The document provides an overview of analytical quality by design (AQbD) and a case study on optimizing an HPLC method for quantification of an unknown impurity in a drug product. Key aspects included:
- Defining the analytical target profile (ATP) and critical quality attributes (CQA) for the method
- Conducting a qualitative risk assessment to identify critical method parameters using a prioritization matrix
- Performing a quantitative risk assessment using FMECA to calculate risk priority numbers and identify high, medium, and low risk factors
- Selecting experimental factors (column temperature, particle size, etc.), response variables (resolution, retention time), and constant factors for the design of experiments study.
The document discusses analytical quality by design (AQbD) and its implementation. It compares traditional analytical methods to AQbD methods. AQbD uses a systematic approach including risk assessment, design of experiments, and establishing a method operable design region. A case study demonstrates developing an HPLC method for assay using an AQbD approach including target measurement, design of experiment, method validation, and establishing a method operable design region. The conclusion states AQbD requires defining the right analytical target profile and using appropriate tools to ensure the right analytics are performed at the right time.
Quality by design in analytical method developmentpptxPriyankasananse1
This document summarizes a student presentation on quality by design in analytical method development. It discusses:
1) Why QbD is important for analytical methods to improve understanding, ease of improvement, and relationship to process control.
2) The key differences between traditional and QbD analytical method development, including use of an analytical target profile, design of experiments to understand method variables, and concept of a method lifecycle rather than one-time validation.
3) Tools used in QbD analytical method development like risk assessment, identification of critical quality attributes, method design, and qualification to ensure method performance.
Analytical method validation as per ich and usp shreyas B R
Analytical method validation is a process of documenting/ proving that an analytical method provides analytical data acceptable for the intended use.After the development of an analytical procedure, it is must important to assure that the procedure will consistently produce the intended a precise result with high degree of accuracy. The method should give a specific result that may not be affected by external matters. This creates a requirement to validate the analytical procedures. The validation procedures consists of some characteristics parameters that makes the method acceptable with addition of statistical tools.
Analytical method transfer involves qualifying a receiving laboratory to perform an analytical test procedure originally developed in a transferring laboratory. It ensures the receiving laboratory has the knowledge and ability to carry out the procedure as intended. There are different types of method transfers, including comparative testing, co-validation between laboratories, revalidation/partial validation, and waivers. Both the transferring and receiving laboratories have responsibilities in the method transfer process, which typically involves testing replicate samples, evaluating acceptance criteria, and documenting the transfer in a protocol.
Analytical Method Validation basics by Dr. A. AmsavelDr. Amsavel A
This document discusses analytical method validation which is the process of confirming that an analytical method is suitable for its intended purpose. Key aspects of method validation discussed include accuracy, precision, specificity, linearity, range, detection limit, quantitation limit, repeatability and intermediate precision. The document outlines validation parameters for different types of analytical methods and provides examples of acceptance criteria. It also discusses guidance from regulatory agencies on analytical method validation.
This presentation was made to solely for students to make them aware/ understand basics of “Validation”. These slides are part of lectures delivered in M. Pharmacy Curriculum & taken up from various books and websites
This document discusses the qualification of manufacturing equipment. It explains that equipment qualification is necessary to ensure equipment works correctly and produces reliable results. There are four types of qualification: design, installation, operational, and performance. Design qualification defines equipment specifications. Installation qualification confirms proper installation. Operational qualification verifies equipment functions as specified. Performance qualification demonstrates consistent performance under routine use. The document then provides details on specific qualification procedures for dry powder mixers and fluidized bed dryers.
The document discusses analytical quality by design (AQbD) and its implementation. It compares traditional analytical methods to AQbD methods. AQbD uses a systematic approach including risk assessment, design of experiments, and establishing a method operable design region. A case study demonstrates developing an HPLC method for assay using an AQbD approach including target measurement, design of experiment, method validation, and establishing a method operable design region. The conclusion states AQbD requires defining the right analytical target profile and using appropriate tools to ensure the right analytics are performed at the right time.
Quality by design in analytical method developmentpptxPriyankasananse1
This document summarizes a student presentation on quality by design in analytical method development. It discusses:
1) Why QbD is important for analytical methods to improve understanding, ease of improvement, and relationship to process control.
2) The key differences between traditional and QbD analytical method development, including use of an analytical target profile, design of experiments to understand method variables, and concept of a method lifecycle rather than one-time validation.
3) Tools used in QbD analytical method development like risk assessment, identification of critical quality attributes, method design, and qualification to ensure method performance.
Analytical method validation as per ich and usp shreyas B R
Analytical method validation is a process of documenting/ proving that an analytical method provides analytical data acceptable for the intended use.After the development of an analytical procedure, it is must important to assure that the procedure will consistently produce the intended a precise result with high degree of accuracy. The method should give a specific result that may not be affected by external matters. This creates a requirement to validate the analytical procedures. The validation procedures consists of some characteristics parameters that makes the method acceptable with addition of statistical tools.
Analytical method transfer involves qualifying a receiving laboratory to perform an analytical test procedure originally developed in a transferring laboratory. It ensures the receiving laboratory has the knowledge and ability to carry out the procedure as intended. There are different types of method transfers, including comparative testing, co-validation between laboratories, revalidation/partial validation, and waivers. Both the transferring and receiving laboratories have responsibilities in the method transfer process, which typically involves testing replicate samples, evaluating acceptance criteria, and documenting the transfer in a protocol.
Analytical Method Validation basics by Dr. A. AmsavelDr. Amsavel A
This document discusses analytical method validation which is the process of confirming that an analytical method is suitable for its intended purpose. Key aspects of method validation discussed include accuracy, precision, specificity, linearity, range, detection limit, quantitation limit, repeatability and intermediate precision. The document outlines validation parameters for different types of analytical methods and provides examples of acceptance criteria. It also discusses guidance from regulatory agencies on analytical method validation.
This presentation was made to solely for students to make them aware/ understand basics of “Validation”. These slides are part of lectures delivered in M. Pharmacy Curriculum & taken up from various books and websites
This document discusses the qualification of manufacturing equipment. It explains that equipment qualification is necessary to ensure equipment works correctly and produces reliable results. There are four types of qualification: design, installation, operational, and performance. Design qualification defines equipment specifications. Installation qualification confirms proper installation. Operational qualification verifies equipment functions as specified. Performance qualification demonstrates consistent performance under routine use. The document then provides details on specific qualification procedures for dry powder mixers and fluidized bed dryers.
This document provides an overview of analytical method validation. It defines validation as proving a method leads to expected results. Validation is required for analytical tests, equipment, and processes. Once validated, a method is expected to remain in control if unchanged. The document discusses types of analytical procedures that must be validated, including identification, quantitative impurity, limit tests, and assays. It also distinguishes between validation and verification. Key aspects of validation covered include system suitability, specificity, linearity, range, precision, accuracy, recovery, and robustness. The validation characteristics and acceptance criteria are defined.
The document discusses a proposed change in the coating process for Dapakan 500mg film coated tablets from a solvent coating to an aqueous coating. It describes changing from coating with Opadry OIC 7000 to coating with Opadry II. A risk assessment is proposed to evaluate any changes in color, weight gain, thickness or process validation needs. The impact on materials management, quality control, quality assurance, production and regulatory requirements is evaluated. References from regulatory bodies on quality guidelines and GMP are also provided.
The document discusses the validation of water supply systems for pharmaceutical use. It outlines the validation process, which includes design qualification to verify the system design, installation qualification to confirm proper installation, operation qualification to test system functionality under static conditions, and performance qualification to demonstrate consistent performance over time under normal operating conditions. Routine monitoring, maintenance, and change control procedures are also required to ensure continued system operation and water quality as specified.
