Kadcyla is an antibody-drug conjugate used to treat HER2-positive breast cancer. After its approval, the manufacturer worked to optimize the supply chain through various manufacturing changes like scale-up and site transfers.
Analytical control strategies ensured comparable product quality during these changes. Testing was conducted at all stages of production - from starting materials to drug substance to drug product. Studies like process validation and comparability assessments demonstrated that quality was maintained with the different manufacturing processes.
The supply chain optimization efforts required extensive collaboration between internal project teams and external partners. Analytical development and quality control played a key role in developing tailored control strategies for each type of change and production stage.
The document provides guidance on post-approval changes to immediate release solid oral dosage forms. It defines three levels (I, II, III) of changes based on their potential impact. Level I changes are minor, Level II are moderate, and Level III are major. It provides recommendations for chemistry, manufacturing, dissolution and bioequivalence testing for components/composition, site, batch size and manufacturing changes. Changes are supported by prior approval supplements, changes being effected supplements or annual reports with stability data as appropriate to the level of change.
Using Fusion QbD as an Analytical Quality by Design Software for Method Devel...Waters Corporation
This presentation describes the benefits of a hardware and software platform that dramatically advances LC and LC-MS method development by applying Analytical Quality by Design (AQbD) approaches in a 100% regulatory compliance supported framework. This AQbD aligned platform includes Waters Empower™ Chromatography Data System Software with enhanced Fusion QbD® Software, the Waters® ACQUITY UPLC H-Class PLUS, a PDA detector, and QDa Mass Detector. New software capabilities that optimize and simplify the use of mass detection in the AQbD method development workflow have been added.
Visit methods.waters.com for more information
SUPAC Guidelines for Pilot plant Scale up vibhutidubey1
The document discusses post-approval changes (SUPAC) to drug manufacturing processes and guidelines for evaluating such changes. It defines four levels of changes - site changes, batch size changes, manufacturing changes, and composition changes. For each level of change, it provides recommendations on chemistry and bioequivalence testing to evaluate the impact on drug quality and performance. The guidelines aim to ensure quality is maintained when changes are made following drug approval.
Guidance for industry cmc postapproval manufacturing changes to be documented...Samir Barragán
This guidance from the FDA provides recommendations to drug application holders regarding CMC post-approval manufacturing changes that should be documented in annual reports rather than submitted as supplements. It includes appendices listing examples of changes that generally have a minimal potential effect on product quality, such as equipment additions or minor manufacturing process changes. The guidance aims to clarify reporting requirements, better allocate FDA resources, and implement a risk-based approach to CMC regulation as recommended in the FDA's Pharmaceutical Quality Initiative.
The document discusses Quality by Design (QbD) in the pharmaceutical industry. It defines QbD and outlines its key benefits, including higher product quality assurance, cost savings, and regulatory flexibility. The main elements of QbD are described as identifying target quality profiles, critical quality attributes, risk assessment, linking attributes and parameters to quality, defining a design space and control strategy. QbD facilitates innovation and continuous improvement across a product's lifecycle.
Modern BioManufacturing: Single-Use Technologies in Configurable, Prefabricat...MilliporeSigma
A co-webinar describing a solution to biopharma's challenge of rapidly and rationally expanding capacity by employing single-use technologies, a templated process train, and pre-fabricated mobile/modular cleanrooms.
Biopharmaceutical companies on the verge of investing into manufacturing or facilities expansion face many questions and challenges. Speed, agility, and flexibility are becoming more critical to executing their changing production and distribution strategies. Platform facility designs which integrate the latest procss technologies wthin innovative pre-fabricated cleanrooms are critical for addressing the trending desire to implement 'clonable' modular facilities that can be delivered in a timely fashion across multiple locations. Companies like Merck KGaA, Darmstadt, Germany and G-CON Manufacturing are working together to combine their technologies and develop simple yet robust platform solutions for industry.
As bioprocessing technologies intensify performance, volumetric requirements become less. As such, 2000L single-use bioreactors - or multiple bioreactors of similar or less volumes - now suffice for the production of novel or biosimilar recombinant proteins. Such a shift in the industry enables the development of more mobile, modular facility designs. We will describe the rationale for this collaboration and its result: a turn-key solution that integrates a templated process train with a rapidly-deployable facility platform. By combining the unique advantages found with the G-CON POD construction and the bioprocess technology expertise from within Merck KGaA, Darmstadt, Germany, the goal of creating a cost-effective, pre-fabricated alternative to historical 'stick built' facilities is being achieved. Additionally, the flexibility inherent to our approach provides for a greater configurability that confers more user-specified choice into the selection of options. Simple in concept, this solution is also robust, cost-effective, and conducive to tight timelines for implementation.
In this webinar you will learn:
- Basic options for facilities/capacity expansion
- The value of templated process trains employing single-use equipment
- How modular, prefabricated PODs® outfitted with such single-use bioprocessing equipment represent an attractive, cost-effective strategy for capacity expansion
POD® is a registered trademark of G-CON Manufacturing, Inc.
m.pharm (pharmaceutics) modern pharmaceutics- unit 2 validation- part 2 Validation of specific dosage form,
Types of validation. Government regulation, Manufacturing Process Model,
URS, DQ, IQ, OQ & P.Q. of facilities.
In this presentation from IVT's GMP Week, Journal of Validation Technology Editor-in-Chief, Paul Pluta, Ph.D., asks "can compliance be improved by using quality by design [QbD] concepts?" Pluta discussed the QbD application, development of validation master plans, and the lifecycle approach to process validation. Furthermore, he discusses how to incorporate these essential parts of the validation process to implement effective, and efficient, compliance by design into the quality system.
