validation Lifecycle as it confirms the process design and demonstrates the expected consistent performance of the manufacturing process. Knowledge and information gained from the design stage through the process qualification stage is used to complete this assessment. Stage 2 demonstrates suitability for successful commercial distribution where the data indicates that the process meets the conditions established in the protocol. Continued Process Verification is initiated for the subsequent commercial batches. Stage 3 assures that the process remains in a state of control during commercial manufacture.
This presentation gives a practical approach to implement the stage 3 of the FDA Process Validation Guide.
This document discusses out-of-trend (OOT) results, which occur when a result does not follow the expected trend based on past data. It notes that identifying OOT results is becoming a regulatory issue and introduces some statistical approaches for doing so, like using a minimum of 25 batches to set a trend range of average ±3 standard deviations. Some challenges of implementing OOT identification for commercial batches are determining the appropriate statistical approach, data requirements, and investigation process. The conclusion states that identifying OOT results is important for regulators and industry, and the method should not be too complex.
The document discusses how particle size affects the scale-up of solid/liquid separations. It defines key terms used in filtration and presents equations showing how specific cake resistance, which depends on particle size, surface area, and volume, impacts filtration pressure and rate. Test results demonstrate that smaller mean particle sizes lead to significantly higher specific cake resistance and slower filtration. The document concludes that particle size distribution and compressibility must be considered for successful filtration scale-up between lab and production scales.
1) Recent advances in continuous flow chemistry allow for safer and more efficient reactions through the use of inline monitoring techniques like ATR-FTIR.
2) A Strecker reaction was optimized in a flow reactor using ATR-FTIR to monitor the reaction in situ which allowed for safer operation and higher yields through rapid stoichiometric optimization.
3) A chemoenzymatic sequence for the stereoselective synthesis of lactones was developed using a single-operation protocol combining continuous flow hydrogenation and biocatalyzed Baeyer-Villiger oxidation which provided a safer and simpler procedure.
An audit of a microbiology laboratory involves independently reviewing the laboratory's records, operations, and procedures to evaluate efficiency, effectiveness, compliance, and risk mitigation. The objectives are to determine the quality systems in place, the knowledge and capabilities of audited staff, and whether continuous improvement is part of the culture. Principles of efficient auditing include proper preparation, documentation, adherence to methods and standard operating procedures, and staff proficiency demonstrations. Types of audits include those of contract manufacturers, contract laboratories, ingredient suppliers, and internal audits. A micro audit works backwards or forwards from samples to comprehensively evaluate microbiological control. The auditing process consists of planning, on-site information gathering, report preparation, exit meeting,
The document discusses Scale-Up and Post Approval Changes (SUPAC) guidelines established by the FDA. It defines SUPAC as changes made to the manufacturing process, equipment, batch size, or site after a drug has received FDA approval. The guidelines establish three levels of changes with varying documentation and reporting requirements depending on the level of change. Level 1 changes have the least requirements while level 3 changes require extensive testing data and may need pre-approval before implementation.
TGA presentation: PICS Guide for GMP and Data Integrity relating to microbiol...TGA Australia
An overview of regulatory requirements introduced as part of the new PIC/s PE009-13 Guide to Good Manufacturing Practice, specifically outlining impact on micro laboratories. Also, a summary of the new PI041-1 Data Integrity Guidance will be provided with a particular focus of Data Integrity in the laboratory
This document summarizes guidelines for analytical method validation from a presentation by the non-profit organization "Drug Regulations". Key points include: analytical methods must be validated for their intended use; validation should demonstrate accuracy, precision, specificity, linearity, range and robustness; changes may require revalidation; and transfer between labs requires verification to ensure equivalent performance.
This presentation describes the principles of qualification and validation which are applicable to the facilities, equipment, utilities and processes used for the manufacture of medicinal products. It is a GMP requirement that manufacturer’s control the critical aspects of their particular operations through qualification and validation over the life cycle of the product and process. Any planned changes to the facilities, equipment, utilities and processes, which may affect the quality of the product, should be formally documented and the impact on the validated status or control strategy assessed.
Analytical Method & Technology Transfer Ispe GuideCrown Cork & Seal
This document provides guidance on effectively transferring analytical methods between laboratories. It recommends a standardized process for transferring technology with minimum documentation. This includes establishing acceptance criteria before transfer, executing training at the receiving unit, and issuing a transfer report confirming the receiving unit's qualification. The guidance outlines experimental designs and acceptance criteria for transferring various analytical methods like assay, content uniformity, impurities testing, and dissolution testing. Acceptance criteria are generally based on statistical analyses showing equivalence between laboratory results.
Continuous Flow Chemistry And The Manufacture Of Active Pharmaceutical Ingr...Stuart Silverman
Continuous Flow Chemistry And The Manufacture Of Active Pharmaceutical Ingredients: A Series Of Informative Disquisitions About Continuous Flow Chemistry - Part Four - Quality Assurance and Control Safety
Presentation on the examination of microbiological data for assessment and trending.
Includes: normalizing data, graphs, and assessment of alert and action levels.
Webinar: How to Develop a Regulatory-compliant Continued Process Verificatio...MilliporeSigma
Participate in the interactive webinar now: http://bit.ly/CPVWebinar
Product life cycle consists of 3 phases: Process Design, Process Performance Qualification and the last and the lengthiest Continued Process Verification (CPV). As more and more biomanufacturing processes enter commercial phases, the critical need to understand how to efficiently perform CPV programs arises.
Explore our webinar library: www.emdmillipore.com/webinars
This presentation discusses approaches for determining the number of process performance qualification (PPQ) batches needed based on a risk-based assessment of product and process knowledge and the control strategy. It describes evaluating the risks associated with product attributes, process parameters, and controls. Factors that influence risk, such as raw material variability, equipment capabilities, and process performance history are reviewed. The goal is to justify the minimum number of PPQ batches required based on the level of process understanding and control.
The document discusses Good Laboratory Practices (GLP). It provides definitions and history of GLP. GLP refers to a quality management system for laboratories conducting non-clinical safety studies. It aims to ensure reliability and integrity of test data. Key aspects of GLP include organization, SOPs, facilities, equipment, test systems, study planning and reporting, archiving. Non-compliance can result in disqualification and rejection of study data by regulatory agencies.
This presentation summarizes recommendations from an ISPE working group for assessing blend and content uniformity. The group proposed modifications to address issues with the withdrawn 2002 FDA guidance. Key recommendations include a two-stage blend testing approach using statistical analysis and flexibility in selecting sampling plans, acceptance criteria, and confidence/coverage levels using a risk-based approach.