LC-MS is a technique that combines liquid chromatography with mass spectrometry. It separates components in a mixture using HPLC and then uses an ion source like ESI or APCI to ionize the molecules and a mass analyzer like a quadrupole or time-of-flight to separate the ions by mass-to-charge ratio. The separated ions are then detected to identify and quantify each component. Validation of LC-MS systems includes tests of vacuum, mass accuracy, linearity, precision, carryover, and signal-to-noise ratio to ensure proper separation, ionization, detection, and quantification capabilities.
The document discusses the Current Good Manufacturing Practices (CGMP) regulations as defined by the United States Food and Drug Administration (USFDA). It provides an overview of the various centers within USFDA including the Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER) that are responsible for regulating drugs and biologics respectively. It also summarizes the key CGMP principles, documentation requirements, and the various subparts outlined in the regulations including facilities, equipment, production controls, packaging and labeling, and record keeping.
The document outlines a Validation Master Plan (VMP) which provides an overview of the validation strategy and activities for a manufacturing facility, including details on design qualification, installation qualification, operational qualification, performance qualification, personnel responsibilities, schedules, documentation requirements, and change control procedures. The VMP describes the purpose and importance of the plan for ensuring all systems, equipment, and processes are qualified and work as intended according to regulatory standards.
The document discusses key concepts in Quality by Design (QbD) for pharmaceutical product development including establishing a Quality Target Product Profile, identifying Critical Quality Attributes and linking them to Critical Material Attributes and Critical Process Parameters through Design of Experiments. It provides examples of establishing a design space for a tablet formulation through a multifactorial study of variables affecting dissolution and for a blending process through assessment of process parameters. The importance of developing a control strategy based on the design space to ensure final product quality is also highlighted.
The Validation Master Plan (VMP) outlines the company's approach to validation. It defines responsibilities, schedules, and documentation requirements for qualification of facilities, equipment, and processes. The VMP ensures management understands validation needs and the validation team understands their tasks. Key elements include qualification of equipment and facilities, process validation, cleaning validation, change control procedures, and periodic revalidation. Qualification includes design, installation, operational, and performance qualification to confirm equipment and facilities operate as intended. Process validation demonstrates manufacturing processes consistently produce products meeting specifications. The VMP helps regulatory inspectors evaluate the company's validation program.
In this slide contains Investigation, reason, case study of OOS.
Presented by: K Venkatsai Preasad. (Department of pharmaceutical analysis and quality assurance).
RIPER, anantapur.
The document provides details on method development for chromatography. It discusses defining key terms, developing a test method plan, optimizing methods through experimental design techniques like factorial design. The method development process involves studying samples, setting goals, reviewing literature, selecting an approach, optimizing parameters, and finalizing the method. Critical parameters like column length and temperature, flow rate, mobile phase composition are identified for optimization. Formal validation is required once the method is developed.
The document discusses analytical quality by design (AQbD) and its implementation. It compares traditional analytical methods to AQbD methods. AQbD uses a systematic approach including risk assessment, design of experiments, and establishing a method operable design region. A case study demonstrates developing an HPLC method for assay using an AQbD approach including target measurement, design of experiment, method validation, and establishing a method operable design region. The conclusion states AQbD requires defining the right analytical target profile and using appropriate tools to ensure the right analytics are performed at the right time.
This presentation includes detail about cleaning levels,equipments for cleaning validation , steps for cleaning method validation and analytical method validation used for cleaning.
This document discusses change control in the pharmaceutical industry. It defines change and change control, and outlines the tasks, principles, regulatory requirements, and elements of a change control system. The document describes the steps in a typical change control process, including classifying, assessing, planning, implementing, evaluating, and closing changes. It provides examples of major and minor changes and discusses the documentation and challenges of maintaining an effective change control system. Maintaining proper communication, turnaround times, documentation, and training are important for managing changes in a controlled manner.
Process validation is establishing documented evidence that a process will consistently produce a product meeting predetermined specifications. This presentation discusses process validation, including its definition, scope, objectives, types (prospective, retrospective, concurrent, revalidation), stages, responsibilities of different departments, protocols, sampling procedures, acceptance criteria, and reports. Key aspects of process validation include protocols, sampling plans, specifications, batch execution records, and data analysis to ensure a process is capable of reproducible commercial manufacturing of pharmaceutical products that meet quality standards.
This document discusses cleaning validation, which provides documented evidence that approved cleaning procedures will produce equipment suitable for processing pharmaceutical products. It defines different levels of cleaning validation based on risk. Key aspects covered include cleaning techniques, establishing acceptance criteria, sampling methods, analytical methods, and documentation requirements. The goal of cleaning validation is to achieve an appropriate level of cleanliness to avoid contamination between product batches.
The document discusses developing a validation master plan (VMP) for a new pharmaceutical facility. Key points:
- A VMP comprehensively describes validation requirements and plans for meeting them. It covers production, storage, utilities, and staff areas.
- The VMP sets goals and limits for validation projects. It defines the scope and systems included.
- Developing the VMP involves determining standards, qualifications for design, installation, operation, and performance, documentation requirements, and change control procedures.
- User requirement specifications (URS) are critical documents that validation is dependent on. Developing clear, testable URS in multiple levels is important, especially for software.
This document discusses analytical method validation. It defines analytical method validation as providing assurance that an analytical method can consistently and accurately determine the presence or quantity of attributes. The objectives of validation are to obtain consistent, reliable and accurate data. Key parameters that are assessed in validation include specificity, accuracy, precision, linearity, range, limits of detection and quantification, ruggedness and robustness. The validation process involves planning, testing method performance characteristics, selecting validation acceptance criteria, and documenting results in a validation report. Validation is important for analytical methods used in pharmaceutical analysis.
The document discusses pharmaceutical process validation. It defines validation as proving a process consistently produces quality products. There are three main types of validation: prospective validation done before use, retrospective using historical data, and concurrent during routine production. Validation ensures quality, reduces costs, and meets regulations. It involves qualification of facilities and equipment, then protocols to test processes over multiple batches and demonstrate control. Periodic revalidation is also required when changes are made.
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.
ICH AND WHO GUIDELINES FOR VALIDATION OF EQUIPMENTS.pptxABG
The document discusses guidelines from the International Conference on Harmonization (ICH) and the World Health Organization (WHO) for validating equipment used in the pharmaceutical industry. It provides an overview of the key stages of validation: design qualification (DQ), installation qualification (IQ), operational qualification (OQ), and performance qualification (PQ). DQ defines the functional specifications for equipment. IQ establishes that equipment is properly installed. OQ demonstrates equipment will function as specified. PQ shows equipment consistently meets performance standards for routine use. The document provides details on documentation requirements and test procedures for each qualification stage according to ICH and WHO guidelines.
Speaker at seminar "The Pharmaceutical quality system: ICH Q8/ICH Q9" - University of Parma, 18 May 2012.
Describing steps, tools, and approaches developed for application of QbD to manufacturing processes that have analogous application to the development and use of analytical methods.
The document discusses customer engagement and employee engagement in business process excellence. It provides examples of how companies have improved customer engagement, such as how airlines have reorganized their processes around customer touchpoints. It also discusses the importance of measuring customer loyalty through metrics like Net Promoter Score. The document concludes with a case study of how one company reduced employee attrition rates through initiatives to improve engagement like identifying problems, implementing solutions, and providing recognition.
This document provides an overview of analytical method validation. It defines validation as proving a method leads to expected results. Validation is required for analytical tests, equipment, and processes. Once validated, a method is expected to remain in control if unchanged. The document discusses types of analytical procedures that must be validated, including identification, quantitative impurity, limit tests, and assays. It also distinguishes between validation and verification. Key aspects of validation covered include system suitability, specificity, linearity, range, precision, accuracy, recovery, and robustness. The validation characteristics and acceptance criteria are defined.