The document provides guidance on post-approval changes to immediate release solid oral dosage forms. It defines three levels (I, II, III) of changes based on their potential impact. Level I changes are minor, Level II are moderate, and Level III are major. It provides recommendations for chemistry, manufacturing, dissolution and bioequivalence testing for components/composition, site, batch size and manufacturing changes. Changes are supported by prior approval supplements, changes being effected supplements or annual reports with stability data as appropriate to the level of change.
Using Fusion QbD as an Analytical Quality by Design Software for Method Devel...Waters Corporation
This presentation describes the benefits of a hardware and software platform that dramatically advances LC and LC-MS method development by applying Analytical Quality by Design (AQbD) approaches in a 100% regulatory compliance supported framework. This AQbD aligned platform includes Waters Empower™ Chromatography Data System Software with enhanced Fusion QbD® Software, the Waters® ACQUITY UPLC H-Class PLUS, a PDA detector, and QDa Mass Detector. New software capabilities that optimize and simplify the use of mass detection in the AQbD method development workflow have been added.
Visit methods.waters.com for more information
SUPAC Guidelines for Pilot plant Scale up vibhutidubey1
The document discusses post-approval changes (SUPAC) to drug manufacturing processes and guidelines for evaluating such changes. It defines four levels of changes - site changes, batch size changes, manufacturing changes, and composition changes. For each level of change, it provides recommendations on chemistry and bioequivalence testing to evaluate the impact on drug quality and performance. The guidelines aim to ensure quality is maintained when changes are made following drug approval.
Guidance for industry cmc postapproval manufacturing changes to be documented...Samir Barragán
This guidance from the FDA provides recommendations to drug application holders regarding CMC post-approval manufacturing changes that should be documented in annual reports rather than submitted as supplements. It includes appendices listing examples of changes that generally have a minimal potential effect on product quality, such as equipment additions or minor manufacturing process changes. The guidance aims to clarify reporting requirements, better allocate FDA resources, and implement a risk-based approach to CMC regulation as recommended in the FDA's Pharmaceutical Quality Initiative.
The document discusses Quality by Design (QbD) in the pharmaceutical industry. It defines QbD and outlines its key benefits, including higher product quality assurance, cost savings, and regulatory flexibility. The main elements of QbD are described as identifying target quality profiles, critical quality attributes, risk assessment, linking attributes and parameters to quality, defining a design space and control strategy. QbD facilitates innovation and continuous improvement across a product's lifecycle.
Modern BioManufacturing: Single-Use Technologies in Configurable, Prefabricat...MilliporeSigma
A co-webinar describing a solution to biopharma's challenge of rapidly and rationally expanding capacity by employing single-use technologies, a templated process train, and pre-fabricated mobile/modular cleanrooms.
Biopharmaceutical companies on the verge of investing into manufacturing or facilities expansion face many questions and challenges. Speed, agility, and flexibility are becoming more critical to executing their changing production and distribution strategies. Platform facility designs which integrate the latest procss technologies wthin innovative pre-fabricated cleanrooms are critical for addressing the trending desire to implement 'clonable' modular facilities that can be delivered in a timely fashion across multiple locations. Companies like Merck KGaA, Darmstadt, Germany and G-CON Manufacturing are working together to combine their technologies and develop simple yet robust platform solutions for industry.
As bioprocessing technologies intensify performance, volumetric requirements become less. As such, 2000L single-use bioreactors - or multiple bioreactors of similar or less volumes - now suffice for the production of novel or biosimilar recombinant proteins. Such a shift in the industry enables the development of more mobile, modular facility designs. We will describe the rationale for this collaboration and its result: a turn-key solution that integrates a templated process train with a rapidly-deployable facility platform. By combining the unique advantages found with the G-CON POD construction and the bioprocess technology expertise from within Merck KGaA, Darmstadt, Germany, the goal of creating a cost-effective, pre-fabricated alternative to historical 'stick built' facilities is being achieved. Additionally, the flexibility inherent to our approach provides for a greater configurability that confers more user-specified choice into the selection of options. Simple in concept, this solution is also robust, cost-effective, and conducive to tight timelines for implementation.
In this webinar you will learn:
- Basic options for facilities/capacity expansion
- The value of templated process trains employing single-use equipment
- How modular, prefabricated PODs® outfitted with such single-use bioprocessing equipment represent an attractive, cost-effective strategy for capacity expansion
POD® is a registered trademark of G-CON Manufacturing, Inc.
m.pharm (pharmaceutics) modern pharmaceutics- unit 2 validation- part 2 Validation of specific dosage form,
Types of validation. Government regulation, Manufacturing Process Model,
URS, DQ, IQ, OQ & P.Q. of facilities.
In this presentation from IVT's GMP Week, Journal of Validation Technology Editor-in-Chief, Paul Pluta, Ph.D., asks "can compliance be improved by using quality by design [QbD] concepts?" Pluta discussed the QbD application, development of validation master plans, and the lifecycle approach to process validation. Furthermore, he discusses how to incorporate these essential parts of the validation process to implement effective, and efficient, compliance by design into the quality system.
M.pharm (Pharmaceutics) Modern Pharmaceutics unit- Validation Part-1 introduction, scope and merits of validation, Validation and calibration of Master plan, ICH & WHO guidelines for calibration and validation of equipment.
