What are the major drivers for the new Annex 1? Join us to know more about implications for Filters & Single Use.
In this webinar, you will learn:
• Closed Processing and Single Use Technology implementation
• Points to consider using Single Use Technology
• Sterile Filtration
The Annex 1 “Manufacture of sterile medicinal products” of the EU GMP Guide is currently being revised. A first draft of the revised version was published in 2017 and released for public comment. The second draft as of February 2020 was open for targeted consultation via stakeholder from selected industry organisations. The current Annex 1 draft emphasises Contamination Control Strategy (CCS) multiple times and as a key consideration.
EU GMP Annex 1 Draft: Implications on Sterilizing Grade Filter ValidationMilliporeSigma
Watch the presentation of this webinar here: https://bit.ly/3kk0Qs1
In this webinar, you will learn:
- About the GMP Annex 1 draft regulatory overview
- How to incorporate the integrity testing & PUPSIT in the filtration systems validation
- How to design a bacterial retention test in terms of organism selection and single vs multiple use validation
Detailed description:
In this webinar we will discuss the implications of the EU GMP Annex 1 draft on the filtration of medicinal products and how this impacts the validation studies.
Bacterial Retention Testing is a critical part of the manufacturing validation process and is required by all regulatory bodies worldwide. Using case studies, our experts will explain how the Annex 1 draft is incorporated into the filtration systems validation exercise, specifically for integrity testing & PUPSIT (Pre-Use Post Sterilization Integrity Testing), the selection and justification of the appropriate test organism, and validation implications of single versus multiple use.
This presentation discusses pre-use post-sterilization integrity testing (PUPSIT) of sterile filters. It provides background on regulatory guidance for integrity testing critical filters before and after use. Masking studies were conducted where flawed filters were exposed to blocking solutions, and in some cases the flaws were able to mask and pass post-use integrity testing. The risk of masking was found to be highly dependent on process conditions like blocking rate and solution concentration. The presentation discusses considerations for final filtration assembly design to enable PUPSIT like using redundant filters and multi-purpose ports. It addresses challenges with maintaining sterility and pressure during PUPSIT.
EU GMP Annex 1 Draft: Implications on Sterilizing Grade Filter ValidationMerck Life Sciences
Watch the presentation of this webinar here: https://bit.ly/3kk0Qs1
In this webinar, you will learn:
- About the GMP Annex 1 draft regulatory overview
- How to incorporate the integrity testing & PUPSIT in the filtration systems validation
- How to design a bacterial retention test in terms of organism selection and single vs multiple use validation
Detailed description:
In this webinar we will discuss the implications of the EU GMP Annex 1 draft on the filtration of medicinal products and how this impacts the validation studies.
Bacterial Retention Testing is a critical part of the manufacturing validation process and is required by all regulatory bodies worldwide. Using case studies, our experts will explain how the Annex 1 draft is incorporated into the filtration systems validation exercise, specifically for integrity testing & PUPSIT (Pre-Use Post Sterilization Integrity Testing), the selection and justification of the appropriate test organism, and validation implications of single versus multiple use.
Potential Impact of Draft Annex 1 on Sterilizing FiltrationMilliporeSigma
The document discusses potential impacts of proposed changes to regulations outlined in Draft Annex 1 regarding sterilizing filtration and single-use systems. Key points include:
- Draft Annex 1 provides more specific recommendations around sterile filtration processes, including validating the filtration system, testing filter integrity before and after use, and carrying out final sterile filtration as close as possible to filling.
- It emphasizes minimizing aseptic connections and qualifying components based on critical quality attributes.
- Recent regulatory guidelines from EMA and PICS have aligned on topics like process validation, continuous verification, and sterilization requirements, showing increased harmonization across agencies.
EU GMP Annex 1 Draft - Closed System Design Consideration with Single-Use Sys...MilliporeSigma
Biopharmaceutical manufacturing capacities have expanded dramatically which has resulted in an increased demand for single-use systems (SUS) as they have their own advantages. Although SUS are well established in the biopharmaceutical industry there is limited guidance on regulatory expectations. Please attend the webinar to learn more!
Implementing and Managing Pre-use Post-sterilization Integrity Testing (PUPSIT)Merck Life Sciences
This presentation explores best practices and case studies in aseptic processing, including how to implement and manage PUPSIT. You will learn:
• Integrity Testing – the background on IT itself, why it is important, and how it works
• Filtration setups and single-use technology
• The PUPSIT debate and how PUPSIT can be achieved with current technology, final filling, formulation, filtration
To learn more about this topic or collaborate with our technical experts, schedule a remote visit at our M Lab™ Collaboration Centers: www.merckmillipore.com/remotevisit
Quality by Design Principles Applied to Sterilizing Filtration by Michael PayneMilliporeSigma
Key regulatory documents and regulatory thinking now includes quality by design (QbD). This webinar focuses on how to integrate practical QbD activities into the process and analytical aspects of sterile medicinal product sterilizing filtration and qualification.
In this webinar, you will learn to:
• Focus on practical QbD terms and approaches
• Highlight critical product quality aspects of sterile medicinal products
• Develop design and control spaces for sterilizing filtration
• Easily integrate QbD into the process and analytical operations in early phase development and into manufacturing phase production
Abstract:
Final sterilizing filtration is the last operation in downstream processing to assure the sterility of medicinal products. Poorly defined product attributes process parameters may attract regulatory scrutiny, affect final product sterility and patient safety. A better understanding of QbD concepts and principles allows for better process and analytical monitoring and control at both early and final phase production. The webinar will show how currently available process cGMP information can be practically incorporated into QbD product quality attributes and process parameters. This is especially vital for the third party conducted laboratory work such as bacterial retention and leachable studies.
EU GMP Annex 1 Draft - Closed System Design Consideration with Single-Use Sys...Merck Life Sciences
Biopharmaceutical manufacturing capacities have expanded dramatically which has resulted in an increased demand for single-use systems (SUS) as they have their own advantages. Although SUS are well established in the biopharmaceutical industry there is limited guidance on regulatory expectations. Please attend the webinar to learn more!
EU GMP Annex 1 Draft: Implications on Sterilizing Grade Filter ValidationMilliporeSigma
Watch the presentation of this webinar here: https://bit.ly/3kk0Qs1
In this webinar, you will learn:
- About the GMP Annex 1 draft regulatory overview
- How to incorporate the integrity testing & PUPSIT in the filtration systems validation
- How to design a bacterial retention test in terms of organism selection and single vs multiple use validation
Detailed description:
In this webinar we will discuss the implications of the EU GMP Annex 1 draft on the filtration of medicinal products and how this impacts the validation studies.
Bacterial Retention Testing is a critical part of the manufacturing validation process and is required by all regulatory bodies worldwide. Using case studies, our experts will explain how the Annex 1 draft is incorporated into the filtration systems validation exercise, specifically for integrity testing & PUPSIT (Pre-Use Post Sterilization Integrity Testing), the selection and justification of the appropriate test organism, and validation implications of single versus multiple use.
This presentation discusses pre-use post-sterilization integrity testing (PUPSIT) of sterile filters. It provides background on regulatory guidance for integrity testing critical filters before and after use. Masking studies were conducted where flawed filters were exposed to blocking solutions, and in some cases the flaws were able to mask and pass post-use integrity testing. The risk of masking was found to be highly dependent on process conditions like blocking rate and solution concentration. The presentation discusses considerations for final filtration assembly design to enable PUPSIT like using redundant filters and multi-purpose ports. It addresses challenges with maintaining sterility and pressure during PUPSIT.
EU GMP Annex 1 Draft: Implications on Sterilizing Grade Filter ValidationMerck Life Sciences
Watch the presentation of this webinar here: https://bit.ly/3kk0Qs1
In this webinar, you will learn:
- About the GMP Annex 1 draft regulatory overview
- How to incorporate the integrity testing & PUPSIT in the filtration systems validation
- How to design a bacterial retention test in terms of organism selection and single vs multiple use validation
Detailed description:
In this webinar we will discuss the implications of the EU GMP Annex 1 draft on the filtration of medicinal products and how this impacts the validation studies.
Bacterial Retention Testing is a critical part of the manufacturing validation process and is required by all regulatory bodies worldwide. Using case studies, our experts will explain how the Annex 1 draft is incorporated into the filtration systems validation exercise, specifically for integrity testing & PUPSIT (Pre-Use Post Sterilization Integrity Testing), the selection and justification of the appropriate test organism, and validation implications of single versus multiple use.
Potential Impact of Draft Annex 1 on Sterilizing FiltrationMilliporeSigma
The document discusses potential impacts of proposed changes to regulations outlined in Draft Annex 1 regarding sterilizing filtration and single-use systems. Key points include:
- Draft Annex 1 provides more specific recommendations around sterile filtration processes, including validating the filtration system, testing filter integrity before and after use, and carrying out final sterile filtration as close as possible to filling.
- It emphasizes minimizing aseptic connections and qualifying components based on critical quality attributes.
- Recent regulatory guidelines from EMA and PICS have aligned on topics like process validation, continuous verification, and sterilization requirements, showing increased harmonization across agencies.
EU GMP Annex 1 Draft - Closed System Design Consideration with Single-Use Sys...MilliporeSigma
Biopharmaceutical manufacturing capacities have expanded dramatically which has resulted in an increased demand for single-use systems (SUS) as they have their own advantages. Although SUS are well established in the biopharmaceutical industry there is limited guidance on regulatory expectations. Please attend the webinar to learn more!