This document provides information from an online resource called Drug Regulations for pharmaceutical professionals. It discusses concepts related to cleaning validation for active pharmaceutical ingredient plants. The presentation covers topics like acceptance criteria, levels of cleaning, control of cleaning processes, bracketing and worst case scenarios, determination of residue amounts, and cleaning validation protocols. It provides examples and guidelines for calculating acceptance limits for cleaning validation.
This document discusses analytical method transfer between laboratories. It defines analytical method transfer as qualifying a receiving laboratory to use a test procedure that originated in another laboratory. There are different types of method transfers, including comparative testing between laboratories, covalidation where both laboratories participate in validation, and complete or partial revalidation of methods in the receiving laboratory. Successful method transfers require several key elements, such as a pre-approved transfer plan, detailed description of test methods and procedures, description of test requirements, rationale for test parameters, acceptance criteria, and documentation of results. The goal is to verify that analytical methods produce equivalent results in different laboratories.
ANALYTICAL METHOD VALIDATION BY P.RAVISANKAR Dr. Ravi Sankar
This document discusses analytical method validation. It begins with an introduction that defines validation and discusses its importance and regulatory requirements. The document then covers specific validation parameters such as specificity, linearity, accuracy, precision, limit of detection, limit of quantification and more. For each parameter, the document provides definitions, procedures for evaluation, and acceptance criteria. It emphasizes that validation demonstrates a method is suitable for its intended purpose and supports the identity, quality, purity and potency of drug substances and products. The overall summary is that analytical method validation is critical to ensure quality and compliance in the pharmaceutical industry.
FDA Process Validation Guidance (Guidance for Industry: Process Validation- General Principles and Practices, Jan. 2011) outlines process validation activities in three stages - Stage 1: Process Design, Stage 2: Process Qualification and Stage 3: Continued Process Verification. Completion of Stage 2 subsequent to Stage 1 is a major milestone in the Process Validation Lifecycle as it confirms the process design and demonstrates the expected consistent performance of the manufacturing process. Knowledge and information gained from the design stage through the process qualification stage is used to complete this assessment. Stage 2 demonstrates suitability for successful commercial distribution where the data indicates that the process meets the conditions established in the protocol. Continued Process Verification is initiated for the subsequent commercial batches. Stage 3 assures that the process remains in a state of control during commercial manufacture.
This presentation gives a practical approach to implement the stage 3 of the FDA Process Validation Guide.
This document discusses out-of-trend (OOT) results, which occur when a result does not follow the expected trend based on past data. It notes that identifying OOT results is becoming a regulatory issue and introduces some statistical approaches for doing so, like using a minimum of 25 batches to set a trend range of average ±3 standard deviations. Some challenges of implementing OOT identification for commercial batches are determining the appropriate statistical approach, data requirements, and investigation process. The conclusion states that identifying OOT results is important for regulators and industry, and the method should not be too complex.
The document discusses how particle size affects the scale-up of solid/liquid separations. It defines key terms used in filtration and presents equations showing how specific cake resistance, which depends on particle size, surface area, and volume, impacts filtration pressure and rate. Test results demonstrate that smaller mean particle sizes lead to significantly higher specific cake resistance and slower filtration. The document concludes that particle size distribution and compressibility must be considered for successful filtration scale-up between lab and production scales.
1) Recent advances in continuous flow chemistry allow for safer and more efficient reactions through the use of inline monitoring techniques like ATR-FTIR.
2) A Strecker reaction was optimized in a flow reactor using ATR-FTIR to monitor the reaction in situ which allowed for safer operation and higher yields through rapid stoichiometric optimization.
3) A chemoenzymatic sequence for the stereoselective synthesis of lactones was developed using a single-operation protocol combining continuous flow hydrogenation and biocatalyzed Baeyer-Villiger oxidation which provided a safer and simpler procedure.
The document discusses the role of process analytical technology (PAT) in green chemistry and green engineering. It provides an overview of the speaker's past and current involvement with green chemistry, including conference presentations and publications. Several case studies are presented that illustrate how PAT tools like calorimetry, ATR-FTIR spectroscopy, and continuous processing can make chemical processes safer, minimize hazards, and enable more nature-like bioprocesses.
The document discusses the use of real-time in situ Fourier transform infrared spectroscopy (FTIR) for kinetic investigation of organic synthesis reactions using a ReactIR flow cell. It provides examples of using the flow cell to monitor a palladium-catalyzed cross-coupling reaction in both continuous flow and batch modes. Reaction progress kinetic analysis of the cross-coupling revealed it to be zero-order in both reactants and first-order in the palladium catalyst, indicating the rate-limiting step is likely reductive elimination.
21st International Conference Organic Process Research & Development 2010 San...dominev
This document discusses using real-time calorimetry to improve operational efficiency. It presents case studies where ReactIR, FBRM, PVM and RTCal were used:
1) ReactIR developed kinetic models to minimize byproducts in pharmaceutical reactions and improve crystallization processes.
2) FBRM and PVM helped optimize a crystallization to reduce impurities below 0.5%.
3) RTCal validated switching to a low copper acrylamide grade for polymerization, showing a shorter induction period but similar maximum heat output. Real-time calorimetry provided process safety evaluation.
1) In-situ FTIR spectroscopy using a ReactIR flow cell allows for real-time monitoring and analysis of continuous chemical reactions without the need for offline sampling.
2) A case study demonstrated the use of in-situ FTIR to develop a continuous process for the ozonolysis of styrene and an API intermediate, allowing characterization of reaction kinetics, intermediates, and optimization of flow rate and reactor size.
3) This led to the safe, efficient production of 2.7 kg of an API intermediate over 4 days with 99% conversion and 85% ozone efficiency. In-situ FTIR enabled continuous monitoring and ensured high product quality and yield.
The document discusses three key strategies for future growth at PHARMACO:
1. Centralizing call handling through a call center to reduce pharmacist and technician phone times.
2. Migrating refill prescriptions from stores to a mail order program to focus on new prescriptions in stores.
3. Focusing on growing the mail order business by installing business processes to fulfill prescriptions through mail order using retail stores, aiming to increase mail order volume to over 30% of prescriptions.
Modeling of Granular Mixing using Markov Chains and the Discrete Element Methodjodoua
The document presents a method for modeling granular mixing using Markov chains and the discrete element method (DEM). It motivates the use of Markov chains to efficiently simulate granular mixing as an alternative to computationally expensive DEM simulations. The theory and definitions of Markov chains and operators are provided. The method is applied to simulate mixing in a cylindrical drum, and the effects of the number of states, time step, and learning time are investigated. Properties of the resulting operator like the invariant distribution and mixing rates are analyzed to characterize the mixing dynamics.