The document discusses a proposed change in the coating process for Dapakan 500mg film coated tablets from a solvent coating to an aqueous coating. It describes changing from coating with Opadry OIC 7000 to coating with Opadry II. A risk assessment is proposed to evaluate any changes in color, weight gain, thickness or process validation needs. The impact on materials management, quality control, quality assurance, production and regulatory requirements is evaluated. References from regulatory bodies on quality guidelines and GMP are also provided.
The document discusses the validation of water supply systems for pharmaceutical use. It outlines the validation process, which includes design qualification to verify the system design, installation qualification to confirm proper installation, operation qualification to test system functionality under static conditions, and performance qualification to demonstrate consistent performance over time under normal operating conditions. Routine monitoring, maintenance, and change control procedures are also required to ensure continued system operation and water quality as specified.
LC-MS is a technique that combines liquid chromatography with mass spectrometry. It separates components in a mixture using HPLC and then uses an ion source like ESI or APCI to ionize the molecules and a mass analyzer like a quadrupole or time-of-flight to separate the ions by mass-to-charge ratio. The separated ions are then detected to identify and quantify each component. Validation of LC-MS systems includes tests of vacuum, mass accuracy, linearity, precision, carryover, and signal-to-noise ratio to ensure proper separation, ionization, detection, and quantification capabilities.
The document discusses the Current Good Manufacturing Practices (CGMP) regulations as defined by the United States Food and Drug Administration (USFDA). It provides an overview of the various centers within USFDA including the Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER) that are responsible for regulating drugs and biologics respectively. It also summarizes the key CGMP principles, documentation requirements, and the various subparts outlined in the regulations including facilities, equipment, production controls, packaging and labeling, and record keeping.
The document outlines a Validation Master Plan (VMP) which provides an overview of the validation strategy and activities for a manufacturing facility, including details on design qualification, installation qualification, operational qualification, performance qualification, personnel responsibilities, schedules, documentation requirements, and change control procedures. The VMP describes the purpose and importance of the plan for ensuring all systems, equipment, and processes are qualified and work as intended according to regulatory standards.
The document discusses key concepts in Quality by Design (QbD) for pharmaceutical product development including establishing a Quality Target Product Profile, identifying Critical Quality Attributes and linking them to Critical Material Attributes and Critical Process Parameters through Design of Experiments. It provides examples of establishing a design space for a tablet formulation through a multifactorial study of variables affecting dissolution and for a blending process through assessment of process parameters. The importance of developing a control strategy based on the design space to ensure final product quality is also highlighted.
The Validation Master Plan (VMP) outlines the company's approach to validation. It defines responsibilities, schedules, and documentation requirements for qualification of facilities, equipment, and processes. The VMP ensures management understands validation needs and the validation team understands their tasks. Key elements include qualification of equipment and facilities, process validation, cleaning validation, change control procedures, and periodic revalidation. Qualification includes design, installation, operational, and performance qualification to confirm equipment and facilities operate as intended. Process validation demonstrates manufacturing processes consistently produce products meeting specifications. The VMP helps regulatory inspectors evaluate the company's validation program.
In this slide contains Investigation, reason, case study of OOS.
Presented by: K Venkatsai Preasad. (Department of pharmaceutical analysis and quality assurance).
RIPER, anantapur.
The document provides details on method development for chromatography. It discusses defining key terms, developing a test method plan, optimizing methods through experimental design techniques like factorial design. The method development process involves studying samples, setting goals, reviewing literature, selecting an approach, optimizing parameters, and finalizing the method. Critical parameters like column length and temperature, flow rate, mobile phase composition are identified for optimization. Formal validation is required once the method is developed.
The document discusses analytical quality by design (AQbD) and its implementation. It compares traditional analytical methods to AQbD methods. AQbD uses a systematic approach including risk assessment, design of experiments, and establishing a method operable design region. A case study demonstrates developing an HPLC method for assay using an AQbD approach including target measurement, design of experiment, method validation, and establishing a method operable design region. The conclusion states AQbD requires defining the right analytical target profile and using appropriate tools to ensure the right analytics are performed at the right time.
This presentation includes detail about cleaning levels,equipments for cleaning validation , steps for cleaning method validation and analytical method validation used for cleaning.
This document discusses change control in the pharmaceutical industry. It defines change and change control, and outlines the tasks, principles, regulatory requirements, and elements of a change control system. The document describes the steps in a typical change control process, including classifying, assessing, planning, implementing, evaluating, and closing changes. It provides examples of major and minor changes and discusses the documentation and challenges of maintaining an effective change control system. Maintaining proper communication, turnaround times, documentation, and training are important for managing changes in a controlled manner.
Process validation is establishing documented evidence that a process will consistently produce a product meeting predetermined specifications. This presentation discusses process validation, including its definition, scope, objectives, types (prospective, retrospective, concurrent, revalidation), stages, responsibilities of different departments, protocols, sampling procedures, acceptance criteria, and reports. Key aspects of process validation include protocols, sampling plans, specifications, batch execution records, and data analysis to ensure a process is capable of reproducible commercial manufacturing of pharmaceutical products that meet quality standards.
This document discusses cleaning validation, which provides documented evidence that approved cleaning procedures will produce equipment suitable for processing pharmaceutical products. It defines different levels of cleaning validation based on risk. Key aspects covered include cleaning techniques, establishing acceptance criteria, sampling methods, analytical methods, and documentation requirements. The goal of cleaning validation is to achieve an appropriate level of cleanliness to avoid contamination between product batches.
The document discusses developing a validation master plan (VMP) for a new pharmaceutical facility. Key points:
- A VMP comprehensively describes validation requirements and plans for meeting them. It covers production, storage, utilities, and staff areas.
- The VMP sets goals and limits for validation projects. It defines the scope and systems included.
- Developing the VMP involves determining standards, qualifications for design, installation, operation, and performance, documentation requirements, and change control procedures.
- User requirement specifications (URS) are critical documents that validation is dependent on. Developing clear, testable URS in multiple levels is important, especially for software.
This document discusses analytical method validation. It defines analytical method validation as providing assurance that an analytical method can consistently and accurately determine the presence or quantity of attributes. The objectives of validation are to obtain consistent, reliable and accurate data. Key parameters that are assessed in validation include specificity, accuracy, precision, linearity, range, limits of detection and quantification, ruggedness and robustness. The validation process involves planning, testing method performance characteristics, selecting validation acceptance criteria, and documenting results in a validation report. Validation is important for analytical methods used in pharmaceutical analysis.
The document discusses pharmaceutical process validation. It defines validation as proving a process consistently produces quality products. There are three main types of validation: prospective validation done before use, retrospective using historical data, and concurrent during routine production. Validation ensures quality, reduces costs, and meets regulations. It involves qualification of facilities and equipment, then protocols to test processes over multiple batches and demonstrate control. Periodic revalidation is also required when changes are made.
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.
ICH AND WHO GUIDELINES FOR VALIDATION OF EQUIPMENTS.pptxABG
The document discusses guidelines from the International Conference on Harmonization (ICH) and the World Health Organization (WHO) for validating equipment used in the pharmaceutical industry. It provides an overview of the key stages of validation: design qualification (DQ), installation qualification (IQ), operational qualification (OQ), and performance qualification (PQ). DQ defines the functional specifications for equipment. IQ establishes that equipment is properly installed. OQ demonstrates equipment will function as specified. PQ shows equipment consistently meets performance standards for routine use. The document provides details on documentation requirements and test procedures for each qualification stage according to ICH and WHO guidelines.