This document provides guidance for industry on scale-up and post-approval changes to immediate release solid oral dosage forms. It defines four levels of changes to components/composition, with Level 1 being minor changes unlikely to affect quality/performance, and Level 4 being major changes requiring new clinical studies. Level 2 changes could significantly impact quality/performance, and the required tests and documentation vary based on factors like therapeutic range, drug solubility and permeability. Level 3 changes involve new excipients or deleting excipients. The guidance provides recommendations on chemistry, manufacturing, dissolution and bioequivalence tests required for documentation for each level of change.
This document outlines the analytical method and specification lifecycle processes during product development and commercialization. It discusses opportunities to accelerate these processes through parallelization and use of analytical platform technology (APT) methods. The ideal lifecycle involves conducting robustness studies, method validation, transfer, and maintenance in parallel rather than sequentially. Case studies are presented showing how specifications were revised based on manufacturing capability and clinical experience for a product. The goal is to understand how APT and parallel steps can support accelerated development programs by reducing analytical method lifecycle timelines.
This document discusses process validation. It defines process validation as establishing documented evidence that a process will consistently produce a product meeting its predetermined specifications. The key aspects of process validation are to obtain consistent and reliable data, demonstrate that the process remains in control, and show the process works as intended. There are different types of process validation including prospective, retrospective, and concurrent validation. Process validation involves multiple phases from process design and qualification to process verification and monitoring. It is important for quality, safety, efficacy and compliance with global regulatory agencies.
The document discusses validation of dissolution apparatus. It begins with an introduction to dissolution testing and factors affecting dissolution. It then covers the various theories of dissolution and describes the common USP dissolution apparatus. The remainder of the document focuses on validation, including equipment validation, validation phases, protocols, and revalidation. It emphasizes establishing documented evidence to ensure dissolution apparatus will consistently produce reliable results.
This document discusses process validation in API facilities. It defines validation and describes the different types of validation including analytical tests, equipment, process, and support process validation. It also discusses facility systems validation including design qualification, installation qualification, operational qualification, and performance qualification. The types of validation including prospective, concurrent and retrospective are described. Process validation is important to demonstrate process control and consistency and comply with regulatory requirements. Process validation requires identifying critical process parameters and critical quality attributes.
Process validation and validation requirementRavish Yadav
The all the content in this profile is completed by the teachers, students as well as other health care peoples.
thank you, all the respected peoples, for giving the information to complete this presentation.
this information is free to use by anyone.
CONCEPT & TYPE OF VALIDATION OF GOVERNMENT REGULATIONArul Packiadhas
This document discusses the concept and types of validation of government regulation for pharmaceutical processes. It defines validation and describes the main types, including analytical method validation, equipment validation, cleaning validation, and process validation. For each type, key aspects and considerations are outlined. The history and regulatory basis for process validation are also summarized.
The Role of Process Characterization in Process ValidationDavid Goodrich
The document discusses the role of process characterization in process validation. It begins by defining process validation and process characterization. Process characterization aims to identify and quantify all significant sources of variation, especially inherent variation in materials and technology as applied to the specific product design. Characterization studies determine how the process performs under worst-case conditions prior to qualification testing. The document then provides two case studies as examples of using design of experiments to characterize processes and identify optimal process settings.
This document outlines acceptance criteria and conditions for continued process verification (CPV) of biopharmaceutical products. It discusses developing control strategies and setting non-microbiological and microbiological quality attribute limits. Typical quality attribute development over the product lifecycle is shown, including accelerated development approaches. Statistical and practical approaches for setting CPV limits are presented. Examples show how drug substance specifications and stability conditions relate to CPV limits. Response levels for out-of-specification or out-of-trend results during process validation and verification are defined based on the potential impact to product quality and process consistency.
The document discusses Supplemental Abbreviated Changes to an Approved Application (SUPAC) guidelines for post-approval changes to pharmaceutical drug products. It defines three levels of changes - minor, moderate, and major - and provides recommendations for documentation and necessary filings based on the level of change for components/composition, manufacturing equipment, processes, batch size, and site changes. Minor changes may only require annual reporting, while major changes involving new excipients, processes, or sites would necessitate prior approval supplements and additional testing.
This document summarizes a discussion forum on ICH Q7 & Q11 regarding DMFs, impurities, CTD, and challenges. It provides an outline of drug master files, types of DMFs, classes of impurities in APIs, elements of a control strategy, sections of the common technical document that contain established conditions, and challenges faced. The presentation focused on established conditions, control strategies, their relationship, and how established conditions are presented in CTD sections.
This document summarizes key points from presentations by Stephan Krause on developing acceptance criteria for commercial processes (CPV) and continued monitoring of quality attributes. It discusses:
1) Developing control strategies and acceptance criteria for non-microbiological and microbiological quality attributes.
2) Using risk assessments to determine critical quality attributes and establish alert and action levels.
3) Considerations for setting CPV limits, including data transformations, understanding batch vs campaign variability, and examples of specifications.
4) Conditions for out-of-trend, out-of-specification, and non-conformance monitoring during commercial production and process/product changes.
FDA (invited) Presentation - Specifications and Analytical Method Lifecycle f...Stephan O. Krause, PhD
Stephan O. Krause presented on analytical method lifecycles for accelerated biological product development. He outlined typical and ideal analytical method lifecycles, highlighting opportunities to reduce steps for accelerated programs using analytical platform technology methods. Krause discussed qualification versus verification approaches for these methods, case studies on HPSEC and AUC methods, and a survey on analytical method transfers. He provided an example of revising HPSEC specifications based on manufacturing and clinical experience.
This document discusses process validation in the pharmaceutical industry. It defines process validation and describes it as having three stages: process design, process qualification, and continued process verification. The objectives and requirements of each stage are explained. Process validation helps ensure a process consistently produces products meeting specifications and quality attributes. It involves understanding and controlling sources of variation. Validation protocols, reports, teams, and the lifecycle are also reviewed to explain how process validation is planned and documented.