13th Brazilian Meeting on Organic Synthesisdominev
Combining real-time analytics and process control can enhance chemical development. FTIR was used as a PAT tool in two case studies:
1) Monitoring a deprotonation reaction in situ allowed precise endpoint determination, minimizing impurities. This improved process was successfully scaled up.
2) FTIR monitored three consecutive continuous reactions for a pharmaceutical intermediate. Real-time feedback controlled base feed rate and ensured proper stoichiometry, minimizing waste and impurities. This continuous process was also successfully scaled up.
Real-time flow analysis using FTIR allows more efficient process optimization, development, and scale-up through in-line monitoring and feedback control.
3rd International Symposium On Green Processingdominev
The document discusses how real-time process analytical technology (PAT) tools like in-line FTIR and reaction calorimetry can help optimize continuous flow chemistry and batch processes to make them more efficient and environmentally friendly by allowing for real-time process monitoring and control. Case studies show how PAT has been used to improve crystallization processes, downstream processing, and assess process safety.
Impact of the Time Step in DEM Simulations on Granular Mixing Propertiesjodoua
The document discusses how the time step in DEM (discrete element method) simulations affects granular mixing properties. It finds that the time step strongly influences velocity profiles and fluctuations, with larger time steps producing non-physical results. Even with time steps an order of magnitude below the critical value, there is still lack of convergence. The implications are that the critical time step should be used as a guide for ensuring solution consistency in DEM simulations of dynamical mixing systems.
Towards Crystallization Using a Strong Electric FieldNorbert Radacsi
This document discusses experiments on applying strong electric fields to influence crystallization. Key findings include:
- Crystal growth rates of isonicotinamide and 4-hydroxybenzoic acid increased up to 15 times in the presence of an electric field.
- The induction time for nucleation of isonicotinamide crystals decreased when an electric field was applied.
- Recrystallization of isonicotinamide in the presence of an electric field produced a different polymorph (form II) than without an electric field (form I).
- The electric field is believed to increase local supersaturation through effects like electromigration, leading to changed crystallization behavior.
The document provides information on protein crystallization, including what is needed to crystallize a protein, how to improve crystallization chances, the theory behind crystallization setups and conditions, evaluating crystallization screens, optimizing conditions if hits are found, adding ligands or modifying the protein if no crystals are obtained initially, and qualities of good crystals. The goal is to crystallize pure, concentrated, monodisperse protein in conditions that will cause it to come out of solution and form ordered crystal lattices for structure determination.
Monitoring and quantifing polymorphic crystallizations (james ward 111203)com...James Ward
The document discusses using Raman spectroscopy to monitor polymorphic crystallizations and the influence of particle properties on Raman spectra. It shows that Raman intensities change with particle size, shape, and concentration due to light scattering effects. Case studies demonstrate that accounting for changing particle dynamics over time is important for quantitative Raman analysis of polymorph ratios during crystallization processes. Taking particle properties into account through techniques like FBRM-Raman coupling and chemometrics allows Raman to be utilized for dynamic crystallization monitoring.
This document discusses using in-line IR spectroscopy to analyze reactions in continuous flow systems. It describes challenges in analyzing continuous reactions and how ReactIR can provide real-time monitoring without sampling. Case studies are presented where ReactIR was used to optimize a Doebner modification reaction in a few hours, monitor a hazardous reaction involving hydrazine for safety, and troubleshoot a multi-step synthesis. ReactIR allows rapid screening and optimization of reaction conditions as well as safer handling of dangerous chemicals through continuous monitoring.
Sequential Design – The Challenge Of Multiphase Systems PdJames Ward
The document outlines an approach to developing a robust process for producing a crystalline form of a drug using mechanistic understanding rather than statistical modeling alone. Key factors like temperature, solvent composition, and water content were identified through solubility studies and reaction monitoring, allowing a targeted design of experiments. The initial process worked well at scale but later required modification when a new solvate form appeared. Repeating the mechanistic work incorporating prior knowledge improved the process design and mitigated issues with particle size and form variability.
Advances in Organic Chemistry in Academia Using Real-Time In Situ Mid-FTIR - ...pscholl
Three case studies from scientific literature that illustrate how real-time in situ mid-FTIR (ReactIR) is used to advance the understanding of chemical reactions. Email me at paul.scholl@mt.com if you are interested in links to technical webinars and whitepapers on the topics of mid-FTIR in situ reaction analysis, process characterization & scale-up and reaction calorimetry.
Flow Structure Mapping of Segregating Granular Mixtures using Radioactive Par...jodoua
The document summarizes a new radioactive particle tracking (RPT) method called bulk radioactive particle tracking (BRPT) to study granular flow structures. BRPT uses multiple tracer particles that match the properties of inert particles to overcome limitations of traditional RPT. Preliminary results from a drum mixer show BRPT can measure radial mixing times and monitor particle content with high precision offline and potentially online. Ongoing work aims to determine concentration profiles and axial dispersion over time.
Upfront Thinking to Design a Better Lab Scale DoEplaced1
Presentation Given at AIChE 2009 and the Dynochem User meeting. Discussion on using mechanistic modeling to support DoE investigations and QbD initiatives for single reaction steps.
The role of process analytical technology (pat) in green chemistry and green ...dominev
This document discusses the use of process analytical technology (PAT) tools in green chemistry and engineering. It presents case studies on using Fourier transform infrared spectroscopy (FTIR) and reaction calorimetry to monitor and develop continuous bioprocesses and chemical reactions. Specifically, it examines how FTIR was used to monitor a biotransformation reaction and develop a continuous multi-step synthesis. It also explores how reaction calorimetry helped classify reaction kinetics and screen conditions to optimize reactions. The document emphasizes how PAT tools can advance green chemistry principles by enabling real-time process monitoring, improving reaction understanding, and facilitating continuous process development and scale-up.
This document presents information on process analytical technology (PAT) for pharmaceutical development, manufacturing, and quality assurance. It discusses the definition, principles, goals, framework, tools, and implementation of PAT. Case studies are provided that demonstrate how PAT tools like in-situ FTIR, Raman spectroscopy, and chemical imaging can be used for reaction monitoring, crystallization, granulation, blending, and identification of raw materials. Barriers to PAT implementation include historical, cultural, organizational challenges but benefits include reduced cycle times, prevention of rejects, continuous improvement, and real-time release. PAT facilitates building quality into pharmaceutical products through process understanding.