Speaker at seminar "The Pharmaceutical quality system: ICH Q8/ICH Q9" - University of Parma, 18 May 2012.
Describing steps, tools, and approaches developed for application of QbD to manufacturing processes that have analogous application to the development and use of analytical methods.
The document discusses customer engagement and employee engagement in business process excellence. It provides examples of how companies have improved customer engagement, such as how airlines have reorganized their processes around customer touchpoints. It also discusses the importance of measuring customer loyalty through metrics like Net Promoter Score. The document concludes with a case study of how one company reduced employee attrition rates through initiatives to improve engagement like identifying problems, implementing solutions, and providing recognition.
Evolution of pharma industry and related opportunitiesBioValley Basel
The document discusses the evolution of the pharmaceutical industry and related career opportunities. It notes that while research was traditionally conducted in-house, there is now more outsourcing of drug discovery and development. New opportunities exist in startups, clinical research organizations, and complementary sectors like diagnostics and medical devices. Skills in areas like project management, communication, and working in multicultural environments are important for career success in the evolving industry.
This document provides an overview of quality initiatives in the pharmaceutical industry, including the FDA's Pharmaceutical Quality for the 21st Century initiative and quality tools like Six Sigma. It discusses key dimensions of the FDA's initiative like having a risk-based and science-based approach. The document also summarizes pharmaceutical product lifecycles, Process Analytical Technology (PAT), and how approaches like Six Sigma can help drive continuous improvement in quality.
The International Conference on Harmonisation (ICH) brings together regulatory authorities and the pharmaceutical industry to discuss drug registration. ICH has evolved to address increasingly global drug development. It consists of quality, safety, efficacy, and multidisciplinary guidelines. The quality guidelines cover topics like stability testing, impurities, good manufacturing practices, pharmaceutical development, quality risk management, and more. Adoption of these guidelines promotes harmonization and innovation in drug development and manufacturing on a global scale.
Regulatory authorities (US-FDA, WHO and ICH)Sagar Savale
To promote the public health by promptly and efficiently reviewing clinical research and taking appropriate action on the marketing of regulated products in a timely manner.
With respect to such products, protect the public health by ensuring that the food are safe, Wholesome, sanitary, and properly labelled; human and veterinary drugs are safe and effective; there is reasonable assurance of the safety and effectiveness of devices intended for human use; cosmetics are safe and properly labelled, and public health and safety are protected from the electronic product radiation.
Participates through appropriate process with representatives of other countries to reduce the burden of regulation, harmonize regulatory requirements, and achieve appropriate reciprocal arrangements.
FDA’s emphasis on quality by design began with the recognition that increased testing does not improve product quality (this has long been recognized in other industries).In order for quality to increase, it must be built into the product. To do this requires understanding how formulation and manufacturing process variables influence product quality.Quality by Design (QbD) is a systematic approach to pharmaceutical development that begins with predefined objectives and emphasizes product and process understanding and process control, based on sound science and quality risk management.
This presentation - Part VI in the series- deals with the concepts of Design of Experiments. This presentation was compiled from material freely available from FDA , ICH , EMEA and other free resources on the world wide web.
Application of Design of Experiments (DOE) using Dr.Taguchi -Orthogonal Array...Karthikeyan Kannappan
The Taguchi method involves reducing the variation in a process through robust design of experiments. The experimental design proposed by Taguchi involves using orthogonal arrays to organize the parameters affecting the process and the levels at which they should be varies. Instead of having to test all possible combinations like the factorial design, the Taguchi method tests pairs of combinations. The Taguchi arrays can be derived or looked up. Small arrays can be drawn out manually; large arrays can be derived from deterministic algorithms. Generally, arrays can be found online. The arrays are selected by the number of parameters (variables) and the number of levels (states).
In this paper, the specific steps involved in the application of the Taguchi method will be described with example.
The document discusses the evolution of quality management in healthcare. It describes the contributions of Walter Shewhart, William Edwards Deming, Joseph Juran, and Philip Crosby to developing concepts of quality management. It defines key terms like quality, outlines the three aspects of quality care, and lists important dimensions of quality like appropriateness, availability, and safety. Finally, it introduces the concept of value as quality of care divided by cost.
The International Conference on Harmonisation (ICH) was created in 1990 as a unique effort between regulators and industry from the EU, Japan, and US to harmonize technical requirements for pharmaceutical registration. ICH aims to ensure safety, efficacy, and quality of medicines while preventing duplicative trials and minimizing animal testing. Through guidelines developed via consensus building among members, ICH has harmonized requirements for drug development and approval processes. However, some concerns remain regarding inclusion of non-members in the decision making and implications for developing countries.
The document provides an overview of Six Sigma, including:
1) It defines Six Sigma as a methodology for continuous improvement and creating high quality products and processes using statistical tools.
2) It discusses the origins and growth of Six Sigma at Motorola and GE in the 1980s-1990s.
3) It describes the DMAIC methodology used for process improvement projects and the roles of Master Black Belts, Black Belts, and Green Belts in a Six Sigma organization.
This document provides an overview of quality management concepts. It discusses definitions of quality, dimensions of quality for manufactured products and services, evolution of quality management thinking with contributions from quality gurus like Deming and Juran, quality tools like flow charts and control charts, total quality management (TQM), quality management systems (QMS), customer focus in quality management, employee roles in quality improvement, quality in services, Six Sigma and Lean Six Sigma approaches, and the impact of quality on profitability.
The document discusses quality improvement initiatives for emergency departments. It notes that timely treatment in the emergency department is key to quality care outcomes for patients. It provides examples of quality indicators for conditions like acute myocardial infarction and pneumonia that can be used to measure and improve care. The document advocates for a multidisciplinary team approach, data sharing between hospitals, and engaging medical staff and customers to support quality improvement goals.
The document discusses applying a lifecycle management model to analytical procedures. It proposes a three stage model: 1) Procedure Design involving development and understanding potential variables, 2) Procedure Performance Qualification demonstrating fitness for purpose, and 3) Continued Procedure Performance Verification involving routine monitoring. Key aspects include defining an Analytical Target Profile specifying performance criteria, conducting risk assessments of potential variables, and establishing control strategies. The lifecycle approach aims to better integrate validation, transfer, and verification, with the Analytical Target Profile serving as an overall reference point.
The document discusses the life cycle of analytical methods from development through continued use. It proposes a new general chapter called "The Analytical Procedure Lifecycle" to provide a holistic framework. Key points include establishing analytical target profiles, assuring methods remain in a state of control, evaluating measurement uncertainty, and using quality-by-design to increase robustness and reduce lifecycle costs. Regular monitoring and trend analysis can identify needs for optimization or revalidation to ensure methods remain fit for their intended purpose over time.
This document discusses the application of quality by design (QbD) approach in developing and validating a reverse phase high performance liquid chromatography (RP-HPLC) method for the simultaneous estimation of antiretroviral drugs in pharmaceutical dosage forms. It provides background on HPLC, QbD, design of experiments (DoE), method development strategy using QbD, and validation parameters. The plan of work involves developing the RP-HPLC method using a QbD approach, validating the method per ICH guidelines, applying it to marketed formulations, conducting forced degradation studies, and finalizing documentation.
Analytical method- Content, Development, validation, Transfer & Life Cycle Ma...Md. Mizanur Rahman Miajee
This document discusses analytical method validation and provides guidelines on developing and validating analytical methods according to regulatory standards. It outlines the key components that should be included in an analytical method as well as considerations for method development such as selecting stationary and mobile phases, operating parameters, and evaluating method performance characteristics during development. The document also discusses best practices for transferring validated analytical methods between laboratories.