This document discusses techniques for scaling up pilot plant operations in the pharmaceutical industry. It begins with definitions of key terms and explains the significance of pilot plants in permitting examination of formulas at an intermediate scale. The document outlines general considerations for pilot plant operations, including personnel requirements, equipment used, production rates, and process evaluation. It also covers master manufacturing procedures, product stability testing, and GMP compliance. Advantages are given as personnel can observe scale up runs and quality materials can be accessed, while disadvantages include reduced interaction between formulators and production staff.
This document discusses SUPAC (Scale Up and Post Approval Changes) guidelines and post-marketing surveillance. It provides details on SUPAC guidelines for immediate release solid oral dosage forms, including definitions of level 1, 2, and 3 changes for components/composition, site changes, batch size changes, and manufacturing process/equipment changes. It also discusses post-marketing surveillance, including the importance of monitoring drug safety after approval and examples of adverse events discovered only after drugs entered the market like Practolol and Thalidomide.
This document provides an overview of SUPAC documents and their use in quality assessment of pharmaceutical products. SUPAC documents issued by the FDA help applicants make post-approval changes. They categorize changes to formulation components, manufacturing processes, equipment, and recommend supporting documentation. Level 1 changes have little impact while Level 3 changes likely impact product quality and require stability testing, dissolution testing and bioequivalence studies. Examples demonstrate how to determine the level of formulation and equipment changes using SUPAC guidance.
This document outlines the process validation plan for a solid dosage anti-tuberculosis drug. It begins with an introduction and outline. It then discusses the stages of process validation, literature review, and plan of work. The document describes the manufacturing process and identifies critical and non-critical process parameters. It discusses sampling plans, statistical tools for analysis, and key references. The overall aim is to assure consistent quality and reduce defects through process validation.
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.
The SUPAC guidelines provide recommendations for post-approval changes to NDAs and ANDAs, including changes to components, manufacturing processes, batch size, and manufacturing sites. The guidelines classify changes as minor (Level 1), moderate (Level 2), or major (Level 3) based on their potential effect on product quality and performance. Level 1 changes require chemistry and dissolution documentation, while Level 2 changes may also require in vivo bioequivalence testing or stability testing. Level 3 changes always require bioequivalence testing and prior approval before implementation. The guidelines aim to streamline regulatory processes for industry while ensuring safety and effectiveness.
M.pharm (Pharmaceutics) Modern Pharmaceutics unit- Validation Part-1 introduction, scope and merits of validation, Validation and calibration of Master plan, ICH & WHO guidelines for calibration and validation of equipment.
This document provides guidance for industry on scale-up and post-approval changes to immediate release solid oral dosage forms. It defines four levels of changes to components/composition, with Level 1 being minor changes unlikely to affect quality/performance, and Level 4 being major changes requiring new clinical studies. Level 2 changes could significantly impact quality/performance, and the required tests and documentation vary based on factors like therapeutic range, drug solubility and permeability. Level 3 changes involve new excipients or deleting excipients. The guidance provides recommendations on chemistry, manufacturing, dissolution and bioequivalence tests required for documentation for each level of change.
This document outlines the analytical method and specification lifecycle processes during product development and commercialization. It discusses opportunities to accelerate these processes through parallelization and use of analytical platform technology (APT) methods. The ideal lifecycle involves conducting robustness studies, method validation, transfer, and maintenance in parallel rather than sequentially. Case studies are presented showing how specifications were revised based on manufacturing capability and clinical experience for a product. The goal is to understand how APT and parallel steps can support accelerated development programs by reducing analytical method lifecycle timelines.
This document discusses process validation. It defines process validation as establishing documented evidence that a process will consistently produce a product meeting its predetermined specifications. The key aspects of process validation are to obtain consistent and reliable data, demonstrate that the process remains in control, and show the process works as intended. There are different types of process validation including prospective, retrospective, and concurrent validation. Process validation involves multiple phases from process design and qualification to process verification and monitoring. It is important for quality, safety, efficacy and compliance with global regulatory agencies.
The document discusses validation of dissolution apparatus. It begins with an introduction to dissolution testing and factors affecting dissolution. It then covers the various theories of dissolution and describes the common USP dissolution apparatus. The remainder of the document focuses on validation, including equipment validation, validation phases, protocols, and revalidation. It emphasizes establishing documented evidence to ensure dissolution apparatus will consistently produce reliable results.
This document discusses process validation in API facilities. It defines validation and describes the different types of validation including analytical tests, equipment, process, and support process validation. It also discusses facility systems validation including design qualification, installation qualification, operational qualification, and performance qualification. The types of validation including prospective, concurrent and retrospective are described. Process validation is important to demonstrate process control and consistency and comply with regulatory requirements. Process validation requires identifying critical process parameters and critical quality attributes.
Process validation and validation requirementRavish Yadav
The all the content in this profile is completed by the teachers, students as well as other health care peoples.
thank you, all the respected peoples, for giving the information to complete this presentation.
this information is free to use by anyone.
CONCEPT & TYPE OF VALIDATION OF GOVERNMENT REGULATIONArul Packiadhas
This document discusses the concept and types of validation of government regulation for pharmaceutical processes. It defines validation and describes the main types, including analytical method validation, equipment validation, cleaning validation, and process validation. For each type, key aspects and considerations are outlined. The history and regulatory basis for process validation are also summarized.