A Novel approach for quantitative real-time particle analysis of lentiviral v...Myriade
Lentiviral vectors are efficient vehicles for stable gene transfer in dividing and non-dividing cells. They tend to be increasingly used as a powerful tool to introduce genes into cells ex vivo, for instance in CAR-T cell therapies.
During manufacturing and production of lentiviral vectors, relevant quality control is necessary to allow batch release (1). Among standard quality control methods that can be used, quantification of lentiviral vector particles – or physical titer – is one of the most important. Up to now, this characterization can be achieved either indirectly with p24 protein quantification or with physical methods like Tunable Resistive Pulse Sensing (TRPS) for example, both methods implying prior preparation of samples (lysis, dilution or filtration). These two methods thus show important limitations as they cannot accurately reflect the true nature of the product, in addition to being relatively time-consuming (2).
Myriade, a French company created in 2017, is developing Videodrop, a new optical technique performing real-time, user-friendly, and label-free measurement of lentiviral vector physical titer. This method, based on full-field interferometry (3), was tested on various lentiviral vector samples: in a context of Drug Product (DP) release as well as in-process controls.
We compared three lentiviral physical titration methods on aratinga.bio productions: p24 ELISA, qNano and Videodrop – Myriade instrument. The correlation between Videodrop analysis and the other two methods appeared to be robust, with high R² values. These results suggest that Myriade technology is relevant for DP release as well as in-process controls, offering the ability to be a tool for continuous improvement. It is an easy-touse and fast alternative to the standard more complex and time-consuming physical titration methods.
Biopharmaceutical manufacturing processes are complex, challenging and utilize living organisms to produce safe and efficacious biopharmaceuticals. These molecules themselves have high molecular weights and complex structures that will exhibit heterogeneity such that at any given vial contains not one active ingredient but a population of biologically active molecules which must have maximal benefit to the patient with minimal deleterious effects. The necessity for controlling variation in processes, and hence product, is self-evident when we consider how our actions affect the lives of the patients our products are developed for. This presentation focuses on understanding the various origins of process variation and examines strategies for reducing their impact or eliminating them all together.
http://parker.com/dh
Dilip Shah is seeking a position in pharmaceutical research utilizing his skills in laboratory instrumentation and assays. He has over 15 years of experience in compound management, high-throughput screening, and assay operations at major pharmaceutical companies. His technical skills include automated liquid handling systems, fluorescence and luminescence detection instruments, and assay techniques for targets such as ion channels, kinases, and phosphodiesterases.
Erica Canzler - Advances and Lessons Learned in DecontaminationMatthew Kirkby
Advances in decontamination technologies and strategies were tested to help improve response to biological incidents. The Biological Operational Test and Evaluation Project tested three decontamination methods - vaporized hydrogen peroxide, bleach, and chlorine dioxide fumigation. Chlorine dioxide was most effective at reducing spore levels, while bleach produced the most waste. Overall costs were dominated by waste management. The methyl bromide fumigation study demonstrated the feasibility of using this technology for decontamination of structures. Efforts are also underway to develop strategies to safely restore contaminated underground transportation systems like subways following an incident.
Structural characterisation and epitope mapping by HDX-MS (Advanced Analytica...Quality Assistance s.a.
Hydrogen-Deuterium Exchange Mass Spectrometry (HDX-MS) is an innovative tool for the characterisation of biotherapeutics. Besides the study of higher-order structures, HDX-MS can also be used for epitope mapping studies in order to determine to which region of the target a monoclonal antibody binds. HDX-MS is a good alternative to techniques such as X-ray diffraction or NMR.
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GLP (Good Laboratory Practice) is a quality system for non-clinical health and environmental safety studies. It was instituted in the US after fraudulent data was submitted by toxicology labs. GLP aims to ensure studies are properly planned, monitored, and reported, and that data accurately reflects results. It promotes international acceptance of safety tests. The OECD principles provide an international standard for GLP, covering topics like facility organization, test system and item characterization, and record keeping. India has established a National GLP Compliance Monitoring Authority to oversee GLP standards.
Adrian Joseph is seeking an entry-level scientist position in cell culture and biopharmaceutical purification. He has 5 years of lab research experience developing novel methods, including scale-down models to efficiently characterize harvest processes involving centrifugation, filtration, and other techniques. He completed internships developing such methods and presenting findings. Joseph holds a PhD focused on characterizing and scaling down mammalian cell culture harvest operations.
The compound characterization market is growing increasingly profitable and competitive at the same time. In order to develop a new compound product, the testing step is indispensable. Unlike drug discovery, compound testing is not as restrictive, but understanding the main workflow is still necessary to excel in the market. In order to help you improve both the efficiency and safety of compound testing, we developed the protocol to assist you in your findings.
This document discusses process changes that may occur over the lifecycle of a drug development process. It defines types of process changes and outlines steps for assessing and implementing changes. These include forming cross-functional teams, using risk analysis tools like FMEA to evaluate impacts, and process analytical technologies to increase understanding and control of critical parameters. The goal is to reduce the frequency of changes by investing in characterization, setting realistic specifications, and combining changes when possible. Case studies of what can go wrong are also presented.
Ronald Preibis has over 17 years of experience in the biotech field, including extensive experience in all aspects of cell culture and purification. He has worked in manufacturing roles at several biotech companies, leading teams and supervising processes. His experience includes process development, cGMP manufacturing, analytical testing, documentation, and ensuring regulatory compliance. He is pursuing additional education in life sciences and biomedical laboratory sciences.
Good Laboratory Practice(GLP) by Kashikant YadavKashikant Yadav
Good Laboratory Practice (GLP) regulations were created by the FDA in 1978 to ensure quality and integrity of safety data from non-clinical health and environmental safety studies. GLP provides a framework for the organizational processes and conditions under which these studies are planned, performed, monitored, recorded, reported and archived. It aims to make sure data submitted to regulatory authorities is a true reflection of study results. Key aspects of GLP include requirements for facilities, equipment, test systems, personnel, standard operating procedures, study plans and reports. The overall goal of GLP is to promote quality test data for regulatory decision making.
Generic product development and technology transfer : At a glanceDr. Girish S Sonar
It’s honor to get invited as a speaker and to address “Pharma Formulation and Regulatory Symposium” organized by Merck Malaysia on 6th Sept, 2018 at Pullman Bangsar, Kuala Lumpur, Malaysia. The topic I presented was “Generic Product Development and Technology Transfer: At a Glance”. Scientists and industry experts from 31 Malaysia Pharma companies and Universities attended this symposium. The presentation covered challenges and remedies come across from product development to approval from regulatory agencies.