Implementing and Managing Pre-use Post-sterilization Integrity Testing (PUPSIT)Merck Life Sciences
This presentation explores best practices and case studies in aseptic processing, including how to implement and manage PUPSIT. You will learn:
• Integrity Testing – the background on IT itself, why it is important, and how it works
• Filtration setups and single-use technology
• The PUPSIT debate and how PUPSIT can be achieved with current technology, final filling, formulation, filtration
To learn more about this topic or collaborate with our technical experts, schedule a remote visit at our M Lab™ Collaboration Centers: www.merckmillipore.com/remotevisit
Quality by Design Principles Applied to Sterilizing Filtration by Michael PayneMilliporeSigma
Key regulatory documents and regulatory thinking now includes quality by design (QbD). This webinar focuses on how to integrate practical QbD activities into the process and analytical aspects of sterile medicinal product sterilizing filtration and qualification.
In this webinar, you will learn to:
• Focus on practical QbD terms and approaches
• Highlight critical product quality aspects of sterile medicinal products
• Develop design and control spaces for sterilizing filtration
• Easily integrate QbD into the process and analytical operations in early phase development and into manufacturing phase production
Abstract:
Final sterilizing filtration is the last operation in downstream processing to assure the sterility of medicinal products. Poorly defined product attributes process parameters may attract regulatory scrutiny, affect final product sterility and patient safety. A better understanding of QbD concepts and principles allows for better process and analytical monitoring and control at both early and final phase production. The webinar will show how currently available process cGMP information can be practically incorporated into QbD product quality attributes and process parameters. This is especially vital for the third party conducted laboratory work such as bacterial retention and leachable studies.
EU GMP Annex 1 Draft - Closed System Design Consideration with Single-Use Sys...Merck Life Sciences
Biopharmaceutical manufacturing capacities have expanded dramatically which has resulted in an increased demand for single-use systems (SUS) as they have their own advantages. Although SUS are well established in the biopharmaceutical industry there is limited guidance on regulatory expectations. Please attend the webinar to learn more!
Implementing and Managing Pre-use Post-sterilization Integrity Testing (PUPSIT)MilliporeSigma
This document summarizes a presentation given at a conference on aseptic processing. It discusses challenges implementing pre-use integrity testing (PUPSIT) of sterile filters for final product filtration and provides case studies of both successful and unsuccessful filtration setups. The presentation addresses common issues like filter sizing, complex product formulations that impact integrity testing, and assembly details. It promotes the ability to achieve PUPSIT with current single-use technology and filtration setup options.
Qualification of membrane filtration apparatusPRAVADA
This document discusses the validation of membrane filtration processes. It defines qualification as ensuring equipment is properly installed and works as expected. There are four types of qualification: design, installation, operational, and performance. Membrane filtration separates solids from liquids using a porous membrane. Validation of membrane filters includes testing reproducibility, sterilization, integrity, operating conditions, inertness, antimicrobial activity, endotoxins, and toxicity to ensure the filter performs as intended. Regular performance qualification is important to check the filter maintains consistent performance over time.
This document discusses hazard and risk management in factories. It covers the Factory Act of 1948 and its provisions regarding health, safety, welfare, and working hours. It describes definitions related to factories and objectives of the Factory Act. Key elements of the Act include provisions for hazardous processes, restrictions on employment of women and children, and annual leave. Accident prevention fundamentals and elements of an effective safety program and management system are also outlined.
Autoclave
Principle of Autoclave
Construction of Autoclave
Working of Autoclave
Qualification of Autoclave
Installation Qualification
Operational Qualification
Performance Qualification
References
Aseptic Process Sampling to address Risk of Contamination & Containment in co...MilliporeSigma
Watch this webinar here: bit.ly/asepticwebinar2020
In this webinar, you will learn:
- The challenges tied to contamination control within a biopharmaceutical environment.
- What closed processing is, and how sampling solutions are an integral component towards that end.
- Advantages of sterile sampling from both a technical and economical viewpoint; with the review of a technical study confirming contamination risk reduction and total cost of ownership.
- Recommendations and requirements stated by these major regulatory authorities around the monitoring of the manufacturing process with the execution of sampling.
Detailed description:
Biopharmaceutical manufacturers are required to ensure drug product quality attributes for patient safety. Strong contamination control strategies should be considered early in process design, and have direct influence on the production environment and equipment selection.
Sampling at each step is a critical component in maintaining a contamination control strategy. Regulators are critical in the sampling process, as it predicts the state of the product or process, and needs to be Representative. A case study will be presented that demonstrates a closed, robust sampling solution capable of maintaining a sterile flow path when challenged with Brevundimonas diminuta. The sampling option you select can help support your goal in achieving a closed process, improving your risk mitigation strategy and product safety.
What is likely to go into the revised Annex 1, including:
Terminal sterilisation vs aseptic processing
WFI produced by reverse osmosis
Guidance for media simulation trials
This remains speculative
This document discusses regulations regarding the manufacture of pharmaceutical products and active ingredients, including requirements for qualifying vendors that supply materials. Strict good manufacturing practices (GMP) are required to ensure quality, safety and efficacy. Vendor qualification is important to provide assurance of drug product performance and avoid risks like contamination. The document refers to other guidance on topics like quality agreements, auditing, and assessing vendor performance on supply assurance, quality, costs, and responsiveness. Packaging component supplier audits are also discussed.
Good Manufacturing PracticeFor LVP,SVP, ophthalmic veterinary medicine, bulk chemicals & invitro diagnostic
For Good business Practice
A control process gives reproducibility & product consistency with in known limits
Provides license to do business.
Aseptic / sterile- “ A state of control attained by using an aseptic work area and performing activities in a manner that precludes microbiological contamination of the exposed sterile product”
The two most commonly used within microbiology are
HACCP (which originated in the food industry) and FMEA
(developed for engineering). This article explores these two
approaches, first with a description of HACCP, followed by a
description and case study of FMEA in sterility testing.
The document summarizes the key changes in the new draft of EU GMP Annex 1 regarding sterile product manufacturing. Some of the major changes include a stronger emphasis on quality risk management and the requirement for a formal contamination control strategy. There is also a focus on advances in sterile manufacturing technology as well as clarifying ambiguities in the current Annex. The new draft contains additional guidance on cleanroom classification limits and testing, environmental monitoring, and controlling exposure times during aseptic processing to minimize contamination risks.
Quality by Design and Process Analytical TechnologyMANIKANDAN V
This document discusses Quality by Design (QbD) and Process Analytical Technology (PAT) as applied to the pharmaceutical industry. It defines key QbD concepts like Quality Target Product Profile, Critical Quality Attributes, Critical Material Attributes, Critical Process Parameters, and design space. It explains how QbD involves systematic development through risk assessment and control strategies to consistently deliver quality products. PAT is described as using real-time measurements and process monitoring to ensure quality and facilitate continuous improvement. The roles of QbD and PAT in drug development and manufacturing are also summarized.
Quality by Design - Presentation by Naveen PathakWPICPE
This document provides a summary of a presentation on Quality-by-Design (QbD) for biopharmaceuticals. It begins with an overview of QbD and its key principles of product and process understanding and control based on science and risk management. The presentation then discusses applying QbD concepts to coffee making as an example. Key aspects of coffee quality are identified and process parameters that impact quality are described. The presentation emphasizes using process understanding to develop a control strategy to ensure consistent quality. It also discusses integrating QbD with process validation approaches.
The document discusses cleaning validation, including definitions, purposes, mechanisms, agents, methods, parameters, groupings, worst case considerations, acceptance criteria, and more. Cleaning validation is defined as the process of removing contaminants from equipment and monitoring such that equipment can be safely reused. It aims to ensure product integrity, prevent cross contamination, and meet regulatory requirements.
The document provides information about auditing a microbiological laboratory. It defines quality audits and outlines the scope and objectives of auditing. Key areas that are audited include laboratory equipment, standard operating procedures, documentation, environmental monitoring, and testing processes. The document discusses auditing the laboratory facility, equipment, documentation systems, and testing methods to ensure compliance with standards.
This document describes a case study on implementing change control for a Brookfield viscometer that was experiencing frequent spindle speed changes without human handling. This was affecting manufacturing processes and resulting in misleading viscosity readings. A change control process was initiated to address calibration intervals and validation procedures for the viscometer. Documentation was created justifying the need for the change and submitted to the quality assurance team for review and approval. Once approved, the change was implemented.
The document discusses auditing of microbiology laboratories. It provides definitions of auditing and outlines areas that should be assessed such as laboratory layout, equipment and facilities, documentation practices, and manufacturing processes. Key areas that are important for auditors to evaluate include laboratory organization, sampling procedures, media preparation, equipment maintenance, method validation, documentation, biosafety, and proficiency testing. The role of the microbiology laboratory in auditing sterile product facilities is also described.
Cleaning validation is important to ensure safety and prevent contamination during pharmaceutical production. It involves collecting data to prove cleaning procedures consistently remove residues to acceptable limits. Key aspects of validation include defining cleaning procedures, acceptance criteria, sampling methods, and analytical techniques. Validation should continue if procedures or products change. Overall, cleaning validation demonstrates equipment is suitably cleaned between batches to maintain quality as required by cGMP regulations.