The document discusses analytical quality by design (AQbD) and its implementation. It compares traditional analytical methods to AQbD methods. AQbD uses a systematic approach including risk assessment, design of experiments, and establishing a method operable design region. A case study demonstrates developing an HPLC method for assay using an AQbD approach including target measurement, design of experiment, method validation, and establishing a method operable design region. The conclusion states AQbD requires defining the right analytical target profile and using appropriate tools to ensure the right analytics are performed at the right time.
Stephan Krause discusses opportunities to accelerate analytical method validation for biosimilars using analytical platform technology (APT) methods. APT methods are analytical methods used for multiple products without modification that may not require full validation for each new product. Krause outlines how APT methods can be applied to product and process characterization methods as well as routine testing methods to reduce validation requirements. He also discusses the need for increased analytical method performance to address differences between biosimilars and reference products and acceptance criteria for various tiers of analytical similarity.
The document discusses phase appropriate method validation. It provides guidelines for validating analytical methods based on the intended use and stage of product development. Validation requirements become more extensive in later phases, from proof of concept in Phase I to full validation in Phase III. Key validation characteristics discussed include specificity, selectivity, range, accuracy, precision, detection limit, quantitation limit, linearity and robustness. The document also covers stress studies, system suitability criteria, and the differences between stability indicating and specificity methods.
JPBA published-a platform aQbD approach for multiple methods developmentJianmei Kochling
The document describes a platform analytical quality by design (AQbD) approach for developing multiple UHPLC-UV and UHPLC-MS methods for protein analysis. The AQbD approach provides a systematic process for understanding method scientific principles and ensures method robustness is built in during development. The knowledge and understanding gained from developing one method (UHPLC-UV peptide mapping) can be transferred to developing two other methods (UHPLC-MS oxidation method and UHPLC-UV C-terminal heterogeneity method) for analyzing the same protein. Following the AQbD approach helps generate reliable analytical methods that can provide high quality data to support product development and help avoid unnecessary post-approval changes.
The document discusses the application of statistical tools to enhance productivity and quality control in industries. It explains key concepts like process control, process capability indices, acceptance sampling plans, and their use in quality management. Statistical process control techniques like control charts are used to monitor processes and make data-driven decisions about product and process quality. Acceptance sampling balances protecting consumers from defects and encouraging quality production.
Points to Consider in QC Method Validation and Transfer for Biological ProductsWeijun Li
The document discusses considerations for analytical method validation and transfer for biological products. It provides three case studies as examples:
1) Creating spiking materials for size exclusion chromatography (SEC) validation by inducing chemical reactions to form aggregates and low molecular weight species for use in spiking studies.
2) Conducting a practice run with mock samples prior to an analytical method transfer to identify potential issues. The practice run failed equivalence testing, indicating differences between the labs.
3) Troubleshooting the practice run by examining potential differences in stock standards and standard curves between labs. Analysis found a less than 1% difference in stock standards but differences in standard curve slopes and intercepts between labs.
Measurement Systems Analysis - Variable Gage R&R Study Metrics, Applications ...Gabor Szabo, CQE
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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.
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The document provides an overview of various quality management concepts and tools including:
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Similar to Analytical QBD -CPHI 25-27 July R00 (20)
4. Origin:
Founded in 1999 in India by Mr. NC Narayanan
Presence:
Global footprint across 20+ Countries with headquarters in
Mumbai, India
Consulting Landscape:
Business transformation across
hundreds of industries including
• Automobile
• Pharma
• FMCG
• Life Science
• Banking & Finance
• Insurance
• Plastics
• Telecommunication
• Packaging
Contribution To The Industry:
• Groomed over 5000 Business excellence
professionals
• Help transformed 100s of organizations
worldwide
• Enabled industries to provide best in class
products and services
• Contributed to sustainable economic
development
5. SSA Leadership Team
Ganesh Iyer BE, MBA (INSEAD)
MD SSA Tech
Vijay Dhonde BE,
CEO
Sashi Iyer B.Com, MBA (INSEAD)
MD SSA India
NC BE, MS (Research)
Chairman
Naveen Narayanan
BE, MBA (USA), MSc (UK)
MD SSA Int
6. SSA’s Pharma Offerings
Pharma
Excellence
R & D
Excellence
QBD / DOE
DFSS / NPI
Lean
CAPA
Investigati
on
Manufacturing
Excellence
Lean Six
Sigma
CAPA
Investigation
Statistical
Analysis
for QA / QC
11. Premium Training & Certification
Lean Six
Sigma
Quality by
Design
DFSSCAPA
Value Stream
Mapping
Problem
Solving Tools
( 7 QC Tools )
Balanced
Scorecard
15. What is QBD ?
As per ICH, QbD is defined as
“A systematic approach to development that begins with
predefined objectives and emphasizes product and
process understanding and process control, based on
sound science and quality risk management.”
16. Analytical Target
Profile (ATP)
identification
Identification includes the selection of method
requirements such as target analytes, analytical
technique category, and product specifications.
Critical Quality
Attributes (CQA)
Identification
Select appropriate analytical technique for
desired measurement. Define method
performance criteria ( critical Quality attributes)
Risk Assessment
using FMECA
Assess risks of method operating parameters
and sample variation.
Method
Development /
Validation using
DOE
Examine potential multi-variate interactions.
Understand method robustness and ruggedness
Establish Control
Strategy
Define control space and system suitability,
meet method performance criteria
Continuous
method
monitoring and
improvement
CMM is final step in AQbD life cycle; it is a
continuous process of sharing knowledge
gained during development and implementation
of design space
AQbD ( Analytical QBD ) Roadmap
17. What’s Needed
QBD Approach Basics of Statistics
Target
measurement
based on
product QTPP
and CQA
Select
Techniques
for desired
measurement
Risk
Assessment
using FMECA
Method
Development /
Validation
using DOE
Establish
Control
Strategy
Continual
Improvement
19. Definition of Quality
ISO 9000 Definition of Quality: “Customer satisfaction”
Statistical Definition of Quality:
Q = f (Hitting the Target ,Reducing the variation)
20. Measures Of Central Tendency
Numerical value that describes the central position of
the data
Represent different ways of characterizing the central
value of a collection of data.
Simply, it is the middle point of a distribution.
Also called as measures of location
Three of these measures are:
• Mean
• Median
• Mode
21. Measures Of Central Tendency
Let us take the following series :7,23,4,8,3,9,9
7+23+4+8+3+9+9
Mean = = 63/7=9
7
3
4
7
8
9
9
23
Median
middle-most value
Average
Mode most repeated value (2 times)
23. Measures Of Dispersion (Variation)
It is the spread or variability of the data set.
Three types of measures of dispersion are
• Range
• Variance and
• Standard Deviation
24. Range
It is the difference between the highest and lowest
observed values
Range = Value of Highest observation - Value of Lowest
observation
Example:
Let us take the following series
3,6,4,9,5,6,7,1,6,3,2,9,8,6,4,2.
Max Value = 9 Min Value = 1
Range= 9 -1=8
25. Observations (x1,x2..xn)
n - total no. of observations
Mean ( µ )
( i - observed item)
Deviation di = Xi- µ
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
* *
variable
frequency
d1
d2
d3
d4 d5
Variance And Standard Deviation
26. Null Hypothesis (H0) :
The hypothesis to be tested, usually an assumption of
status quo (equality, i.e.. no difference).
No Significant impact on CQA / Response ( P > 0.050 )
Alternate Hypothesis (Ha) :
The condition of equality assumed in the Null hypothesis is
not true.
There is a Significant impact on CQA / Response( P < 0.05)
USE ANOVA ( Analysis of Variance ) for analysis
Types of Hypothesis
27. Hypothesis Testing
Statistical Hypothesis:
There is no difference
between the old machines
and the improved one.