Pleasured to share desk with Dr. Torsten Schadendorf, Marketing Manager Merck Germany, Dr. Gudrun Birk, Head of Controlled Release, Merck Germany and Professor Tin Wui Wong, Universiti Teknologi MARA, Malaysia.
Testing for microbial excursions in pharmaceutical waters has meant lengthy delays due to plate counting or sample preparation requiring stains and reagents. With the application of advanced laser based technology, on-line 7000RMS (Real-time Microbial System) delivers continuous measurement of microbes and inert particles in real time.
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The Role of BPOG Extractables Data in the Effective Adoption of Single-Use Sy...Merck Life Sciences
The successful adoption of single-use technologies in a biopharmaceutical process largely relies on confidently selecting the right components for use in the fluid path of a product, within a specific process. An important step in choosing such components requires generating an extractables profile, which can be done by carefully selecting the solvent streams and extraction conditions to model the product and process steps complemented with the right analytical strategy.
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● The important stages in the risk assessment process as demonstrated by case studies from typical drug manufacturing processes where single-use components were used.
Good laboratory practices awervness course ayAdel Younis
The document discusses good laboratory practice (GLP) standards, including the history and purpose of GLP, key aspects of GLP such as facilities, equipment, personnel, documentation, and quality assurance, and the consequences for noncompliance with GLP, which include potential disqualification from conducting laboratory studies and starting new studies. GLP standards were established to ensure the integrity and reliability of nonclinical safety data submitted to regulatory authorities and promote consistent practices internationally.
Sitec Labs provides contract research services with the vision to be a global leader in the industry through innovation and quality excellence. Their mission is to support drug discovery and development, ensure compliance with quality standards, and be a long-term trusted partner. They have over 350 staff members across two facilities totaling 75,000 square feet. Services include analytical research, impurity synthesis, bioavailability/bioequivalence studies, and regulatory compliance.
Similar to 4th International Conference on Process Analytical Technologies in Organic Process R&D Brussels 2009 (20)
This document discusses several studies utilizing continuous flow microreactors for organic synthesis. One study produced an unstable Vilsmeier-Haack formylation intermediate in a safe and controlled manner using inline infrared analysis to optimize reaction conditions. Another used inline infrared to study gas-liquid homogeneous catalysis kinetics at high pressures. A third demonstrated automated optimization of a Pall-Knorr reaction using online infrared data in a microfluidic system.
AiChE National Meeting 2012 Pittsburgh Presentation Flow Continuousdominev
1) In-situ FTIR spectroscopy using a ReactIR flow cell allows for real-time monitoring and analysis of continuous chemical reactions without interrupting flow.
2) Case studies demonstrated its use in optimizing a continuous ozonolysis reaction for safer API production, achieving a 2.7kg yield in 4 days.
3) Rapid screening and optimization of a Doebner modification reaction was also demonstrated, identifying optimal conditions within hours using on-the-fly variation of temperature and residence time analyzed via the in-situ FTIR.
Dom Hebrault presented on using real time in situ FTIR analytics to enhance development and control of continuous processes. He discussed three case studies: [1] rapidly optimizing a Doebner modification reaction using inline FTIR to monitor concentrations in real time; [2] safely monitoring a hazardous indazole synthesis using hydrazine in flow; and [3] improving product quality of a Grignard reaction for drug synthesis from 40% to 1% impurity using inline FTIR process control. The case studies demonstrated how inline FTIR can provide major benefits for continuous flow reaction optimization, monitoring hazardous substances, and process quality control.
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1) Developing a continuous ozonolysis process for an API intermediate using in-situ FTIR to monitor the reaction in real-time, allowing production of 2.7kg of product in 2 weeks.
2) Optimizing a Doebner modification of the Knoevenagel reaction in continuous mode using in-line FTIR to visually monitor the reaction and screen conditions.
In both cases, in-line FTIR provided real-time analysis of the reaction and intermediates, enabling rapid process development and optimization without the need for offline sampling and analysis. This
This document discusses the use of in situ FTIR spectroscopy for monitoring organic synthesis reactions in real time. It describes how ReactIR, a flow cell accessory, allows for non-destructive analysis of reactions under normal operating conditions. This enables continuous monitoring of reaction kinetics, pathways and intermediates. The document presents examples of using the real-time spectral data from ReactIR to control reaction parameters and optimize multi-step continuous flow processes. Specifically, it shows how reactant addition can be automatically controlled based on measured intermediate concentrations to improve efficiency and reduce waste. Overall, the document illustrates how in situ FTIR spectroscopy is enhancing the development, analysis and control of continuous chemical synthesis.
This document discusses using in-line infrared (IR) spectroscopy to monitor and control multi-step continuous flow chemical reactions. It describes how ReactIR in-situ IR spectroscopy can provide real-time analysis of reaction kinetics and intermediates. The document also shows how ReactIR data can be used to automatically control the addition of a third reagent stream in stoichiometric amounts, improving reaction efficiency and product purity compared to manual control. ReactIR can be applied to microscale, mesoscale, and kilolab flow reactors.
4th International Conference on Process Analytical Technologies in Organic Process R&D Brussels 2009
1. PAT and Process Control: Hybrid Real-Time
Technologies for Enhanced Chemical
Development
Dominique Hebrault
Sr. Technology & Application
Consultant
Brussels, March 17-18, 2009
2. Presentation Outline
Introduction
- PAT
- Process Control
Case Studies
- Real Time In Situ Reaction Monitoring with ReactIR™
- Kinetics, Scale-up, and Process Safety with RC1e, and ReactIR™
- Crystallization with FBRM®, PVM® and ReactIR™
- Experiment Design, Data Acquisition, Analysis with Enhanced
Software Tools
1
4. Introduction
FDA’s View of Process Analytical Technologies
Process Analytical Technology (PAT)
- 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
- With the goal of ensuring final product quality
PAT Fundamental Tenets
- Quality cannot be tested into the product; it should be built-in or should
be by design
PAT Goals
- Enhance understanding and control of processes
3
5. Introduction
PAT tools can be categorized as:
- Process analyzers
- Process control tools
- Multivariate tools for design, data acquisition and analysis
- Continuous improvement and knowledge management tools
PAT tools are used:
- Process development
Process monitoring to develop mechanistic understanding
Statistical DOE and model building to enhance process
understanding
Use of risk analysis in establishment of design space
- Manufacturing
4
6. Introduction
API Development Scale up Production API
Understanding Optimization Scale-up Production
ReactIR™ iC10 ReactIR™ 45 MonARC
FBRM® in the lab PVM® in the lab FBRM® in the plant
RTCal™ for real-time
reaction calorimetry at
lab scale
7. Introduction
Poor temperature control
– Side reactions, slow kinetics
– Supersaturation control issues → broad distribution, impurity, polymorph
Manual addition
– High reagent concentration → by-products
– Supersaturation spikes → oiling out
Poor mixing
– Slow reaction
– Concentration gradient→ side-reaction
– Solid breakage, attrition
Reduce risk of experimental error
Reproducibility, traceability, data
logging, modeling
8. Presentation Outline
Introduction
- PAT
- Process Control
Case Studies
- Real Time In Situ Reaction Monitoring with ReactIR™
- Kinetics, Scale-up, and Process Safety with RC1e, and ReactIR™
- Crystallization with FBRM®, PVM® and ReactIR™
- Experiment Design, Data Acquisition, Analysis with Enhanced
Software Tools
7
9. Case Study: FTIR, PAT Tool in Pharma Development
Development of a Safe and Scalable
Oxidation Process for the Preparation of
6-Hydroxybuspirone
Introduction
Active metabolite of Buspirone,
manufactured and marketed as Buspar,
employed for the treatment of anxiety
disorders and depression
Multi Kg amount needed for clinical dev.