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.
WHO Guideline on Quality Risk Management PostgradoMLCC
This document outlines a proposed guideline on quality risk management from the World Health Organization. It discusses applying risk management principles to both medicines regulatory authorities and pharmaceutical manufacturers. The goal is to help focus resources on risks to patients, encourage science-based decision making, and improve communication between organizations. The draft guideline is being circulated for comment before finalization.
Challenges using Multiple Single-use Systems: Functionality versus Extractabl...MilliporeSigma
As single-use technologies continue to expand in pharmaceutical manufacturing processes, the risk assessment for extractables and leachables becomes increasingly complex. Join this webinar to obtain guidance on how to perform risk evaluation on a process with multiple single-use components.
A Single-Use System (SUS) is typically designed for a specific process step. In many cases, single-use components are chosen based on their functionality. The challenge arises when there are multiple processing steps-- as the different applications and product matrices are evaluated, the complexity of the risk assessment increases. Complexity includes component evaluation, process conditions, and model solvents streams which ultimately relates to the patient safety risk.
This webinar will evaluate the different single-use components with respect to compatibility and extractables and leachables. A case study will be used to demonstrate the complexity and potential concerns when performing a risk evaluation on the manufacturing process.
In this webinar, you will learn:
- Risk assessment of extractables
- Single-use component evaluation
- Complexity when evaluating multiple assemblies
Implementing and Managing Pre-use Post-sterilization Integrity Testing (PUPSIT)MilliporeSigma
This document summarizes a presentation given at a conference on aseptic processing. It discusses challenges implementing pre-use integrity testing (PUPSIT) of sterile filters for final product filtration and provides case studies of both successful and unsuccessful filtration setups. The presentation addresses common issues like filter sizing, complex product formulations that impact integrity testing, and assembly details. It promotes the ability to achieve PUPSIT with current single-use technology and filtration setup options.
Qualification of membrane filtration apparatusPRAVADA
This document discusses the validation of membrane filtration processes. It defines qualification as ensuring equipment is properly installed and works as expected. There are four types of qualification: design, installation, operational, and performance. Membrane filtration separates solids from liquids using a porous membrane. Validation of membrane filters includes testing reproducibility, sterilization, integrity, operating conditions, inertness, antimicrobial activity, endotoxins, and toxicity to ensure the filter performs as intended. Regular performance qualification is important to check the filter maintains consistent performance over time.
This document discusses hazard and risk management in factories. It covers the Factory Act of 1948 and its provisions regarding health, safety, welfare, and working hours. It describes definitions related to factories and objectives of the Factory Act. Key elements of the Act include provisions for hazardous processes, restrictions on employment of women and children, and annual leave. Accident prevention fundamentals and elements of an effective safety program and management system are also outlined.
Autoclave
Principle of Autoclave
Construction of Autoclave
Working of Autoclave
Qualification of Autoclave
Installation Qualification
Operational Qualification
Performance Qualification
References
Aseptic Process Sampling to address Risk of Contamination & Containment in co...MilliporeSigma
Watch this webinar here: bit.ly/asepticwebinar2020
In this webinar, you will learn:
- The challenges tied to contamination control within a biopharmaceutical environment.
- What closed processing is, and how sampling solutions are an integral component towards that end.
- Advantages of sterile sampling from both a technical and economical viewpoint; with the review of a technical study confirming contamination risk reduction and total cost of ownership.
- Recommendations and requirements stated by these major regulatory authorities around the monitoring of the manufacturing process with the execution of sampling.
Detailed description:
Biopharmaceutical manufacturers are required to ensure drug product quality attributes for patient safety. Strong contamination control strategies should be considered early in process design, and have direct influence on the production environment and equipment selection.
Sampling at each step is a critical component in maintaining a contamination control strategy. Regulators are critical in the sampling process, as it predicts the state of the product or process, and needs to be Representative. A case study will be presented that demonstrates a closed, robust sampling solution capable of maintaining a sterile flow path when challenged with Brevundimonas diminuta. The sampling option you select can help support your goal in achieving a closed process, improving your risk mitigation strategy and product safety.
What is likely to go into the revised Annex 1, including:
Terminal sterilisation vs aseptic processing
WFI produced by reverse osmosis
Guidance for media simulation trials
This remains speculative
This document discusses regulations regarding the manufacture of pharmaceutical products and active ingredients, including requirements for qualifying vendors that supply materials. Strict good manufacturing practices (GMP) are required to ensure quality, safety and efficacy. Vendor qualification is important to provide assurance of drug product performance and avoid risks like contamination. The document refers to other guidance on topics like quality agreements, auditing, and assessing vendor performance on supply assurance, quality, costs, and responsiveness. Packaging component supplier audits are also discussed.
Good Manufacturing PracticeFor LVP,SVP, ophthalmic veterinary medicine, bulk chemicals & invitro diagnostic
For Good business Practice
A control process gives reproducibility & product consistency with in known limits
Provides license to do business.
Aseptic / sterile- “ A state of control attained by using an aseptic work area and performing activities in a manner that precludes microbiological contamination of the exposed sterile product”
The two most commonly used within microbiology are
HACCP (which originated in the food industry) and FMEA
(developed for engineering). This article explores these two
approaches, first with a description of HACCP, followed by a
description and case study of FMEA in sterility testing.
The document summarizes the key changes in the new draft of EU GMP Annex 1 regarding sterile product manufacturing. Some of the major changes include a stronger emphasis on quality risk management and the requirement for a formal contamination control strategy. There is also a focus on advances in sterile manufacturing technology as well as clarifying ambiguities in the current Annex. The new draft contains additional guidance on cleanroom classification limits and testing, environmental monitoring, and controlling exposure times during aseptic processing to minimize contamination risks.
Quality by Design and Process Analytical TechnologyMANIKANDAN V
This document discusses Quality by Design (QbD) and Process Analytical Technology (PAT) as applied to the pharmaceutical industry. It defines key QbD concepts like Quality Target Product Profile, Critical Quality Attributes, Critical Material Attributes, Critical Process Parameters, and design space. It explains how QbD involves systematic development through risk assessment and control strategies to consistently deliver quality products. PAT is described as using real-time measurements and process monitoring to ensure quality and facilitate continuous improvement. The roles of QbD and PAT in drug development and manufacturing are also summarized.
Quality by Design - Presentation by Naveen PathakWPICPE
This document provides a summary of a presentation on Quality-by-Design (QbD) for biopharmaceuticals. It begins with an overview of QbD and its key principles of product and process understanding and control based on science and risk management. The presentation then discusses applying QbD concepts to coffee making as an example. Key aspects of coffee quality are identified and process parameters that impact quality are described. The presentation emphasizes using process understanding to develop a control strategy to ensure consistent quality. It also discusses integrating QbD with process validation approaches.
The document discusses cleaning validation, including definitions, purposes, mechanisms, agents, methods, parameters, groupings, worst case considerations, acceptance criteria, and more. Cleaning validation is defined as the process of removing contaminants from equipment and monitoring such that equipment can be safely reused. It aims to ensure product integrity, prevent cross contamination, and meet regulatory requirements.
The document provides information about auditing a microbiological laboratory. It defines quality audits and outlines the scope and objectives of auditing. Key areas that are audited include laboratory equipment, standard operating procedures, documentation, environmental monitoring, and testing processes. The document discusses auditing the laboratory facility, equipment, documentation systems, and testing methods to ensure compliance with standards.
This document describes a case study on implementing change control for a Brookfield viscometer that was experiencing frequent spindle speed changes without human handling. This was affecting manufacturing processes and resulting in misleading viscosity readings. A change control process was initiated to address calibration intervals and validation procedures for the viscometer. Documentation was created justifying the need for the change and submitted to the quality assurance team for review and approval. Once approved, the change was implemented.
The document discusses auditing of microbiology laboratories. It provides definitions of auditing and outlines areas that should be assessed such as laboratory layout, equipment and facilities, documentation practices, and manufacturing processes. Key areas that are important for auditors to evaluate include laboratory organization, sampling procedures, media preparation, equipment maintenance, method validation, documentation, biosafety, and proficiency testing. The role of the microbiology laboratory in auditing sterile product facilities is also described.
Cleaning validation is important to ensure safety and prevent contamination during pharmaceutical production. It involves collecting data to prove cleaning procedures consistently remove residues to acceptable limits. Key aspects of validation include defining cleaning procedures, acceptance criteria, sampling methods, and analytical techniques. Validation should continue if procedures or products change. Overall, cleaning validation demonstrates equipment is suitably cleaned between batches to maintain quality as required by cGMP regulations.
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.
WHO Guideline on Quality Risk Management PostgradoMLCC
This document outlines a proposed guideline on quality risk management from the World Health Organization. It discusses applying risk management principles to both medicines regulatory authorities and pharmaceutical manufacturers. The goal is to help focus resources on risks to patients, encourage science-based decision making, and improve communication between organizations. The draft guideline is being circulated for comment before finalization.
Challenges using Multiple Single-use Systems: Functionality versus Extractabl...MilliporeSigma
As single-use technologies continue to expand in pharmaceutical manufacturing processes, the risk assessment for extractables and leachables becomes increasingly complex. Join this webinar to obtain guidance on how to perform risk evaluation on a process with multiple single-use components.