This is called the Null
Hypothesis (Ho)
• Real Life Hypothesis: The
newly modified machine will
reduce defects.
• This is called the Alternative
Hypothesis (Ha)
Ho:
Ha:
a
a
m m
m m
=
<
b
b
• We must show that the values we observed were so unlikely to come
from the same process, that Ho must be wrong.
28. X (Input)
y (Output)
• Tells the relationship between the
two variables X and Y
• X is the input variable on
x(horizontal)-axis
• Y is the output variable on the
Y(vertical)-axis
Use R-Sq Value for Model
Significance
Correlation & Regression Analysis
30. Project Scenario
To optimise Related Substance Method that is Specific, Selective,
Reproducible and Robust and is acceptable to the plant and
regulatory agencies. This project is due for technology transfer at the
manufacturing location.
• To develop the robust and reproducible method for the quantification
of Unknown impurity eluting at the tail of XYZ Peak with USP
Resolution of NLT 3.5 between main peak and unknown impurity
along with resolution of all other known impurities.
– Resolution
– Retention time
31. Analytical Target Profile (ATP)
• General ATP for analytical procedures is as follows:
– Target analytes selection (API and impurities)
• ICH Q3 and all other regulatory guidance explained the consideration of impurities in
the API synthetic route
– Technique selection (HPLC, GC, HPTLC, Ion Chromatography, chiral
HPLC, etc.)
• Analytical test item and purpose of test are also important for selecting the technique
– Method requirements selection (assay or impurity profile or residual
solvents)
• Method requirements can vary from one method to another. The common ATPs for
impurity profile by HPLC method
32. Critical Quality Attributes (CQA)
CQA for analytical methods includes method attributes and method
parameters. Each analytical technique has different CQA.
• HPLC (UV or RID) CQA are mobile phase buffer, pH, diluent, column
selection, organic modifier, and elution method.
• GC methods CQA are gas flow, oven temperature and program,
injection temperature, sample diluent, and concentration.
• HPTLC method CQA are TLC plate, mobile phase, injection
concentration and volume, plate development time, color development
reagent, and detection method
Note : Nature of impurities and DS can define the CQA
for analytical method development such as solubility, pH
value, polarity, charged functional groups, boiling point,
and solution stability
34. Mapping the Linkage : Method
attributes and Method Parameters
M1
M2
Method Attributes
P1
P2
Method
Parameters
P3
CQA1
CQA2
Critical
Quality
Attributes
CQA3
P2 might not be needed in
the establishment of Design
Space
Source: CDER & FDA
Purpose:
Understand & Control the variability of
Method Attributes & Critical method
Parameters to meet CQA’s
35. Qualitative Risk Assessment Criteria
Red Color High Risks
Risks that need to be addressed by actual
studies to establish acceptable ranges
Yellow Color Medium Risks
Possibility for a change in factor level to affect
method robustness but small variations in this
factor do not adversely affect pharmaceutical
quality
Green Color Low risks Factors having wide range of acceptability
• Risk estimation helps to identify what to study as a part of analytical
method development
• Evaluation of qualitative risk is ultimately linked back to potential harm to
the patient
36. Qualitative Risk Assessment : Prioritization Matrix
Attributes Resolution Justification
Column type Kept constant
Column make Kept constant
Particle size of the column has impact on Resolution
Column length has impact on Resolution
% Carbon loading
Column make is constant so %
Carbon loading is constant
Internal diameter of column Kept constant
Mobile phase buffer
Kept constant (potassium
dihydrogen phosphate)
Modifier used in Buffer and its qty has impact on Resolution
Mobile phase composition
has impact on Resolution as polarity
of solvents are diff
System make No impact on resolution
Detector sensitivity (UV/PDA)
This impacts the Limit of detection
and quantitation but will have no
impact on resolution
37. Qualitative Risk Assessment : Prioritization Matrix
Attributes Resolution Justification
UV Lamp hours
This impacts the Limit of detection
and quantitation but will have no
impact on resolution
Type of elution (Gradient/ Isocratic) Kept constant (Gradient)
Make of reagents Kept constant
Different lots of Drug Product tested Kept constant
Analyst Constant
Column temperature
Column temperature influences the
resolution between peaks
Flow rate of system
Flow rate changes the retention time
but this may or may not impact
resolution
pH of the mobile phase buffer
Has impact on Resolution as different
peaks will have different retention
time at diff pH due to their pKa values
Detection wavelength Kept constant at 240 nm
Lot number of the column Kept constant
Sample preparation technique
(Intact/crushed) Kept constant
Organic used in Mobile phase
has impact on Resolution as polarity
of solvents are diff
39. FMECA – Identify critical factors
To study the critical factors, the team conducted a risk
assessment using a FMECA.
Output from the risk assessment study was based on
risk score which was used to identify the critical factors
required for the study
Risk priority scores included an estimate for
detectability, severity and probability
40. Severity Scores Rating
Score Severity Description of impact on patient if failure to meet acceptance
criteria
1 Minor No impact on patient
2 Major Some impact on product, but reversible
3 Critical Impact on product but not product life threatening (rejection)
4 Catastrophic High impact on product which is irreversible and potentially
wastage
Probability Scores Rating
Score Probability of not meeting
acceptance
Comment
1 Extremely low Extremely low chance of occurring, never
seen
2 Low Low chance of occurring, but could happen
3 Medium Will happen
4 High High occurrence of failure
41. Detectability Scores Rating
Score Detectability
scores
Comment
1 Very high Failure can be detected in unit operation
2 High Failure can be detected after unit operation and before end
product testing
3 Low Will happen
4 None High occurrence of failure
Risk Score
Risk priority number range Risk rating
1 to 17 Low
18 to 35 Medium
36 to 64 High
RPN scores were grouped into high, medium, and low risk. The boundaries
for differentiation between high, medium, and low were established by the
risk assessment team for this exercise.