Process lack of ruggedness and
unreliable product quality
Source: Daniel J. Watson,* Eric D. Dowdy, Jeffrey S. DePue, Atul S. Kotnis, Simon Leung, and Brian C. O’Reilly, Bristol-Myers Squibb
Pharmaceutical Research Institute, NJ, USA, Organic Process Research and Development, 2004, 8, 616-623; Mettler Toledo Real Time Analytics
Users’ Forum 2004, London, UK
10. Case Study: FTIR, PAT Tool in Pharma Development
Challenges KHMDS
Monitor deprotonation of 1 for:
- More precise determination of endpoint
to minimize bis-deprotonation
- Allow for variations in the base titer,
water content, and phosphite quality
Observations 1627cm-1
- Deprotonation complete within 5’
1677cm-1
- Enolate anion 3 stable at -25⁰C for 12h
- Addition of P(OEt)3 before addition of
the base → no impact on IR signal
- Kinetics of enolate degradation
Source: Daniel J. Watson,* Eric D. Dowdy, Jeffrey S. DePue, Atul S. Kotnis, Simon Leung, and Brian C. O’Reilly, Bristol-Myers Squibb
Pharmaceutical Research Institute, NJ, USA, Organic Process Research and Development, 2004, 8, 616-623; Mettler Toledo Real Time Analytics
Users’ Forum 2004, London, UK
11. Case Study: FTIR, PAT Tool in Pharma Development
Challenges KHMDS
Monitor deprotonation of 1 for:
- More precise determination of endpoint
to minimize bis-deprotonation
- Allow for variations in the base titer,
water content, and phosphite quality
Observations
- Deprotonation complete within 5’
- Enolate anion 3 stable at -25⁰C for 12h
- Addition of P(OEt)3 before addition of
the base → no impact on IR signal
- Kinetics of enolate degradation
Source: Daniel J. Watson,* Eric D. Dowdy, Jeffrey S. DePue, Atul S. Kotnis, Simon Leung, and Brian C. O’Reilly, Bristol-Myers Squibb
Pharmaceutical Research Institute, NJ, USA, Organic Process Research and Development, 2004, 8, 616-623; Mettler Toledo Real Time Analytics
Users’ Forum 2004, London, UK
12. Case Study: FTIR, PAT Tool in Pharma Development
Improved process KHMDS
- Charged the base to 1 until complete
consumption → Stable signal (1677cm-1)
- 1 / THF charged back to the vessel
until the signal increased → 1-3%
excess of the starting material
(quantified FTIR)
- Result: Impurity 8 is minimized
Source: Daniel J. Watson,* Eric D. Dowdy, Jeffrey S. DePue, Atul S. Kotnis, Simon Leung, and Brian C. O’Reilly, Bristol-Myers Squibb
Pharmaceutical Research Institute, NJ, USA, Organic Process Research and Development, 2004, 8, 616-623; Mettler Toledo Real Time Analytics
Users’ Forum 2004, London, UK
13. Case Study: FTIR, PAT Tool in Pharma Development
Conclusion
- ReactIR™ allowed titration of the
correct amount of base, prevented
accidental overcharge due to
ambiguous concentration
- Implementation to the pilot plant (13Kg)
- 69% yield and >99 area %, need for
recrystallization eliminated Buspirone enolate
- Robust, superior process &
crystallization thanks to the successful Buspirone
use of PAT
Source: Daniel J. Watson,* Eric D. Dowdy, Jeffrey S. DePue, Atul S. Kotnis, Simon Leung, and Brian C. O’Reilly, Bristol-Myers Squibb
Pharmaceutical Research Institute, NJ, USA, Organic Process Research and Development, 2004, 8, 616-623; Mettler Toledo Real Time Analytics
Users’ Forum 2004, London, UK
14. Case Study: FTIR as PAT Tool for Continuous Process
Development and Scale-up of Three
Consecutive Continuous Reactions for
Production of 6-Hydroxybuspirone
Introduction
Control base / buspirone stoichiometry is
critical to product quality
Optimization based on offline analysis is
time consuming and wasteful
Actual feed rate adjusted based on the
feedback from inline FTIR: Flow cell and
ReactIR™ DiComp probe
Source: Thomas L. LaPorte,* Mourad Hamedi, Jeffrey S. DePue, Lifen Shen, Daniel Watson, and Daniel Hsieh, Bristol-Myers Squibb
Pharmaceutical Research Institute, NJ, USA, Organic Process Research and Development, 2008, 12, 956-966; Mettler Toledo Real Time
Analytics Users’ Forum 2005 - New York
15. Case Study: FTIR as PAT tool for Continuous Process
KHMDS
Implemented startup strategy
- Start with slight undercharge of base
(feed rate) to reduce diol 8
- Flow rate increased at 1% increments
until no decrease of Buspirone 1 signal
is observed
- Base feed rate was reduced 1-3%
- Works well because enolization fast,
equilibrium reached within minutes
Source: Thomas L. LaPorte,* Mourad Hamedi, Jeffrey S. DePue, Lifen Shen, Daniel Watson, and Daniel Hsieh, Bristol-Myers Squibb
Pharmaceutical Research Institute, NJ, USA, Organic Process Research and Development, 2008, 12, 956-966; Mettler Toledo Real Time
Analytics Users’ Forum 2005 - New York
16. Case Study: FTIR as PAT Tool for Continuous Process
Outcome
- Ensure product quality via proper ratio
and base feed rate
- Minimize waste of starting material
- Faster reach of steady state via real-
time detection of phase transitions
- FTIR also used for enolization
monitoring during steady state
Scale-up
- Lab reactor: Over 40 hours at steady
state
- Pilot-plant reactor: Successful
implementation (3-batch, 47kg/batch)
Source: Thomas L. LaPorte,* Mourad Hamedi, Jeffrey S. DePue, Lifen Shen, Daniel Watson, and Daniel Hsieh, Bristol-Myers Squibb
Pharmaceutical Research Institute, NJ, USA, Organic Process Research and Development, 2008, 12, 956-966; Mettler Toledo Real Time
Analytics Users’ Forum 2005 - New York
17. Presentation Outline
Introduction
- PAT
- Process Control
Case Studies
- Real Time In Situ Reaction Monitoring with ReactIR™
- Kinetics, Scale-up, and Process Safety with RC1e, and ReactIR™
- Crystallization with FBRM®, PVM® and ReactIR™