A Single-Use System (SUS) is typically designed for a specific process step. In many cases, single-use components are chosen based on their functionality. The challenge arises when there are multiple processing steps-- as the different applications and product matrices are evaluated, the complexity of the risk assessment increases. Complexity includes component evaluation, process conditions, and model solvents streams which ultimately relates to the patient safety risk.
This webinar will evaluate the different single-use components with respect to compatibility and extractables and leachables. A case study will be used to demonstrate the complexity and potential concerns when performing a risk evaluation on the manufacturing process.
In this webinar, you will learn:
- Risk assessment of extractables
- Single-use component evaluation
- Complexity when evaluating multiple assemblies
Challenges using Multiple Single-use Systems: Functionality versus Extractabl...Merck Life Sciences
As single-use technologies continue to expand in pharmaceutical manufacturing processes, the risk assessment for extractables and leachables becomes increasingly complex. Join this webinar to obtain guidance on how to perform risk evaluation on a process with multiple single-use components.
A Single-Use System (SUS) is typically designed for a specific process step. In many cases, single-use components are chosen based on their functionality. The challenge arises when there are multiple processing steps-- as the different applications and product matrices are evaluated, the complexity of the risk assessment increases. Complexity includes component evaluation, process conditions, and model solvents streams which ultimately relates to the patient safety risk.
This webinar will evaluate the different single-use components with respect to compatibility and extractables and leachables. A case study will be used to demonstrate the complexity and potential concerns when performing a risk evaluation on the manufacturing process.
In this webinar, you will learn:
- Risk assessment of extractables
- Single-use component evaluation
- Complexity when evaluating multiple assemblies
Aseptic Process Sampling to address Risk of Contamination & Containment in co...Merck Life Sciences
In this webinar, you will learn:
- The challenges tied to contamination control within a biopharmaceutical environment.
- What closed processing is, and how sampling solutions are an integral component towards that end.
- Advantages of sterile sampling from both a technical and economical viewpoint; with the review of a technical study confirming contamination risk reduction and total cost of ownership.
- Recommendations and requirements stated by these major regulatory authorities around the monitoring of the manufacturing process with the execution of sampling.
Detailed description:
Biopharmaceutical manufacturers are required to ensure drug product quality attributes for patient safety. Strong contamination control strategies should be considered early in process design, and have direct influence on the production environment and equipment selection.
Sampling at each step is a critical component in maintaining a contamination control strategy. Regulators are critical in the sampling process, as it predicts the state of the product or process, and needs to be Representative. A case study will be presented that demonstrates a closed, robust sampling solution capable of maintaining a sterile flow path when challenged with Brevundimonas diminuta. The sampling option you select can help support your goal in achieving a closed process, improving your risk mitigation strategy and product safety.
Upcoming USP 665 - Level of Characterization of Single-Use Systems Today and ...Merck Life Sciences
This document discusses regulatory expectations for characterization of single-use systems used in biopharmaceutical manufacturing. It summarizes guidance from USP <665> on characterizing components based on risk levels. A component's risk level depends on its materials of construction, contact temperature and duration, and chemical composition of the process stream. Higher risk components require a higher level of characterization, such as extractable and leachable profiling. The document provides an example of characterizing components in a typical monoclonal antibody process and assessing the total mass of potential leachables through the process. It notes that while standards like USP <665> provide guidance, individual organizations may have their own risk assessment templates. The overall goal of characterization is to ensure patient safety
Upcoming USP 665 - Level of Characterization of Single-Use Systems Today and ...MilliporeSigma
Register for the interactive, on-demand webinar now: https://bit.ly/USP665
Single-use plastic systems are being utilized more frequently especially for COVID-19 vaccine manufacturing. However, there are issues regarding standardization of quality information that limits implementation efficiencies. One of the challenges is the evaluation of leachables derived from a variety of different plastic components in a timely manner.
Since the USP <665> highlights a risk assessment approach with no typical pass/fail limit, approaches to decision-making based on the extractables data package will be reviewed. In addition, we will highlight legacy testing requirements which may not be necessary once USP <665> is implemented.
In this webinar, we will discuss:
- Regulatory expectations of extractables and leachables assessment today and tomorrow
- The right criteria that need to be assessed to select the type and quality of plastic materials for use in biopharmaceutical manufacturing
This document summarizes a report published by the Bio-Process Systems Alliance (BPSA) regarding recommendations for testing, evaluation, and control of particulates from single-use process equipment. The BPSA is a trade association that facilitates implementation of single-use technologies through various initiatives. The report was created by a working group consisting of subject matter experts from single-use technology suppliers and end users. It provides guidance on characterizing and minimizing particulate levels throughout the lifecycle of single-use technologies, including manufacturing, storage, handling and end use. It also discusses investigation and mitigation of particulate deviations. The BPSA recommends further work to develop standardized measurement methods, application-specific requirements, a catalog of particle types,
New PDA/IPEC Technical Report on Excipient Risk Assessment - insights for dru...MilliporeSigma
Access the interactive recording: https://bit.ly/37HqbTK
Abstract:
Since March 2016 the EU Guideline to ascertain the appropriate GMP for pharmaceutical excipients is legally binding. Although the EU Guideline itself provides a high level description how to perform the risk assessment, the implementation can be challenging. In January 2018 PDA and IPEC formed a joint Task Force with the objective to develop a joint Technical Report to share best practices with industry. This Technical Report was published in December 2019. In this webinar you will be introduced to the new Technical Report, its objective, proposed approaches and examples shared by PDA/IPEC member companies.
New PDA/IPEC Technical Report on Excipient Risk Assessment - insights for dru...Merck Life Sciences
The document provides an overview of a joint PDA/IPEC technical report on formalized risk assessment for excipients. It discusses the purpose and scope of the report, which is to provide guidance on conducting excipient risk assessments based on ICH Q9 principles. It also summarizes some of the key sections of the report, including describing the roles in the excipient supply chain and their responsibilities, presenting a model for quality risk management of excipients, and providing tools for assessing intrinsic excipient risks and supply chain risks. The report aims to help companies evaluate excipient risks and ensure the quality of excipients used in pharmaceutical products.
This presentation consist a consolidated list all Regulatory Guidelines for Cleaning Validation. Hyperlink of the applicable guidelines are also given in the presentation.
Safe feed and food starts with secure risk management. For this, GMP+ International offers knowledge and information through the Feed Support Products (FSP). The Feed Support Products are intended to support all (future) GMP+ certified companies when setting up their company-specific HACCP system
This document provides guidance on quality risk management principles and tools. It describes a general quality risk management process that includes risk assessment, risk control, risk communication, and risk review. Risk assessment involves risk identification, analysis, and evaluation. Risk control focuses on reducing risks to an acceptable level through actions like risk mitigation or accepting the residual risk. Effective communication and ongoing review are also important parts of the quality risk management process. The guideline provides examples of tools that can be used for a risk management methodology, including Failure Mode Effects Analysis and Hazard Analysis Critical Control Points.
This document provides guidance for ensuring sterility in the manufacture of sterile medicinal products through a contamination control strategy (CCS). The CCS should establish robust assurance of contamination prevention from microbial, endotoxin/pyrogen and particulate sources. It involves identifying risks to product quality using quality risk management and putting in place controls like facility design, equipment qualification, environmental monitoring, personnel training and change control to minimize these risks. The CCS must describe all elements of the manufacturing process and be reviewed periodically for effectiveness in assuring sterility of the final product.
Problem formulation for environmental risk assessment in the context of EC Re...OECD Environment
The seminar on Problem Formulation for the Risk Assessment of Biopesticides stemmed from a previous CRP-sponsored event on Innovating Microbial Pesticide Testing that identified the need for an overarching guidance document to determine when in vivo tests are necessary. Problem Formulation, a common practice in pesticide risk assessment, was highlighted as a useful approach for addressing uncertainties in data requirements for biopesticides.
The seminar featured presentations from various perspectives, including industry, regulatory bodies, and academia. Topics included the history and principles of Problem Formulation, industry perspectives on Problem Formulation and how it is applied internally for microbial pesticides, regulatory approaches, and specific case studies. The seminar provided an overview of the challenges, considerations, and potential solutions in harmonising Problem Formulation for biopesticide risk assessment. It emphasised the need for collaboration and discussion to develop Problem Formulation guidance for biopesticides.
1) GMP (Good Manufacturing Practice) guidelines are important regulations that help ensure animal vaccines and other drugs/medical products are produced safely and are effective. They cover all aspects of production from materials to equipment to staff training.
2) Key components of GMP include quality management, quality control, sanitation, validation, documentation and more. Strict adherence to GMP helps reduce risks like contamination and errors that could harm patients.
3) For animal vaccines specifically, following GMP is critical given the live organisms involved and safety precautions needed. Facilities must be designed to properly handle biosafety requirements as well as aseptic processing.
International conference-harmonisation-technical-requirements-registration-ph...ibrahimbouzina
This document provides guidance on quality risk management principles and tools for use across the pharmaceutical product lifecycle. It outlines a general quality risk management process that includes risk assessment, control, communication and review. The level of effort for quality risk management should be commensurate with the level of risk. Quality risk management can help facilitate more informed decision making and regulatory oversight while ensuring product quality protects patient safety.