42. Quantitative Risk Assessment: FMECA
Process
Parameter or
Material Attribute
Effect/ Suggested contingency/
Comment
Probability
(P)
Severity
(S)
Control
(C) RPN
Risk
Rating
Column
temperature Justification 4 3 2 24 Medium
Flow rate of
system To be studied 2 2 2 8 Low
Detector
sensitivity
(UV/PDA) To be kept constant at 1 mL/minute 2 2 1 4 Low
Column make Kept Constant UV Detector of All-15 4 2 1 8 Low
Particle size of
the column
based on earlier expts the make
giving best resolution is selected and
is kept constant 4 4 3 48 High
Mobile phase
composition
(aqueous and
organic)
To be studied for the impact of change
in micron over resolution 4 4 3 48 High
Modifier used in
Buffer and its qty
decided to keep the composition as
constant and vary the type of organic
(Gradient program is constant) 3 3 2 18 Medium
Type of organic
used in Mobile
phase In this case no modifier used 4 4 3 48 High
pH of the mobile
phase buffer to be studied for ACN and methanol 4 4 3 48 High
Column length To be studied 4 4 3 48 High
43. Response ( CQA )
Response Unit Target Comment
Resolution Numbers NLT 3.5
Retention time Mins NMT 75
Analysis needs to be
completed before 75 mins
else the impurity is not
detected
44. Experimental Factors
Experimental Factor Unit
Low
Level
High
Level
Comments/ Remarks
Column temperature deg C 25 45
Currently selected column temperature
is 30 deg C and lower range selected at
room temp and higher range at 45 deg
is within the cut off temperature of 60
deg C
Particle size of the column micron 3 5
Particle size impacts separation, lower
& higher values selected based on the
availability
Column length cm 150 250
Column length impacts separation,
lower & higher values selected based
on the availability
Acetonitrial % 50 100
100% Methanol not selected as this
may increase the back pressure and
may go beyond operating range for 3µ
column
pH of the mobile phase buffer 2 7
Current pH of the mobile phase is 3.5
and range is selected based on the
optimum operating range of the column
45. Constant Factors
Constant Factors Unit Level
System make HPLC Alliance -15
UV Lamp hours Hours
Same instrument will be used so
this will remain constant
throughout
Calibration of the HPLC Yes
Calibrated instrument will be
used
Volume of Mobile phase prepared mL
1000 mL (same qty of mobile
phase will be prepared each set)
Analyst Sandeep Gawas
% Carbon loading 15%
Age of the column
New Column will be used for
study and same will be used for
all expt except for the change in
column
Column type Inertsil ODS 3 L1
Different lots of Drug Product tested Batch No. A-12
Internal diameter of column mm 4.6 mm
Lot number of the column
Make of reagents AR Grade
Merck and same Lot No. from
one bottle will be used
Water Quality HPLC Grade TKA of fourth floor
Age of the sample
3 Month old
sample CRT sample
46. Constant Factors
Constant Factors Unit Level
Column Equilibriation time Hour 1 Hour before the injection acquisition
Detection wavelength nm Fixed at 240 nm
Injection volume µL Fixed at 20µL
Type of elution (Gradient/ Isocratic) Gradient program fixed
Previous use of the column (Product/washing solvent) New column to be used for the expt
Mobile phase buffer
potassium dihydrogen orthophosphate
1.36 gm/L
Type of filter used for Mobile Phase filtration Millipore 0.45 µ
Order of addition of diluent Fixed as per STP
Sample concentration ppm Fixed at 600 ppm as per STP
Sample preparation technique (Intact/crushed)
Crushed Method to be followed as per
STP
Sample solution stability Days
Same Sample preparation to be used
for 8 Days
Sampling (Representative sample)
Sample to be used from single
container at the start of expt
Room temperature and Humidity
deg C & %
RH 25+/- 5 deg and 65+/-5% RH
Storage of the samples In Laboratory
pH meter A197
Balance used A200
Cylinder used for Volume measurement Class A
Same Cylinder to be used through out
the expt
Sonnicator A199
Sample preparation Filter 0.45 µ Make MDI, discard volume 1 mL
47. Design Selection Matrix
Parameter Fractional Factorial Half Fraction Full Factorial Mixture RSM
Type of
design Screening Basic Basic
Basic +
Optimization Optimization
No. of
Responses 1-2 1-2 1-3 2-3 2 or more
Factors More than 5 4-5 3-4 3-4 3-4
Expected
outcome
• Identify significant
factors with main
effect only
• Eliminate
insignificant factors
for next level of
experiment
• Identify the
main effects &
interaction
effect
• Get prediction
equation
• Curvature with
1 center point
• Identify the
main effects &
interaction
effect
• Get prediction
equation
• Curvature with
1 center point
• Identify design
space
• Identify the
main effects &
interaction
effect
• Optimum
proportion for
mixture
• Get prediction
equation
• Identify design
space
• Identify right
factor settings
for optimum
operation
• Identify design
space
Pre-requisite
None None • None
•Composition
type
•Quantitative
All should be
quantitative
Additional
elements
None
• Include center
point to check
curvature
• Include center
point to check
curvature
• Augmentation
done to get
precise results • None
49. Residual Analysis : Sanity check of
Experimental Trials
As seen from the residual above, the residuals are normally distributed, with
random variation and within the limits of +/-2%. Hence, it can be
concluded that the experimental error is minimum
50. Initial results For Resolution: ANOVA
R-Sq = 99.59% R-Sq(pred) = 97.87% R-Sq(adj) = 99.13%
Analysis of Variance for Resolution (coded units)
Source DF Seq SS Adj SS Adj MS F P
Blocks 1 0.2233 0.2233 0.2233 4.40 0.074
Main Effects 5 82.868 82.868 16.5736 326.63 0.000
Column temperatu 1 1.1396 1.1396 1.1396 22.46 0.002
Particle size of 1 3.9105 3.9105 3.9105 77.07 0.000
%Acetonitrile 1 0.7613 0.7613 0.7613 15.00 0.006
Column length 1 2.8815 2.8815 2.8815 56.79 0.000
pH of the mobile 1 74.1752 74.1752 74.1752 1461.81 0.000
2-Way Interactions 2 3.5921 3.5921 1.796 35.40 0.000
Particle size of the
column*%Acetonitrile
1 0.7613 0.7613 0.7613 15.00 0.006
Particle size of the column*pH
of the mobile phase buffer
1 2.8308 2.8308 2.8308 55.79 0.000
Residual Error 7 0.3552 0.3552 0.0507
Total 15 87.0385 0.2233 0.2233
P Value for Linear , Interaction term is less
than 0.05 hence very significant
51. R-Sq = 99.99% R-Sq(pred) = 99.95% R-Sq(adj) = 99.98%
Analysis of Variance for Retention Time (coded units)
Source DF Seq SS Adj SS Adj MS
Blocks 1 0.03 0.026 0.076
Main Effects 4 1049.66 880.170 220.043
Column temperature 1 104.15 214.096 214.096
Particle size of the column 1 131.45 8.492 8.492
%Acetonitrile 1 195.16 307.751 307.751
Column length 1 618.90 500.927 500.927
2-Way Interactions 1 10.37 10.373 10.373
Particle size of the column*%Acetonitrile 1 10.37 10.373 10.373
Residual Error 7 0.14 0.140 0.020
Total 13 1060.20
Source F P
Blocks 1.33 0.287
Main Effects 11040.61 0.000
Column temperature 10742.26 0.000
Particle size of the column 426.08 0.000
%Acetonitrile 15441.38 0.000
Column length 25133.95 0.000
2-Way Interactions 520.45 0.000
Particle size of the column*%Acetonitrile 520.45 0.000
Residual Error
Total
Initial Result For Retention Time: ANOVA
P Value for Linear , Interaction term is less
than 0.05 hence very significant
52. Why RSM
Most surfaces are flatter further away from optimal settings.
• Use linear models when we are far from the optimums.
• Use quadratics to approximate the surfaces near the peaks
Curved line represents the response better as compared to the straight line
53. R00 0512
Response Surface Methodology uses a quadratic
model (that includes the squared term).
For one X the equation is:
This model produces parabolas such as:
The Quadratic Model : Curvature
2
1 2y a b x b x=
54. Result Summary for Resolution and Retention Time
• Based on the results for Resolution & Retention Time and considering
that no terms have been dropped for Resolution, it was decided to
add 2 more trials with centre point setting. It would help in
analysing the response better as well and identify the curvature if
present in the design. Since column length is a discrete factor and in
future it would be advisable to use the column length at 150, it was
decided to set it as constant. Also, based on team’s domain
knowledge and expertise particle size was set at 5 micron.