- Experiment Design, Data Acquisition, Analysis with Enhanced
Software Tools
16
18. Case Study: Calo for Reaction Kinetics Screening
An Integrated Approach Combining Type A: Very fast, t1/2< 1 s, controlled by
Reaction Engineering and Design of mixing
Experiments for Optimizing Reactions
Introduction Type B: Rapid, 1 s < t1/2< 10 min, mostly
kinetically controlled
Early phase RC1e experiments to obtain
a basic understanding of: Type C: Slow, t1/2 > 10 min, safety issue
in a batch mode
- Enthalpy
- Kinetics
- Mass Balance
- Type of phases
50% of reactions in the
fine/pharmaceutical industry could
benefit from a continuous process
(microreactors)
Source: D.M. Roberge, Department of Process Research, Lonza, Switzerland, Organic Process Research and Development, 2004, 8, 1049-1053;
Mettler Toledo 15th International Process Development Conference 2008, Annapolis, USA; Chem. Eng. Tech., 2005, 28, No. 3, 318-323
19. Case Study: Calo for Reaction Kinetics Screening
RC1e allows precise measurement of Type A: Very fast, t1/2< 1 s
controlled by mixing
reaction enthalpy
Instantaneous reaction heat is related to
reaction rate
Results: Very fast reaction
- No heat accumulation
- Dosing controlled
C=C double bond oxidized / cleaved by
aqueous NaOCl catalyzed by Ru
Source: D.M. Roberge, Organic Process Research and Development, 2004, 8, 1049-1053; Mettler Toledo 15th International Process Development
Conference 2008, Annapolis, USA; Chem. Eng. Tech., 2005, 28, No. 3, 318-323
20. Case Study: Calo for Reaction Kinetics Screening
Type B: Rapid, 1 s < t1/2< 10 min, mostly
Results: Rapid reaction kinetically controlled
- Heat signal function of dosing rate
- Reagent accumulates and reacts
after the end of the dosage
- Lower temperatures favor high
accumulation
- Higher temperatures favor formation
of side products
Quench of ozonolysis into methanol /
dimethyl sulphide
Source: D.M. Roberge, Organic Process Research and Development, 2004, 8, 1049-1053; Mettler Toledo 15th International Process Development
Conference 2008, Annapolis, USA; Chem. Eng. Tech., 2005, 28, No. 3, 318-323
21. Case Study: Calo for Reaction Kinetics Screening
Results: Slow reaction Type C: Slow, t1/2 > 10 min, safety
issue in a batch mode
- Accumulation of energy > 70%
- Most of the heat potential evolves
after the end of addition
- Typically initiated by temperature
increase or catalyst addition
- Autocatalytic reaction and / or
induction period
Conclusion
Real time RC1e calorimetry also for early Knoevenagel-type reaction catalyzed by NaOH:
on kinetics and safety assessment intramolecular aromatic ring condensation
Source: D.M. Roberge, Organic Process Research and Development, 2004, 8, 1049-1053; Mettler Toledo 15th International Process Development
Conference 2008, Annapolis, USA; Chem. Eng. Tech., 2005, 28, No. 3, 318-323
22. Case Study: Integrated PAT for Industrial Scale-Up
Thorough Examination of a Wittig-Horner
Reaction Using Reaction Calorimetry
(RC-1), LabMax®, and ReactIR™
Introduction
Process not ready for industrial
development: Lack of robustness due to
poor understanding of water effect, base
form, kinetics, and thermo-dynamics
- RC1™ used for kinetic and heat
information Side-reaction: Benzyl phosphonate hydrolysis
- ReactIR™ and LabMax® used for
quantitative kinetic simulation under
well controlled conditions
Source: Michael Grabarnick and Sharona Zamir*, Makhteshim Chemical Works Ltd., Israel, Organic Process Research and Development, 2003, 7,
237-243, Mettler Toledo 2001 RXE User Forum
23. Case Study: Integrated PAT for Industrial Scale-Up
Results
Heat flow from RC1™ used as a real-time
monitoring technique
Initial RC1™ and DOE study results
showed reaction is fast and yield
sensitive to base addition
Source: Michael Grabarnick and Sharona Zamir*, Makhteshim Chemical Works Ltd., Israel, Organic Process Research and Development, 2003, 7,
237-243, Mettler Toledo 2001 RXE User Forum
24. Case Study: Integrated PAT for Industrial Scale-Up
- Eahydrolysis > Eastilbene_formation → Validation Run
temperature↓
- Stilbene formation more sensitive to
H2O than hydrolysis → [H2O] ↓. Impact
on reaction rate constant
- Stilbene formation 2nd order versus
[BA] → [BA] ↑
- Stilbene formation 1st order versus
[KOH]
- Validation experiment under improved
conditions in RC1™
Source: Michael Grabarnick and Sharona Zamir*, Makhteshim Chemical Works Ltd., Israel, Organic Process Research and Development, 2003, 7,
237-243, Mettler Toledo 2001 RXE User Forum
25. Case Study: Integrated PAT for Industrial Scale-Up
Process simulation
- BA/stilbene concentration
- Plant reactor temperature (Cp, heat
data from RC1)
Validation of the simulation process with
ReactIR™ and LabMax® - Reactants dissolution at 50⁰C
- Tj: -10⁰C
- Real-time concentration data, under - Once 30 < Tr < 40⁰C, aq. KOH added
well controlled scaled-down conditions
- Comparison to simulated profiles: good
fit, confirmed 94% yield
- Model tested: 8 m3 production reactor
Source: Michael Grabarnick and Sharona Zamir*, Makhteshim Chemical Works Ltd., Israel, Organic Process Research and Development, 2003, 7,
237-243, Mettler Toledo 2001 RXE User Forum
26. Case Study: Integrated PAT for Industrial Scale-Up
Conclusion
Use of real-time analytics (FTIR, heat)
and modeling to study the mechanism of
a Wittig-Horner reaction via a thorough
kinetic and thermodynamic research
Improved large scale conditions were
obtained
Preparation of mathematical model to
plan industrial equipment: Need for a
more effective heat exchanger for yield
improvement