This document discusses ensuring a critical supply of vaccines by focusing on the raw materials perspective. It emphasizes that vaccine manufacturing is a complex, regulated process requiring an efficient supply chain. It identifies potential risks at various stages of the process from raw materials to facilities. It also outlines approaches to ensuring supply, including inventory management, risk assessment, secondary sourcing, and qualifying suppliers. The document promotes using pre-qualified raw materials and suppliers to help prevent unnecessary process changes and reduce qualification efforts and testing of incoming goods.
Process equipment characterization – how standardized extractables data suppo...MilliporeSigma
View the recording here: https://bit.ly/35KIwBb
Biopharmaceutical Industry recently increased adoption of Single-Use systems and components in manufacturing process operations. Drug manufacturers are responsible for the characterization of SU components and systems used for the production to ensure patient safety. SUS Suppliers are encouraged by BPOG and BPSA to provide comprehensive extractables data package to support drug manufacturer’s E&L assessments.
This webinar will give an overview of the E&L evaluation workflow and practical study approaches from both supplier and end-user perspective, in accordance with the latest industry’s standards and upcoming USP <665> requirements. Case studies will be presented on how the data from suppliers are used to mitigate risk associated to SU materials, highlighting the key role of collaboration between the supplier and the drug manufacturer.
Similar to EU GMP Annex 1 – Implications on Filtration and Single Use Technology by Somasudaram and Simone Biel (20)
The Viscosity Reduction Platform: Viscosity-reducing excipients for improveme...Merck Life Sciences
Protein viscosity is a major challenge in preparing highly concentrated protein formulations suitable for subcutaneous injection. Recently, the Viscosity Reduction Platform (VRP) was introduced and its technical key features and benefits for formulations were discussed. However, highly viscous solutions do not only pose a challenge when administering a drug to a patient, they can also impose technical limitations in the manufacturing process.
This white paper evaluates the effect of the excipients in the Viscosity Reduction Platform on ultrafiltration processes used to produce a highly concentrated formulation of a monoclonal antibody (mAb). Two filtration methods are demonstrated in this work.
Find more information about the Viscosity Reduction Platform on our website: https://www.sigmaaldrich.com/products/pharma-and-biopharma-manufacturing/formulation/viscosity-reduction-platform
Use of Excipients in Downstream Processing to Improve Protein PurificationMerck Life Sciences
Excipients are used to improve the stability of protein-based therapeutics by protecting the protein against a range of stress conditions such as temperature changes, pH changes, or agitation. Similar stresses are applied to proteins during downstream purification. Shifts in pH during Protein A chromatography, subsequent incubations at low pH for virus inactivation, and changes in conductivity in ion exchange chromatography can lead to aggregation, fragmentation, or other chemical modifications of the therapeutic protein. Given the potential impact on the protein’s structural integrity, there is a need for approaches to reduce the risk presented by the conditions during downstream processing. For example, integration of a solution to prevent aggregation of proteins would be a more efficient strategy than implementing steps to remove multimeric forms.
This white paper highlights the results from a recent paper by Stange et. al., in which protein stabilizing excipients such as polyols, sugars, and polyethylene glycol (PEG4000) were used as buffer system additives. Effect of the excipients on elution patterns, stabilization of the monomer antibody, host-cell protein removal, virus inactivation rates and binding capacity of cation exchange chromatography were explored.
Exploring the protein stabilizing capability of surfactants against agitation...Merck Life Sciences
Agitation of therapeutic protein solutions during manufacturing, shipping and handling is one of the major initiators for protein aggregation and particle formation during the life history of a protein drug. Adsorption of protein molecules to liquid-air interfaces leads to the formation of highly concentrated protein surface films. The rupture of these protein films due to various mechanical processes can then result in the appearance of protein aggregates and particles in the bulk solution phase.
One technique to stabilize proteins against stress induced by liquid-air interfaces is the use of non-ionic surfactants. About 91% of antibody formulations commercially available in 2021 contained a surfactant. Polysorbate 20 and 80, composed of a hydrophilic polyoxyethylene sorbitan and hydrophobic fatty acid esters, made up the largest part being employed in 87% of said formulations.
Despite their frequent use in parenteral drug products, concerns have been raised for decades about the application of polysorbates as surfactants in biopharmaceutical formulations. Autoxidation of polysorbate, caused by residual peroxides in polysorbates, can damage the proteins and can further drive the oxidative degradation of polysorbate. Chemical and enzymatic hydrolysis of polysorbate may lead to the formation of free fatty acid particles, which may become visible; and both mechanisms eventually lead to the reduction in polysorbate concentration. Therefore, the purpose of the current study was to compare various molecules for their capabilities to reduced agitation-induced protein aggregation and particle formation; and furthermore, investigate their underlying protein stabilizing mechanisms.
The Viscosity Reduction Platform: Viscosity Reducing Excipients for Protein F...Merck Life Sciences
Protein viscosity is one of the major obstacles in preparing highly concentrated protein formulations suitable for subcutaneous injection.
This whitepaper examines how combining an amino acid with a second viscosity-reducing excipient circumvents adverse effects on protein stability and improves viscosity-reducing capacity.
To find more information about the Viscosity Reduction Platform, please visit our website: https://sigmaaldrich.com/products/pharma-and-biopharma-manufacturing/formulation/viscosity-reduction-platform
Characterization of monoclonal antibodies and Antibody drug conjugates by Sur...Merck Life Sciences
Watch the presentation of this webinar: https://bit.ly/3Pjpjvr
Highlights of this webinar:
- Surface plasmon resonance as a powerful tool for biologic characterization including mAbs and ADCs.
- SPR allows rapid binding analysis in real time without using labels for SARS-CoV-2 receptor binding domain mutations.
- Kinetic data is indicative of possible neutralizing activity allowed assessment of neutralizing ability of therapeutic monoclonal antibodies.
- The application can provide preliminarily efficacy information and facilitated mAbs/ACDs candidate selection process
Detailed description:
Characterization of therapeutic monoclonal antibodies (mAbs) or Antibody drug conjugates (ADCs) is challenging due to their ability to bind to a variety of proteins via their Fc and Fab domains, giving rise to diverse biological functions associated with each domain. The Fc domain of mAbs interacts with Fc receptors with varying affinities, which can influence biological processes such as Complement-dependent cytotoxicity (CDC) and Antibody-dependent cellular cytotoxicity (ADCC), transcytosis, phagocytosis, and/or serum half-life.
An important characteristic of an antibody is its Fc effector function. Antibodies can be engineered to obtain desired binding of the Fc region to Fc receptors expressed on effector cells. Hence, it is crucial to evaluate the binding interaction of mAbs/ADC with Fc receptors in the early phase of drug development to understand the potential biological activity of the product in vivo.
Surface Plasmon Resonance (SPR) is a powerful technique to establish binding kinetics in real-time, label free, and high sensitivity with low sample consumption. Along with target antigen binding, it is crucial to evaluate the binding interaction of antibodies and ADCs with Fc receptors. Our SPR case studies investigated the impact on binding kinetics of ADCs with different linkers and the binding interactions of SARS-CoV-2 spike protein variants and evaluated the neutralizing ability of therapeutic mAbs. SPR characterisation can be facilitated in all stages of the product life cycle to ensure the quality and safety of mAbs and ADCs.
The Role of BioPhorum Extractables Data in the Effective Adoption of Single-U...Merck Life Sciences
Regulatory expectation does require patient safety evaluations with supporting data for manufacturing components that directly come into contact with drug manufacturing process streams. Readily available extractables data can help manufacturers using singleuse technology to accelerate product qualifications, risk assessments and process optimization
This white paper guides you on how to save time and resources with supplier-provided single-use system extractables data and gives you an overview about the overall strategy for Extractables & Leachables. At the end you will find a case study.
Find more information about filters and single-use components on our website: https://www.sigmaaldrich.com/DE/en/services/product-services/emprove-program/emprove-filter-and-single-use-component-portfolio
Watch the recording of this presentation here: https://bit.ly/3zTOpe4
Detailed description:
SARS-CoV-2 showed us that technology supports us during our inspection activity even if on-site visits are not possible. Travel restrictions of various kinds will remain a risk in the future. The use of new technologies has shown that inspections and audits can be carried out despite these restrictions. We will focus on what possibilities the new technologies offer and take a look at the future of inspections and audits.
In this webinar, you will learn:
• Regulatory overview of remote audits
• The technologies needed to support the audit process
• What types of inspections are possible with the use of these technologies
• How audits may look in the future
Presented by:
Daniel Buescher, Product Manager - Digital Solutions
Moving your Gene Therapy from R&D to IND: How to navigate the Regulatory Land...Merck Life Sciences
Watch the recording of this presentation here: https://bit.ly/3SqOsoP
Novel therapies, including cell and gene therapies, continue to be central to innovation in healthcare and represent the fastest growing area of therapeutic medicine. As a consequence, the number of gene therapies undergoing clinical trials has increased significantly in the last five years.
Manufacturing processes for these novel therapeutics are very complex with a high risk of contamination. Regulatory agencies world-wide have responded by issuing guidance to outline their expectations for development and manufacture of cell and gene therapies. Currently, regulatory guidance is not harmonized globally and can often lead to confusion within industry and increased risk of non-compliance.
In this webinar, we'll answer:
• Which regulatory guidelines do you need to comply for your INDs?
• When do you start implementing GMPs and validated assays?
• How do you get your QC testing strategy ‘right the first time’?
• How do you ensure testing is not your rate limiting step for the IND submission?