• Settings for centre points run are:
– Column Length – 150 (constant)
– Particle Size – 5 micron (constant)
– pH of mobile phase – 4.5 (center)
– Column temperature – 35 Deg (center)
– % Acetronitrile – 75% (center
56. Resolution analysis with centre point :Anova
Analysis: Resolution
Figure below shows the results of centre point analysis conducted on the experiment results for Resolution
R-Sq = 96.01% R-Sq(pred) = 78.73% R-Sq(adj) = 93.21%
Analysis of Variance for Resolution (coded units)
Source DF Seq SS Adj SS Adj MS F P
Blocks 1 2.3717 0.2233 0.2233 0.56 0.470
Main Effects 5 89.4256 82.8680 16.5736 41.93 0.000
Column temperature 1 1.1396 1.1396 1.1396 2.88 0.120
Particle size of the column 1 7.9974 3.9105 3.9105 9.89 0.010
%Acetonitrile 1 0.7613 0.7613 0.7613 1.93 0.195
Column length 1 5.3522 2.8815 2.8815 7.29 0.022
pH of the mobile phase buffer 1 74.1752 74.1752 74.1752 187.68 0.000
Curvature 1 3.2137 3.2137 3.2137 8.13 0.017
Residual Error 10 3.9523 3.9523 0.3952
Lack of Fit 9 3.9473 3.9473 0.4386 87.72 0.083
Pure Error 1 0.0050 0.0050 0.0050
Total 17 98.9632
57. Prioritized Terms for Resolution
Based on the results from the above analysis, it can be clearly seen that:
Curvature effect is present which urges for a RSM model to predict the
response
The factors identified as significant are: pH of mobile phase, Particle size,
and Column length
58. Analysis: Retention Time
S = 1.04461 PRESS = 45.2842
R-Sq = 99.23% R-Sq(pred) = 96.01% R-Sq(adj) = 98.56%
Analysis of Variance for rt of Imp A (coded units)
Source DF Seq SS Adj SS Adj MS F P
Blocks 1 9.02 0.03 0.026 0.02 0.880
Main Effects 5 1110.61 1052.03 210.406 192.82 0.000
Column temperature 1 96.22 263.03 263.032 241.04 0.000
Particle size of the column 1 75.81 1.76 1.763 1.62 0.239
%Acetonitrile 1 195.16 365.92 365.922 335.33 0.000
Column length 1 740.11 574.45 574.448 526.43 0.000
pH of the mobile phase buffer 1 3.31 2.37 2.366 2.17 0.179
Curvature 1 5.54 5.54 5.537 5.07 0.054
Residual Error 8 8.73 8.73 1.091
Lack of Fit 7 8.15 8.15 1.164 2.00 0.498
Pure Error 1 0.58 0.58 0.583
Total 15 1133.89
Retention Time with centre point :Anova
59. Particle size of the column
pH of the mobile phase buffer
Column temperature
%Acetonitrile
Column length
2520151050
Term
Standardized Effect
2.31
Pareto Chart of the Standardized Effects
(response is rt of Imp A, Alpha = 0.05)
Based on the results from the above ANOVA table and Pareto Chart, we can conclude
Curvature effect is present for this response
The factors identified as significant are: Column length, % Acetonitrile, and
Column temperature
Prioritized Terms for Retention Time
60. Significant Factors
• Out of the five factors selected for the screening design, the factors
that are significant are:
• After discussion and analysis with the team, it was decided that the
following factors will be selected for optimization design:
– Column length (Experimental): Axial Low (150), Axial High (250)
– Column Temperature: Axial Low (25), Axial High (45)
– pH: Axial Low (2), Axial High (7)
– %ACN: Axial Low (100), Axial High (100)
– Particle Size (Constant): 5 micron
• A 30 trial Central Composite design has been suggested for
optimization
Response 1 - Resolution Response 2 – Retention time
pH Column temperature
particle size %ACN
column length Column length
62. Final Model for Resolution : ANOVA
Reduced Model (Resolution)
S = 0.453124 PRESS = 9.91394
R-Sq = 88.33% R-Sq(pred) = 74.40% R-Sq(adj) = 84.62%
Analysis of Variance for Resolution
Source DF Seq SS Adj SS Adj MS F P
Regression 7 34.2053 34.2053 4.8865 23.80 0.000
Linear 4 17.0199 17.0199 4.2550 20.72 0.000
Col Temp 1 0.4272 0.4272 0.4272 2.08 0.163
%ACN 1 0.1285 0.1285 0.1285 0.63 0.437
pH 1 13.9586 13.9586 13.9586 67.98 0.000
Column Length 1 2.5056 2.5056 2.5056 12.20 0.002
Square 1 14.4146 14.4146 14.4146 70.20 0.000
pH*pH 1 14.4146 14.4146 14.4146 70.20 0.000
Interaction 2 2.7707 2.7707 1.3854 6.75 0.005
Col Temp*pH 1 0.9702 0.9702 0.9702 4.73 0.041
pH*Column Length 1 1.8005 1.8005 1.8005 8.77 0.007
Residual Error 22 4.5171 4.5171 0.2053
Total 29 38.7223
63. Resolution : Model Interpretation
As per the ANOVA table above, it can be seen
that:
– The squared term pH is significant for resolution
– There is an interaction between Column temp & pH,
and Column length & pH
– The R-Sq values are 88.83% which determines that the
model is good for prediction of the response
64. Reduced Model (Retention Time)
S = 0.221488 PRESS = 3.08824
R-Sq = 99.95% R-Sq(pred) = 99.82% R-Sq(adj) = 99.93%
Analysis of Variance for Retention Time
Source DF Seq SS Adj SS Adj MS F P
Regression 9 1711.39 1711.39 190.15 3876.21 0.000
Linear 4 1697.67 1351.38 337.84 6886.80 0.000
Col Temp 1 136.47 277.18 277.18 5650.10 0.000
%ACN 1 98.11 245.63 245.63 5007.11 0.000
pH 1 0.07 0.07 0.07 1.33 0.264
Column Length 1 1463.02 1273.40 1273.40 25957.74 0.000
Square 2 1.04 1.15 0.58 11.75 0.001
Col Temp*Col Temp 1 0.98 0.81 0.81 16.54 0.001
%ACN*%ACN 1 0.06 0.70 0.70 14.32 0.001
Interaction 3 12.68 12.68 4.23 86.17 0.000
Col Temp*%ACN 1 0.04 2.02 2.02 41.19 0.000
Col Temp*Column Length 1 4.15 7.35 7.35 149.86 0.000
%ACN*Column Length 1 8.49 8.49 8.49 173.02 0.000
Residual Error 17 0.83 0.83 0.05
Total 26 1712.22
Final Model for Retention Time : ANOVA
65. As seen from the ANOVA tables above, it can be
concluded that:
– There is a squared effect of Column Temperature and %
Acetonitrile on the response
– Interaction exists between Column Temperature & %ACN,
Column Temp & Column Length, and %ACN & Column
Length
– Also, the R-Sq value of the reduced model is 99.95% which
is in indicator that the predictability of the model will be
very good
Retention Time : Model Interpretation
67. Optimization Settings
Cur
High
Low0.71144
D
New
d = 0.50614
Maximum
Resoluti
y = 5.0123
d = 1.0000
Minimum
Retentio
y = 52.2091
0.71144
Desirability
Composite
150.0
250.0
2.0
7.0
50.0
100.0
25.0
45.0
%ACN pH Column LCol Temp
[40.0] [100.0] [6.60] [150.0]
68. Validation Trials
• Validation runs were conducted to test the settings identified using
DOE. The results after validation run were as follows:
Date Analyst LNB Ref Resolution
Rt of
Impurity A
30-12-2013 Sandeep SL1030-71 5.32 59.733
01-01-2014 Varsha SL1030-73 5.52 59.781
02-01-2014 Varsha SL1030-75 5.60 59.849
69. Design Space
• The desired profile for both the responses are:
– Response Goal Lower Target Upper
– Resolution Maximum 4 6 6
– Retention Ti Minimum 55 55 75
70. Design Space
• Based on the above desired response values, the design space is
identified as below
Design Space
Design Space
The design space for both the parameters (highlighted in yellow in the above figure) has been identified which is
as given below
%ACN – 50 to 70
Column length – 150 constant as it is a discrete factor
Column temperature – 35 to 45
pH value – 6.2 to 6.8