The Role of Process Characterization in Process ValidationDavid Goodrich
The document discusses the role of process characterization in process validation. It begins by defining process validation and process characterization. Process characterization aims to identify and quantify all significant sources of variation, especially inherent variation in materials and technology as applied to the specific product design. Characterization studies determine how the process performs under worst-case conditions prior to qualification testing. The document then provides two case studies as examples of using design of experiments to characterize processes and identify optimal process settings.
This document outlines acceptance criteria and conditions for continued process verification (CPV) of biopharmaceutical products. It discusses developing control strategies and setting non-microbiological and microbiological quality attribute limits. Typical quality attribute development over the product lifecycle is shown, including accelerated development approaches. Statistical and practical approaches for setting CPV limits are presented. Examples show how drug substance specifications and stability conditions relate to CPV limits. Response levels for out-of-specification or out-of-trend results during process validation and verification are defined based on the potential impact to product quality and process consistency.
The document discusses Supplemental Abbreviated Changes to an Approved Application (SUPAC) guidelines for post-approval changes to pharmaceutical drug products. It defines three levels of changes - minor, moderate, and major - and provides recommendations for documentation and necessary filings based on the level of change for components/composition, manufacturing equipment, processes, batch size, and site changes. Minor changes may only require annual reporting, while major changes involving new excipients, processes, or sites would necessitate prior approval supplements and additional testing.
This document summarizes a discussion forum on ICH Q7 & Q11 regarding DMFs, impurities, CTD, and challenges. It provides an outline of drug master files, types of DMFs, classes of impurities in APIs, elements of a control strategy, sections of the common technical document that contain established conditions, and challenges faced. The presentation focused on established conditions, control strategies, their relationship, and how established conditions are presented in CTD sections.
This document summarizes key points from presentations by Stephan Krause on developing acceptance criteria for commercial processes (CPV) and continued monitoring of quality attributes. It discusses:
1) Developing control strategies and acceptance criteria for non-microbiological and microbiological quality attributes.
2) Using risk assessments to determine critical quality attributes and establish alert and action levels.
3) Considerations for setting CPV limits, including data transformations, understanding batch vs campaign variability, and examples of specifications.
4) Conditions for out-of-trend, out-of-specification, and non-conformance monitoring during commercial production and process/product changes.
FDA (invited) Presentation - Specifications and Analytical Method Lifecycle f...Stephan O. Krause, PhD
Stephan O. Krause presented on analytical method lifecycles for accelerated biological product development. He outlined typical and ideal analytical method lifecycles, highlighting opportunities to reduce steps for accelerated programs using analytical platform technology methods. Krause discussed qualification versus verification approaches for these methods, case studies on HPSEC and AUC methods, and a survey on analytical method transfers. He provided an example of revising HPSEC specifications based on manufacturing and clinical experience.
This document discusses process validation in the pharmaceutical industry. It defines process validation and describes it as having three stages: process design, process qualification, and continued process verification. The objectives and requirements of each stage are explained. Process validation helps ensure a process consistently produces products meeting specifications and quality attributes. It involves understanding and controlling sources of variation. Validation protocols, reports, teams, and the lifecycle are also reviewed to explain how process validation is planned and documented.
This document discusses techniques for scaling up pilot plant operations in the pharmaceutical industry. It begins with definitions of key terms and explains the significance of pilot plants in permitting examination of formulas at an intermediate scale. The document outlines general considerations for pilot plant operations, including personnel requirements, equipment used, production rates, and process evaluation. It also covers master manufacturing procedures, product stability testing, and GMP compliance. Advantages are given as personnel can observe scale up runs and quality materials can be accessed, while disadvantages include reduced interaction between formulators and production staff.
This document discusses SUPAC (Scale Up and Post Approval Changes) guidelines and post-marketing surveillance. It provides details on SUPAC guidelines for immediate release solid oral dosage forms, including definitions of level 1, 2, and 3 changes for components/composition, site changes, batch size changes, and manufacturing process/equipment changes. It also discusses post-marketing surveillance, including the importance of monitoring drug safety after approval and examples of adverse events discovered only after drugs entered the market like Practolol and Thalidomide.
This document provides an overview of SUPAC documents and their use in quality assessment of pharmaceutical products. SUPAC documents issued by the FDA help applicants make post-approval changes. They categorize changes to formulation components, manufacturing processes, equipment, and recommend supporting documentation. Level 1 changes have little impact while Level 3 changes likely impact product quality and require stability testing, dissolution testing and bioequivalence studies. Examples demonstrate how to determine the level of formulation and equipment changes using SUPAC guidance.
This document outlines the process validation plan for a solid dosage anti-tuberculosis drug. It begins with an introduction and outline. It then discusses the stages of process validation, literature review, and plan of work. The document describes the manufacturing process and identifies critical and non-critical process parameters. It discusses sampling plans, statistical tools for analysis, and key references. The overall aim is to assure consistent quality and reduce defects through process validation.
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.
The SUPAC guidelines provide recommendations for post-approval changes to NDAs and ANDAs, including changes to components, manufacturing processes, batch size, and manufacturing sites. The guidelines classify changes as minor (Level 1), moderate (Level 2), or major (Level 3) based on their potential effect on product quality and performance. Level 1 changes require chemistry and dissolution documentation, while Level 2 changes may also require in vivo bioequivalence testing or stability testing. Level 3 changes always require bioequivalence testing and prior approval before implementation. The guidelines aim to streamline regulatory processes for industry while ensuring safety and effectiveness.
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.
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.
Considering Quality by Design (QbD) in Analytical Development for Protein The...Weijun Li
1) The document discusses applying Quality by Design (QbD) principles to analytical method development for protein therapeutics.