Presented by:
Manjula Aysola, Senior Regulatory Consultant
Dr. Alison Armstrong, Sr. Director, Technical and Scientific Solutions
Identity testing by NGS as a means of risk mitigation for viral gene therapiesMerck Life Sciences
Watch the presentation of this webinar here: https://bit.ly/3RijkHC
Detailed description:
Imagine you’ve just completed a manufacturing run for your viral vector. Identity testing is performed to confirm the vector sequence. But when the results come back the data reveals unexpected sequence variants! With an appropriate risk mitigation testing strategy, this situation can be prevented.
The situation described above is not hypothetical, and happens more that you think, costing valuable time and resources.
Investigatory testing has shown that sequence variants present in starting materials (e.g. plasmids) are likely to make their way to the final product. Adequate identification of low-level variants with an appropriately sensitive method is critical in ensuring the quality of the final product. A risk-based testing strategy, in the context of identity, for viral vector manufacturing will be presented, focusing on key testing points. NGS assays for identity and variant detection will be highlighted due to their extremely sensitive nature compared to traditional approaches.
In this webinar, we'll explore:
• Regulatory requirements for identity testing
• NGS applications for identity testing as compared to traditional methods
• A case study on the impact of not establishing a proper risk-based testing strategy
Presented by: Bradley Hasson, Director of Lab Operations for NGS Services
Latest advancements of melt based 3D printing technologies for oral drug deli...Merck Life Sciences
Watch the presentation of this webinar here: https://bit.ly/3A2WcH4
The application of polymer excipients in 3D printing manufacturing is usually limited due to the concerns of filament strength, high processing temperature and large scale manufacturing.
Latest technology developments are targeting a direct melt deposition to simplify the process and enable a constant and efficient process. Two different processing approaches will be presented:
The advanced melt drop deposition, where individual three dimensional geometries can be created by depostition of polymer droplets and the MED® 3D printing technology which allows by precise layer-by-layer deposition to produce objects with well-designed geometric structures.
In this webinar, you will learn:
• Latest advancements of melt based 3D printing approaches
• Application examples for the individual technologies
• Deep dive in the MED® 3D printing technology to design dedicated drug release profiles
Presented by:
Dr. Thomas Kipping, Head of Drug Carriers
Dr. Xianghao Zuo, Deputy Director of R&D, Triastek
CAR-T Manufacturing Innovations that Work - Automating Low Volume Processes a...Merck Life Sciences
Watch the presentation of this webinar here: https://bit.ly/3NDNIKe
Automated, fit-for-purpose tools are essential in CAR-T processing to support sustainable manufacturing of clinical and market-approved cell therapy products. This webinar will discuss how the ekko™ Acoustic Cell Processing System uses acoustic technology as a touchless approach to manipulate cells, enabling a modular tool across the CAR-T manufacturing workflow. Typical performance of templated ekko™ System processes for DMSO washout of leukapheresis material, low volume and high cell concentrate for electroporation preparation, and harvest of expanded T cells will be reviewed.
This webinar will also give an early glimpse at the ekko™ Select System for unmatched T cell selection.
In this webinar, you will:
• Uncover how the ekko™ System supports the broad industrialization of cell therapy, with particular focus on how to achieve low volume, high concentrate cell product for critical transduction and transfection steps
• Discover how ekko™ System for wash and concentrate processes throughout the cell therapy workflow achieve high cell recovery, viability, and effective residual removal
• Preview to ekko™ Select, our cell therapy selection platform, to achieve unmatched ease-of-use with direct processing from leukopaks reducing the need for preparation steps
Presented by:
Benjamin Ross-Johnsrud, Acoustic Technology Expert
Robert Scott, Mechanical Engineer III
Viral safety of biologics: What's changing with the ICH Q5A revision?Merck Life Sciences
Watch the presentation of this webinar here: https://bit.ly/3t7X9tg
How does the ICH Q5A revision impact viral safety strategies for biologics?
Biologics continue to grow at a fast pace. Manufactured using cell lines of human or animal origin, these are at risk of viral contamination making safety strategies critical. A comprehensive risk mitigation strategy using multiple orthogonal measures is a regulatory expectation. ICH Q5A, the globally-harmonized guideline outlines the expectations. ICH Q5A is currently being revised to address recent scientific advancements including novel therapeutic modalities, new manufacturing paradigms, updates in viral clearance applications, and alternate detection technologies. We’ll discuss the expected changes and potential impact on viral safety strategies with case studies and examples.
In this webinar, you will learn about:
• The Importance of virus testing in biologics products
• Regulatory landscape, expectations for the Q5A revision
• What's new and changing
• Examples of alternate testing schedules, impact on viral clearance
Presented by:
Manjula Aysola, Senior Regulatory Consultant
Alison Armstrong, PhD, Sr. Director, Technical and Scientific Solutions
Improve Operational Efficiency by Over 30% with Product, Process, & Systems A...Merck Life Sciences
Watch the presentation of this webinar here: https://bit.ly/3adaxWh
When implementing new automation systems, organizations must consider things like deployment time, user adoption, and costs.
They must also consider the cost of doing nothing – that is, what competitive advantage is lost in standing still? What time and quality is lost in repetitive, manual tasks rather than an automated, digital workflow? What operational efficiencies are lost?
In this webinar we examine how a product, process, and system agnostic automation platform can be deployed faster than traditional system specific software while bringing greater operational efficiencies (in many cases over 30% improvement).
To remain competitive in the market, biopharma manufacturers must adopt automation and digital technologies, but most plants still have island of automation consisting of independently functioning, standalone unit operations. This results in operational inefficiency, regulatory concerns, and a poor understanding of the process and product life cycle.
Taking the first, right step must include considering risks, costs, timelines, and technology alternatives. Traditional automation approaches tied to specific systems, processes, and products are, by their nature, limited; while an agnostic platform will address current biomanufacturing business challenges and ensure future readiness. With the right platform, a phased automation implementation can yield operational efficiency gains of up to 30% and improved product quality and regulatory compliance.
In this webinar, let's explore:
• Challenges of automation and digital technology adoption
• What a product, process, and system agnostic platform entails
• Applications and benefits of a process orchestration platform
• Ensuring future readiness with process orchestration
Presented by:
Braj Nandan Thakur, Global Product Manager - Automation
Insights from a Global Collaboration Accelerating Vaccine Development with an...Merck Life Sciences
Watch the presentation of this webinar here: https://bit.ly/3Nbb5ug
Get insights and best practices from a multinational team establishing a platform for vaccine production. See how a long-term collaboration on a bench-scale process used to produce a Virus Like Particle (VLP) vaccine for SARS-CoV-2 was successfully converted to a robust GMP-compatible, scalable process.
The COVID-19 pandemic further emphasized the need for collaboration in the development of urgently needed vaccines and therapeutics. In this webinar, we take you behind the scenes of our collaboration with Technovax and Innovative Biotech in which a scalable VLP vaccine platform was optimized for use in a production facility in Nigeria in response to the need for local production of SARS-CoV-2 vaccines. The flexibility and robustness of the platform will enable its rapid deployment to support the West African pandemic readiness program. Initial development of the VLP process began in late 2019 and by March 2020, was already adapted for production of a SARS-CoV-2 vaccine.
In this webinar, you will learn:
• About building a priceless collaborative network with integrated solutions
• Virus-Like Particle Vaccines
• Process Development Overview and Challenges
• Pre-clinical Results and Next Steps
Presented by:
Jose M. Galarza, PhD,
President and Founder of TechnoVax
Naomi Baer,
Business development consultant, Emerging Biotech, BioProcess division
Youssef Gaabouri, Eng. ,
Associate Director, Head of Sales Middle East & Africa, BioProcess division
Risk-Based Qualification of X-Ray Sterilization for Single-Use SystemsMerck Life Sciences
The document discusses testing done to qualify the use of x-ray sterilization for a Lynx S2S connector. Physical, chemical, and biological tests were performed on connectors that underwent either x-ray or gamma sterilization. Test results showed comparable extractable levels, thermal properties, and chromatographic profiles between the two sterilization methods. This provides evidence that x-ray sterilization is a suitable alternative to gamma sterilization for this connector.
Rapid replication competent adenovirus (rRCA) detection: Accelerate your lot ...Merck Life Sciences
Watch the presentation of this webinar here: https://bit.ly/3MJ4u9V
Testing for presence of replication competent adenovirus (RCA) is a key component to ensure patient safety and a requirement for all biologicals manufactured using adenoviral vectors. For many adenoviral-based products, the RCA assay is a rate-limiting assay for lot release.
Join this webinar to learn about a rapid RCA detection assay currently in development, which combines a 7-day culture assay with a highly sensitive molecular endpoint specific for RCA. The method can detect presence of as little as 1 RCA in adenoviral vector material at an approximate concentration of 5x107 - 2x108 vector particles (VP)/mL, making it a suitable method to meet regulatory requirements while accelerating your lot release timelines.
In this webinar, you will learn about:
• Regulatory framework for adenoviral vector products
• Considerations for lot release testing of adenoviral-based therapies
• Advantages of a rapid method for RCA testing on production lot material
Presented by:
Axel Fun, Ph.D.,
Principal Scientist
Alberto Santana, MBA,
Product Manager, Biologics Biosafety Testing
The High Intensity Sweeteners Neotame and Sucralose: 2 Ways to ace the Patien...Merck Life Sciences
Watch the presentation of this webinar here: https://bit.ly/3vQyN7K
Bitter medicines are an important issue, especially for pediatric applications. As several APIs have bitter tasting components, high intensity sweeteners for taste optimization are of great interest. Join our webinar to discover our new sweetener toolbox enabling safe and stable formulations.