Source: Michael Grabarnick and Sharona Zamir*, Makhteshim Chemical Works Ltd., Israel, Organic Process Research and Development, 2003, 7,
237-243, Mettler Toledo 2001 RXE User Forum
27. Presentation Outline
Introduction
- PAT
- Process Control
Case Studies
- Real Time In Situ Reaction Monitoring with ReactIR™
- Kinetics, Scale-up, and Process Safety with RC1e, and ReactIR™
- Crystallization with FBRM®, PVM® and ReactIR™
- Experiment Design, Data Acquisition, Analysis with Enhanced
Software Tools
26
28. FBRM® PVM®
FBRM® Technology
PVM® Technology
Focused Beam Reflectance Measurement Particle Video Microscope
Track real-time changes in particles and Microscope quality images, in-process and in
droplets as they naturally exist in the process real-time
Characterize particle systems from 0.5μm to 3mm Characterize particle systems from 2μm to 1mm
27
29. Case Study: Integrated PAT for Crystallization
Process Design and Scale-Up
Elements for Solvent Mediated
Polymorphic Controlled Tecastemizole
Crystallization
Introduction
Tecastemizole: Active metabolite of
histamine H1-receptor antagonist
Astemizole, 2 polymorphic forms A
(stable) and B
800L scale process history shows high
risk of not obtaining desirable polymorph:
Seed controlled to solvent mediated
interconversion
Raman spectroscopy and DSC
unsuitable for interconversion monitoring
Source: Kostas Saranteas,* Roger Bakale, Yaping Hong, Hoa Luong, Reza Foroughi, and Stephen Wald Chemistry and Pharma Sciences,
Sepracor Inc., MA, USA, Organic Process Research and Development, 2005, 9, 911-922, Mettler Toledo 2001 Lasentec® Users' Forum
30. Case Study: Integrated PAT for Crystallization
Challenges
Water added
Methodical study under well
controlled conditions
IR Peak Area, 1513 cm-1
- Need for computer control of
batch temperature, agitation
rate, and dose control of the
antisolvent addition (LabMax® ) Tr
Particle # / sec
- Real time supersaturation Seeding
determination (ReactIR™)
- In situ particle count and size
measurements (FBRM®) Results
Interconversion rate influenced by
temperature, mixing, B agglomerate size,
initial seed composition
Source: Kostas Saranteas,* Roger Bakale, Yaping Hong, Hoa Luong, Reza Foroughi, and Stephen Wald Chemistry and Pharma Sciences,
Sepracor Inc., MA, USA, Organic Process Research and Development, 2005, 9, 911-922, Mettler Toledo 2001 Lasentec® Users' Forum
31. Case Study: Integrated PAT for Crystallization
- Significant effect on interconversion - Interconversion rate-limiting step is
rate of hold and cooling temperature growth of form A
profile following addition of water
- Nonlinear cooling profile takes advantage of the temperature rate
effect on form interconversion (4 h above 70⁰C)
Source: Kostas Saranteas,* Roger Bakale, Yaping Hong, Hoa Luong, Reza Foroughi, and Stephen Wald Chemistry and Pharma Sciences,
Sepracor Inc., MA, USA, Organic Process Research and Development, 2005, 9, 911-922, Mettler Toledo 2001 Lasentec® Users' Forum
32. Case Study: Integrated PAT for Crystallization
Summary and conclusion
Scale-down version of the crystallization
step performed at lab scale under well
controlled conditions with LabMax®,
FBRM®, and ReactIR™
Tr
New profile
After better crystallization understanding,
Old profile
and optimization, scale-up successfully
validated at both pilot (1200L) and full-
scale manufacturing (6000L)
Time
Source: Kostas Saranteas,* Roger Bakale, Yaping Hong, Hoa Luong, Reza Foroughi, and Stephen Wald Chemistry and Pharma Sciences,
Sepracor Inc., MA, USA, Organic Process Research and Development, 2005, 9, 911-922, Mettler Toledo 2001 Lasentec® Users' Forum
33. Presentation Outline
Introduction
- PAT
- Process Control
Case Studies
- Real Time In Situ Reaction Monitoring with ReactIR™
- Kinetics, Scale-up, and Process Safety with RC1e, and ReactIR™
- Crystallization with FBRM®, PVM® and ReactIR™
- Experiment Design, Data Acquisition, Analysis with Enhanced
Software Tools
32
34. Software for Design, Data Acquisition and Analysis
Process Analyzers Multivariate analysis
– Control lab reactor based on trend data – ConcIRT™ live algorithm:
– Live drag/drop data exchange with reactor Converts in situ FTIR/Raman
data into concentration profiles
– iC Quant™ determines
component concentrations in
an unknown mixture
Automated Lab Reactor Data to information software tools
– Initiate and control PAT experiments – iC SafetyTM converts reaction
calorimetry data into process
– Live drag/drop data exchange with reactor
safety information
35. Summary
Process chemistry challenges: ReactIR™, calorimetry and automated reactors
- Did the reaction work?
- Understand selectivity and reactivity
- Identify intermediates or by-products
- How long did it take?
- Endpoint, initiation-point, stall-point
- Can this process be scaled-up?
- Identify key control parameters
- Understand reaction kinetics
- Will it be safe?
- Measure reaction heat/enthalpy
- Determine heat capacity, heat
transfer coefficient
- Worst case scenario estimation
- Thermal accumulation and
conversion
36. Summary
Crystallization development: ReactIR™, FBRM®, PVM®, automated reactors
- Do the particles have the right
dimensions, distribution,
morphology?
- Do product scale-up consistently
meet specifications? Does it
require rework?
- How is filtration rate? How about
drying time? Is it consistent?
- Measure solubility and screen MSZ
- Understand, monitor, and control
supersaturation
- Track nucleation and growth kinetics of
crystallization
- Identify and control critical parameters
- Scale-down experiments in the lab