2) A case study is presented on applying QbD to size exclusion chromatography (SEC) method development, breaking the process down into 9 steps including defining method parameters and critical method attributes, performing an initial design of experiments to identify critical method parameters, modeling their effects, and confirming robustness.
3) The goal is to establish a design space and system suitability parameters to control the method and support validation.
This document discusses granulation processes and quality management in the pharmaceutical industry. It covers topics like cGMP, SUPAC guidelines for post-approval changes, validation of granulation equipment and processes, and questionnaires for auditing granulation. The key points are that granulation is a critical manufacturing step that must be validated; SUPAC provides guidance on composition, batch size, site and equipment changes; and validation involves qualifying equipment and demonstrating consistent product quality through processes.
The document discusses opportunities to reduce the analytical method lifecycle for accelerated biologics development programs. It outlines typical lifecycles and proposes parallelizing steps like method validation, transfer, and maintenance across analytical platform technologies, product characterization methods, and new product-specific methods. The goal is to understand how platform methods and parallel analytical development can support faster programs. Specific opportunities discussed include leveraging historical data, conducting partial validations, and transferring feasibility rather than formally transferring methods.
SUPAC, BACPAC, Post Marketing SurveillanceMANIKANDAN V
This document discusses various guidelines related to product development and technology transfer in the pharmaceutical industry. It covers SUPAC, BACPAC, and post-marketing surveillance. SUPAC provides guidance for scale-up and post-approval changes, categorizing changes into different levels based on their potential impact. BACPAC guidance addresses post-approval changes for bulk active pharmaceutical ingredients. Post-marketing surveillance involves monitoring adverse drug events after approval to ensure ongoing safety and effectiveness.
This document summarizes guidance on scale up and post-approval changes for pharmaceutical products. It outlines 3 levels for various changes based on their potential impact. Level 1 changes are unlikely to impact quality or performance. Level 2 changes may significantly impact quality or performance. Level 3 changes require full bioequivalence testing. The guidance covers changes to components, manufacturing site, batch size, equipment, and processes. Documentation requirements increase based on the level of change, ranging from chemistry testing to full bioequivalence studies.
This document summarizes guidance on scale up and post-approval changes for pharmaceutical products. It outlines 3 levels for various changes based on their potential impact. Level 1 changes are unlikely to impact quality or performance. Level 2 changes may significantly impact quality or performance. Level 3 changes require full bioequivalence testing. The guidance covers changes to components, manufacturing site, batch size, equipment, and processes. Documentation requirements increase based on the level of change from annual reports to chemistry testing and bioequivalence studies.
This document provides an overview of Quality by Design (QbD) for pharmaceutical technical professionals. It discusses that QbD aims to build in quality rather than test it in through a systematic approach focusing on product and process understanding. Key elements of QbD include identifying and controlling critical quality attributes and critical process parameters, using a design space and control strategy to ensure the process remains within acceptable limits, and utilizing tools like design of experiments and process analytical technology. The document outlines implications of QbD for various roles like research and development, manufacturing, quality, and engineering in terms of new skills, technologies, and approaches required.
This document provides an overview of Quality by Design (QbD), a systematic approach to pharmaceutical development and manufacturing that emphasizes product and process understanding. It discusses key QbD concepts like critical quality attributes, design space, and control strategy. The document also outlines some advantages of QbD like improved quality, flexibility, and reduced regulatory oversight. Finally, it examines implications of QbD for various technical roles, including new skills needed and a shift towards more predictive and science-based approaches.
This presentation provides information about Real Time Release Testing (RTRT) from the online resource Drug Regulations. It defines RTRT, compares it to conventional testing, discusses RTRT control strategies and process monitoring, and provides examples of using spectroscopic techniques like NIR for RTRT. The presentation emphasizes that RTRT relies on enhanced process and product knowledge to assure quality through in-process monitoring and controls rather than end-product testing alone.
Aplication of on line data analytics to a continuous process polybetene unitEmerson Exchange
This Emerson Exchange, 2013 presentation summarizes the 2013 field trail results achieved by applying on-line continuous data analytics to Lubrizol’s continuous polybutene process. Continuous data analytics may be used to provide an on-line prediction of quality parameters, and enable on-line detection of fault conditions. Information is provided on improvements made in the model used for quality parameter prediction, and how the field trail platform was integrated into the process unit. Presenters Qiwei Li, production engineer, Efren Hernandez and Robert Wojewodka, Lubrizol Corp., and Terry Blevins, principal technologist at Emerson, won best in conference in the process optimization track for this presentation.
Considerations to Extractables and Leachables Testing SGS
How to organize Extractables Assessments? FDA continues to issue Warning Letters to companies that fail to properly complete Design Verification, Design Validation, and Process Validation, and recently to include failures of manufacturers in Risk Management. The evaluation of extractables and leachables has become an increasingly important aspect in the Quality by Design (QbD) initiative of the FDA in the area of drug product design, including materials used in the drug product production process and container and closure systems used for product packaging. This presentation provides general approaches and practical aspects in E&L testing.
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Similar to 2015 Frankfurt_World ADC summit -Lan-16Feb2015 (20)
1. Analytical Support for Commercial Supply Chain
Optimization of T-DM1/Kadcyla®
Lan Dai, Analytical Development and Quality Control, @ 2015 World ADC Frankfurt
2. Kadcyla® Bell Ringing on Campus in
Feb, 2013
CMC Work Continued in Supporting
Post-launch Manufacturing Changes
for Global Commercialization
3. 3
I. Background
1.1 Goal & Challenge
1.2 Product, Process & Supply Chain
1.3 Project Team Governance
II. Analytical Control for Manufacturing Changes
2.0 Overview: Control via Process Validation & Comparability
2.1 Reagents, Starting Materials & Intermediates
2.2 Drug Substance
2.3 Drug Product
III. Summary
4. The Theme: Supply Chain Optimization
4
1.1 Goal and challenge
Goal: Achieve a robust supply chain
CMC Challenges: Overcome ADC unique complexities
Meeting increasing
market demand
Improving supply
chain resilience
DRIVER
1
DRIVER
2
Establishing work process
• Setting standards
- study, documentation, etc.