Mask bitter aftertaste for a sweeter pill to swallow! Patients’ compliance and the therapeutic benefit are supported by a pleasant taste of pharmaceutical formulations. With the high intensity sweeteners Neotame and Sucralose, you have efficient tools at hand which are superior to other sweeteners in many aspects:
• excellent sugar-like taste profile
• outstanding sweetness factors
• use effectiveness
• enhanced stability
We will present our new toolbox of two high performance sweeteners and focus on aspects of stability, safety, the application in various dosage forms, and market perception.
In this webinar, you will learn:
• How to optimize the patients' taste experience of your pharmaceuticals
• How sweeteners can be differentiated by their sensory profiles and features
• How our new product offering Neotame can be effectively used in your targeted formulations
Presented by:
Almut von der Brelie,
Senior Manager Strategic Marketing
Excipients for Solid Applications
The Developability Classification System (DCS): Enabling an Optimized Approac...Merck Life Sciences
This whitepaper by Dr. Daniel Joseph Price outlines how poorly soluble drug formulations can be designed using the developability classification system (DCS).
The DCS identifies the root cause of low solubility and enables lean, cost-effective and effective formulations to be developed.
#solubility #pharmaceuticalmanufacturing #oralsoliddosage #drugdevelopment
The webinar discusses services from MilliporeSigma to accelerate antibody-drug conjugate (ADC) development through their ADC Express and ADCore product lines. ADC Express provides integrated antibody, linker, payload, and conjugation services to generate multiple ADC candidates for evaluation. The ADCore product line offers intermediates that simplify payload synthesis and accelerate development timelines. ChetoSensar technology incorporates a chito-oligosaccharide to enhance ADC solubility and efficacy.
These lecture slides, by Dr Sidra Arshad, offer a quick overview of the physiological basis of a normal electrocardiogram.
Learning objectives:
1. Define an electrocardiogram (ECG) and electrocardiography
2. Describe how dipoles generated by the heart produce the waveforms of the ECG
3. Describe the components of a normal electrocardiogram of a typical bipolar lead (limb II)
4. Differentiate between intervals and segments
5. Enlist some common indications for obtaining an ECG
6. Describe the flow of current around the heart during the cardiac cycle
7. Discuss the placement and polarity of the leads of electrocardiograph
8. Describe the normal electrocardiograms recorded from the limb leads and explain the physiological basis of the different records that are obtained
9. Define mean electrical vector (axis) of the heart and give the normal range
10. Define the mean QRS vector
11. Describe the axes of leads (hexagonal reference system)
12. Comprehend the vectorial analysis of the normal ECG
13. Determine the mean electrical axis of the ventricular QRS and appreciate the mean axis deviation
14. Explain the concepts of current of injury, J point, and their significance
Study Resources:
1. Chapter 11, Guyton and Hall Textbook of Medical Physiology, 14th edition
2. Chapter 9, Human Physiology - From Cells to Systems, Lauralee Sherwood, 9th edition
3. Chapter 29, Ganong’s Review of Medical Physiology, 26th edition
4. Electrocardiogram, StatPearls - https://www.ncbi.nlm.nih.gov/books/NBK549803/
5. ECG in Medical Practice by ABM Abdullah, 4th edition
6. Chapter 3, Cardiology Explained, https://www.ncbi.nlm.nih.gov/books/NBK2214/
7. ECG Basics, http://www.nataliescasebook.com/tag/e-c-g-basics
TEST BANK For An Introduction to Brain and Behavior, 7th Edition by Bryan Kol...rightmanforbloodline
TEST BANK For An Introduction to Brain and Behavior, 7th Edition by Bryan Kolb, Ian Q. Whishaw, Verified Chapters 1 - 16, Complete Newest Versio
TEST BANK For An Introduction to Brain and Behavior, 7th Edition by Bryan Kolb, Ian Q. Whishaw, Verified Chapters 1 - 16, Complete Newest Version
TEST BANK For An Introduction to Brain and Behavior, 7th Edition by Bryan Kolb, Ian Q. Whishaw, Verified Chapters 1 - 16, Complete Newest Version
Cell Therapy Expansion and Challenges in Autoimmune DiseaseHealth Advances
There is increasing confidence that cell therapies will soon play a role in the treatment of autoimmune disorders, but the extent of this impact remains to be seen. Early readouts on autologous CAR-Ts in lupus are encouraging, but manufacturing and cost limitations are likely to restrict access to highly refractory patients. Allogeneic CAR-Ts have the potential to broaden access to earlier lines of treatment due to their inherent cost benefits, however they will need to demonstrate comparable or improved efficacy to established modalities.
In addition to infrastructure and capacity constraints, CAR-Ts face a very different risk-benefit dynamic in autoimmune compared to oncology, highlighting the need for tolerable therapies with low adverse event risk. CAR-NK and Treg-based therapies are also being developed in certain autoimmune disorders and may demonstrate favorable safety profiles. Several novel non-cell therapies such as bispecific antibodies, nanobodies, and RNAi drugs, may also offer future alternative competitive solutions with variable value propositions.
Widespread adoption of cell therapies will not only require strong efficacy and safety data, but also adapted pricing and access strategies. At oncology-based price points, CAR-Ts are unlikely to achieve broad market access in autoimmune disorders, with eligible patient populations that are potentially orders of magnitude greater than the number of currently addressable cancer patients. Developers have made strides towards reducing cell therapy COGS while improving manufacturing efficiency, but payors will inevitably restrict access until more sustainable pricing is achieved.
Despite these headwinds, industry leaders and investors remain confident that cell therapies are poised to address significant unmet need in patients suffering from autoimmune disorders. However, the extent of this impact on the treatment landscape remains to be seen, as the industry rapidly approaches an inflection point.
TEST BANK For Basic and Clinical Pharmacology, 14th Edition by Bertram G. Kat...rightmanforbloodline
TEST BANK For Basic and Clinical Pharmacology, 14th Edition by Bertram G. Katzung, Verified Chapters 1 - 66, Complete Newest Version.
TEST BANK For Basic and Clinical Pharmacology, 14th Edition by Bertram G. Katzung, Verified Chapters 1 - 66, Complete Newest Version.
TEST BANK For Basic and Clinical Pharmacology, 14th Edition by Bertram G. Katzung, Verified Chapters 1 - 66, Complete Newest Version.
TEST BANK For Basic and Clinical Pharmacology, 14th Edition by Bertram G. Katzung, Verified Chapters 1 - 66, Complete Newest Version.
Basavarajeeyam is a Sreshta Sangraha grantha (Compiled book ), written by Neelkanta kotturu Basavaraja Virachita. It contains 25 Prakaranas, First 24 Chapters related to Rogas& 25th to Rasadravyas.
Osteoporosis - Definition , Evaluation and Management .pdfJim Jacob Roy
Osteoporosis is an increasing cause of morbidity among the elderly.
In this document , a brief outline of osteoporosis is given , including the risk factors of osteoporosis fractures , the indications for testing bone mineral density and the management of osteoporosis
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Here is the updated list of Top Best Ayurvedic medicine for Gas and Indigestion and those are Gas-O-Go Syp for Dyspepsia | Lavizyme Syrup for Acidity | Yumzyme Hepatoprotective Capsules etc
Rasamanikya is a excellent preparation in the field of Rasashastra, it is used in various Kushtha Roga, Shwasa, Vicharchika, Bhagandara, Vatarakta, and Phiranga Roga. In this article Preparation& Comparative analytical profile for both Formulationon i.e Rasamanikya prepared by Kushmanda swarasa & Churnodhaka Shodita Haratala. The study aims to provide insights into the comparative efficacy and analytical aspects of these formulations for enhanced therapeutic outcomes.
EU GMP Annex 1 – Implications on Filtration and Single Use Technology by Somasudaram and Simone Biel
1. The life science business of Merck KGaA,
Darmstadt, Germany operates as
MilliporeSigma in the U.S. and Canada.
EU GMP Annex 1 Draft
Implication on Sterilizing
Filtration & Single-Use Systems
Somasundaram (Som)
Senior Technical Consultant
Asia Pacific
Dr. Simone Biel
Senior Regulatory Consultant
4. Boost Covid-19 vaccine production would not be possible without SUT
Fast Growing Biopharmaceutical Market Challenges
4
Business driver to implement SUT
Speed to Market
High flexibility
Quick changeover of equipment
Ensure patient safety
Identity
Efficacy
Purity
5. Sterile Medicinal Product
subject to regulatory guidelines
compliant filter qualification
EU GMP Annex 1 – guidance on sterile medicinal product manufacturing
Contamination Risks Throughout the Process
Sterile media filtration
Not subject to regulatory guidelines
BUT should require aspects of sterilizing filter
qualification
6. Sterilizing-grade designation is a functional definition
6
Sterilizing Grade Filter – Definition
EU GMP, Annex 1 draft, Feb 2020
“Sterilizing grade filter – A filter that, when appropriately
validated, will remove a defined microbial challenge from a fluid or
gas producing a sterile effluent. Usually, such filters have a pore size
equal or less than 0.22 μm”
PDA TR 26, revised 2008
A filter that reproducibly removes test microorganisms from the
process stream, producing a sterile filtrate.