• Reaching alignment
- development to commercial
- compliance w/ local site policy
- roles & responsibilities
Fulfilling global market requirements
Complex nature of ADCs
Lack of internal precedents
Additional outside regulatory
hurdles
SOURCES SPECIFICS
CMC: Chemistry, Manufacturing and Controls
5. Product Info
5
1.2 Product, process and supply chain
mAb (Trastuzumab, Tmab) + Linker (SMCC) + Drug (Maytansinoids, DM1)
Lysine conjugates: ~3.5 average Drug to Antibody Ratio
Lyophilized, 160 and 100 mg/vial, intravenous infusion
Her2 + metastatic breast cancer; clinical trails ongoing for other indications
Approval by the FDA and EMA in 2013; global filing ongoing
Drug: Maytansinoid (DM1) Linker: SMCC Mab:
Trastuzumab
(Herceptin®)
6. Complicated Manufacturing Process
6
1.2 Product, process and supply chain
mAb
Drug
Store ≤ -60°C
DS
Release
Testing
Frozen Bulk DS
Linker
Tmab
DM1
SMCC
Drug Product (DP)Drug Substance (DS)
Starting Materials &
Intermediates
DP
Release
Testing
Lyophilized
T-DM1
Aseptic Fill
Lyophilization
Store at 2-8°C
Liquid Tmab
MODIFICATION
Linker
Linker
modified
Tmab
Leaving
group
CONJUGATION
Drug
Formulated
liquid T-DM1
7. Complex Supply Chain (post-launch)
7
1.2 Product, process and supply chain
a: for example, organic solvent used for dissolving SMCC and DM1
Examples of planned changes (scale-up and site transfer)
Tmab
Site Transfer
SMCC
Scale-Up
Site Transfer
DM1
Scale-Up
Site Transfer
Critical Reagents a
Site Transfer
DS
Scale-Up
Site Transfer
DP
Scale-Up
Site Transfer
Drug Product (DP)Drug Substance (DS)
Reagents, Starting
Materials & Intermediates
8. Complex Supply Chain (post-launch)
8
1.2 Product, process and supply chain
Examples of planned changes (scale-up and site transfer)
Tmab
Site Transfer
SMCC
Scale-Up
Site Transfer
DM1
Scale-Up
Site Transfer
Critical Reagents a
Site Transfer
DS
Scale-Up
Site Transfer
DP
Scale-Up
Site Transfer
Drug Product (DP)Drug Substance (DS)
Reagents, Starting
Materials & Intermediates
Many combinations of changes;
Bundling changes to minimize supply chain variants
Type of change
Local market/HA requirements
Study planning (purpose, scope & timeline)
Integration of filing and supply chain strategies
HA: Health Authority
9. Extensive Team Interactions
9
1.3 Project team governance
GNE: Genentech
CMO: Contract Manufacturing Organization
Tailored project team setup
ADQC: Analytical development and Quality Control
Tech Dev Team
(GNE/Roche)
DP Team
Small molecule
DS Team
Large molecule
DS Team
Project B
Project A
Project C
Interactions across sites and with external parties
RocheCMOs
GNE
ANALYTICAL
SUPPORT
Who we are - ADQC
(development)
QC method transfer and
management
(commercial)
QC testing
(commercial)
OTHER SUPPORT
QA / QA external
Formulation
Manufacturing/Process
Pharm Engineering
Regulatory
Leadership (Tech lead
and project manager)
10. 10
I. Background
1.1 Goal & challenge
1.2 Product, Process & Supply Chain
1.3 Project governance
II. Analytical Control for Manufacturing Changes
2.0 Overview: Control via Process Validation & Comparability
2.1 Reagents, Starting Materials & Intermediates
2.2 Drug Substance
2.3 Drug Product
III. Summary
11. Overview: analytical control at all stages
11
2.0 Analytical control for manufacturing changes - Overview
Control on routine basis:
Batch release testing
Selective stability testing
Control in the event of changes (scale-up/transfer):
Batch release testing
Selective stability testing
Process validation studies
Comparability studies (change/stage specific)
Drug Product (DP)Drug Substance (DS)
Reagents, Starting
Materials & Intermediates
Must comply with local regulatory requirements in manufacturers
making post-approval changes
12. 12
I. Background
1.1 Goal & Challenge
1.2 Product, Process & Supply Chain
1.3 Project Team Governance
II. Analytical Control for Manufacturing Changes
2.0 Overview
2.1 Reagents, Starting Materials & Intermediates
2.2 Drug Substance
2.3 Drug Product
III. Summary
13. Demonstration of suitability of new materials
13
2.1 Analytical control for manufacturing changes at reagents, starting materials & intermediates level
Current Analytical Testing Strategy
a: change specific and market specific
Change Category Material Study
Changes w/o
regulatory restriction
Reagents & Starting
Materials:
Critical reagents
SMCC
1. reagent stability
2. scale-down use test
3. at-scale comparability
Changes requiring
regulatory submission
Intermediates:
Tmab
DM1
1. reagent stability
2. scale-down use test
3. at-scale comparability
4. next-level release /stability
testing a
14. Example of workflow
14
2.1 Analytical control for manufacturing changes at reagents, starting materials & intermediates level
Strategies aligned
at Tech Dev Team
Level
Completion of
study protocol w/
CMO
Execution of
study protocol at
CMO
Completion of
study report w/
CMO
Submission for
regulatory approval
if required
Change is effective
Internal
Committees
Change Proposed
15. 15I. Background
1.1 Goal and Challenge
1.2 Product, Process and Supply Chain
1.3 Project Team Governance
II. Analytical Control for Manufacturing Changes
2.0 Overview
2.1 Reagents, Starting Materials and Intermediates
2.2 Drug Substance
A case study in DS production scale-up
(Example: comparability study )
2.3 Drug Product
III. Summary
16. DS comparability : a case study in scale-up
16
DS Comparability Protocol
2.2 Analytical control for manufacturing changes at DS level
CoA: Certificate of Analysis
DS release
testing
Quantitative
assessment
Qualitative assessment
Stressed
comparability
Process
related
impurities
Statistical analysis
on CoA Data
Selection of CQAs
sensitive to
process changes
Determination of
tightened
acceptance
criteria with
respect to release
specification
Intact analysis by
LC-MS
Reduced analysis by
LC-MS
Peptide map by
LC-UV
SEC
Free maytansinoids
(free drug) by RPLC
CE-SDS
iCIEF
Stressed to
induce
significant
changes
Comparison of
degradation
profiles
Homogeneity
analysis of
degradation
rates
17. Consistent profiles in drug load distribution by LC-MS
17
2.2 Analytical control for manufacturing changes at DS level
Reference Material
Old Process
New Process
18. Consistent profiles in peptide map (214 and 252nm) by LC-UV
18
2.2 Analytical control for manufacturing changes at DS level
214nm: full view 252nm: expanded view in drug containing region
New
Process
Old
Process
New
Process
Old
Process
Reference
Material
Reference
Material
19. 19
I. Background
1.1 Goal & Challenge
1.2 Product, Process & Supply Chain
1.3 Project Team Governance
II. Analytical Control for Manufacturing Changes
2.0 Overview
2.1 Reagents, Starting Materials & Intermediates
2.2 Drug Substance
2.3 Drug Product
A case study in DP scale up + site transfer
(Example: process validation & comparability studies)
III. Summary
20. Goal: Assess the impact of residual H2O2 on DP stability & set VHP limit
Study Design
Various levels of H2O2
Three temperature conditions: 2-8◦C, 25◦C & 50◦C
4-year stability program
Selected CQAs tested, including methionine oxidation
DP Process validation (Example: peroxide spiking study)
20
2.3 Analytical control for manufacturing changes at DP level
An example of process difference
Vaporized H2O2 (VHP) used to sterilize the filling line at the recipient site, but not at the donor site
PV studies to address the process difference
Two PV studies to ensure no impact of residual H2O2 on product quality
a) VHP uptake study
b) Peroxide spiking study
CQAs: Critical Quality Attributes
21. LC-MS peptide map to assess methionine oxidation
21
2.3 Analytical control for manufacturing changes at DS level
• Linearity and accuracy (recovery) by a comix study
• Precision (repeatability & intermediate precision) by an extremely
high level sample
• “Change in oxidation” defined based on SD obtained from assay qualification
• ±3SD criteria applied to 1 month interim data, limit determined to be 500ppb
• Ongoing study
• No change at 9month for samples spiked w/ H2O2 ≤ 500ppb under
all 3 temp conditions
ASSAY
QUALIFICATION
ESTABLISHING
VHP LIMIT
CONTINUOUS
MONITORING
22. DP comparability: a case study in scale-up + site transfer
22
2.3 Analytical control for manufacturing changes at DP level
DP Comparability Protocol
Positive feedback received from HA regarding the strategy prior to execution
DP release
testing
Quantitative assessment Qualitative assessment
Stressed
comparability
Statistical analysis on
CoA Data
Selection of CQAs
sensitive to process
changes
Determination of
tightened acceptance
criteria
Example: Upper limit of free
drug adjusted to account for
process difference (longer hold
time), still far below release
specification
SEC
Free maytansinoids
(free drug) by RPLC
iCIEF
HA: Health Authority
23. Consistent profile in SEC, free drug and iCIEF
23
2.3 Analytical control for manufacturing changes at DP level
SEC
iCIEF
Free drug
Reference Material
Recipient site
Donor Site
Reference Material
Recipient site
Donor Site
Reference Material
(1:2 dilution)
Recipient site
Donor Site
24. Summary
24
Post-launch CMC Challenges in Optimizing Supply Chain
Complexity of manufacturing process & supply chain
Establishing an efficient work process with harmonized business practices/standards
Fulfilling global market requirements for post-launch changes
Adequate Analytical Control for Manufacturing Changes at All Stages
Tailored strategy for each type of change at each stage
Process validation & comparability studies critical for demonstrating comparable product quality
The Journey of Each Kadcyla® Vial
25. Acknowledgement
25
SM DS
team
DP team
LM DS
team
CMOs
Tech Dev
Team
Product
Dev
Team
Too many contributors to list
ADQC
Fred Jacobson
Yan Chen
Laura Zheng
Pat Rancatore
……
Other Functions
Andrea Ji
Yasushi Ogawa
Mike Geier
Patrick Devillier
Hoang Phan
Jagan Sundaram
Fred Lim
Jay Howlett
Matt Hutchinson
……
Roche Colleagues
CMO Team Players
Committee-1
Committee-2
Committee-3