FDA cGMP, Guidance for Industry, 2004
“A sterilizing grade filter should be validated to reproducibly
remove viable microorganisms from the process stream,
producing a sterile effluent. Currently, such filters usually have a
rated pore size of 0.2 μm or smaller.”
Demonstrate removal of a
standard test organism
Brevundimonas diminuta
At minimum concentrations
of 107 cfu/cm2
ASTM F 838-05 is a
“Standard Test Method
for Determining Bacterial
Retention of Membrane
Filters Utilized for Liquid
Filtration”
7. Critical steps are transferred from end-user to supplier
Drug Product Manufacturing
7
8. Risk assessment (starting point)
− Sterility/integrity
− Particles
− Process fluid interaction with SUS
SUS supplier’s data as basic information
Additional validation studies if required
Supplier management
− Audit, audit reports and follow up
Incoming control
Transport, storage, material flow at end-user’s site
Operator training
Usage of SUS
Documentation
…
8
“Do you know what your supplier does?”
The GMP Inspector
10. Ongoing consultation of new draft – global approach
10
EU GMP, Annex 1: Manufacture of Sterile Products
1971 → ensure sterility of medicinal
products
− Since then several updates
2017 → full review of Annex 1
− 140 companies provided more than
6200 comments
2020 → targeted stakeholder
consultation
− 16 organisations
− WHO and PIC/S to maintain
global alignment
PIC/S, The Pharmaceutical Inspection Co-
operation Scheme
non-binding, informal co-operative
arrangement between Regulatory
Authorities in the field of Good
Manufacturing Practice (GMP) of medicinal
products
54 participating authorities from Europe,
Africa, America, Asia and Australia
Mission:
lead the international development,
implementation and maintenance of
harmonised GMP standards and quality
systems of inspectorates in the field of
medicinal products.
11. Prevent any contamination in the final product
11
QRM through entire document
Key Changes
Introduction of new sections
Introduction of Quality Risk Management (QRM)
Principles
Restructured to give more logical flow
Added detail to a number of the previous sections to
provide further clarity
Annex 1 draft, 2020
https://ec.europa.eu/health/sites/health/files/files/gmp/
2020_annex1ps_sterile_medicinal_products_en.pdf
12. Established ICH Quality Guidelines
Manufacturing and Control Strategy
ICH Q8 (R2), Pharmaceutical Development
− “Quality by Design” – understand the process and
its control early in development, based on sound
science and quality risk management
ICH Q9, Quality Risk Management
− Systematic process for assessment, control,
communication, and review of risks to protect the
patient
− Higher risk require higher level of qualification
ICH Q10, Pharmaceutical Quality System
− Knowledge management – systematic approach to
acquiring, analysing, storing, and disseminating
information
Quality Guidelines of the International Council for Harmonisation (ICH) Overview of a typical quality risk management process
(ICH Q9)
12
13. Keep it close and sterile
13
CCS = Contamination Control Strategy
General considerations
“aseptic process should be clearly defined”
“identify risks”
“control”
“describe”
“document residual risks”
“minimize contamination”
Specific guidance
Sterile filtration and PUPSIT
Closed processing
Single-Use Systems
14. EU GMP Annex 1 draft (Feb 2020)
“specific risks associated with SUS” → contamination control strategy
− Interaction with DP and SUS surface
− Integrity (“fragile”, “risk of holes and leakage”, “complexity”
− Risk of particulate contamination
What to do?
− Supplier qualification, including sterilization verification
− Evaluation of adsorption and reactivity of product
− Verification of integrity throughout the process
− Establish acceptance criteria and incoming control procedure
− Operator training
14
Finally, regulatory expectations are formalized!
SUS in Aseptic Processing
15. Who is doing what?
Regulatory and Industry Expectations
Biosafety Seminar | 22 October 2020
Law
Country specific drug law
Regulatory Agencies
Provide regulations and recommendations
Market authorization
Surveillance
Compendia - Reference for quality control of
medicines
Ph. Eur is legally binding
USP standards are legally recognized
Harmonization effort
Through consensus organizations
Industry expectations
Interpretation and elaboration on regulatory
expectations
15
16. Guidelines on primary packaging materials and container
16
Supporting documents – Drag and Drop
Ph. Eur. 3.1.x, Materials used for the manufacture of containers
USP <661>, Plastic Packaging Systems and Their Materials of
Construction (obsolete in 2025)
<661.1>, Plastic Materials of Construction
<661.2>, Plastic Packaging Systems for Pharmaceutical Use
USP <87>, Biological Reactivity Test, In Vitro
USP <88>, Biological Reactivity Test, In Vivo
ISO 10993-xx, Biological evaluation of medical devices
USP <85>, Ph. Eur. 2.6.14 and JP 4.01 , Bacterial endotoxin
testing
USP <788>, Ph. Eur. 2.9.19, JP 6.07 sub-visible particulate
testing
<665>
Plastic components used in
manufacturing, draft 2020
First and only standard approach
on SUS component qualification
17. Interpretation of regulatory guidance and filling the gap
17
Industry Associations
BioPhorum
Extractables & Leachables
User requirement specification (BPSA)
Change notification (BPSA)
Sterile filtration (PDA), 2020
Supply partner program
BPSA
Particles
Integrity
Cell & Gene Therapy
ISPE
Good Practice Guide: Single-Use Technology
(2019)
PDA
TR 26, Sterilizing Filtration of Liquids
(revised 2008)
TR 66, Application of Single-Use Systems in
Pharmaceutical Manufacturing (2014)
ASTM - Standard test methods
Bacterial retention
Filter integrity
Single-use systems integrity
19. Annex 1 to Volume 4 of EU GMP
“The integrity of the sterilised filter should be verified before use
and should be confirmed immediately after use by an appropriate
method such as a bubble point, diffusive flow or pressure hold” test.
2017 PIC/S guidelines
“The integrity of the sterilised filter should be verified before use
and should be confirmed immediately after use by an appropriate method
such as a bubble point, diffusive flow or pressure hold test.”
Draft Annex 1 (Feb 2020)
8.88 The integrity of the sterilised filter assembly should be verified by testing
before use, in case of damage and loss of integrity caused by processing, and
should be verified by on line testing immediately after use by an appropriate
method such as a bubble point, diffusive flow,
water intrusion or pressure hold test.
Regulatory PUPSIT References
20. 20
Since 1998, the EU Guidelines to Good Manufacturing Practice: Medicinal Products for Human
and Veterinary Use, Annex 1 (Manufacture of Sterile Medicinal Products) or “Annex 1” has
contained the requirement for verifying the integrity of a sterilizing grade filter before
use and after its sterilization.
The requirement remained in the 2008 revision and in the 2017 and 2020 draft revisions
to Annex 1. Concerns by European and other Health Authorities over the risk of filtration
failure resulted in an increase in enforcement of this requirement. This enforcement started
a discussion within the industry of the of the challenges, benefit, and aseptic process
related risk of PUPSIT.
The resulting debate has exposed a need for scientific evidence to support and effective
risk-based approach to PUPSIT use. To help meet that need, BioPhorum and the PDA
formed the Sterile Filtration Quality Risk Management (SFQRM) Consortium, which has been
working to provide objective, unbiased, scientific data to help guide informed decisions about
sterile filtration control measures.
PDA/BioPhorum conducted Series of Webinars in from
September 2020
PDA & BioPhorum Task Force
21. EMA response was to keep PUPSIT
• The EU’s rationale for keeping PUPSIT was offered by Andrew Hopkins, rapporteur for the
revision’s drafting group and an expert GMDP inspector with the UK’s Medicines and
Healthcare products Regulatory Agency. He said, “PUPSIT is necessary.”
• “sterilization is an aggressive process, even the irradiation mode; that filter
manufacturing is not always consistent and damaged filters can go undetected
through the manufacturing process.”
• “the argument against is that manufacturers don’t like it, that it is difficult to do such
testing.” It “has been a reality since 2007” to comply with Annex 1 and that “it is not
sufficient to say that such testing is unnecessary; rather these arguments need to be
supported by scientific rationale.”
Rationale is a scientifically and fact based risk assessment document
October 2017 PDA Meeting – Proposal to Remove PUPSIT
23. “8.15-16 Aseptic manipulations (including non-intrinsic aseptic connections) should
be minimized using engineering solutions such as the use of preassembled
and sterilized equipment. Whenever feasible, product contact piping and
equipment should be pre-assembled, then cleaned and sterilized in place.”
8.82 “Due to the potential additional risks of a sterile filtration process, as compared
with other sterilization processes, a second filtration through a sterile sterilizing
grade filter, immediately prior to filling, should be considered as part of an overall
CCS.”
− Added explanation avoids the question of “How close is close”
- result should be focus on connections and risk of loss of sterility
− Places major focus on aseptic risk reduction (CCS) including SUS systems
Example of Additional Specific Recommendations in Draft Annex 1
Revision – 2nd SGF as close as possible
24. 8.81 If the product cannot be sterilized in the final container, solutions or liquids should be
sterilized by filtration through a sterile sterilizing grade filter (with a nominal pore size of 0.22
μm (or less) that has been appropriately validated to obtain a sterile filtrate) and
subsequently aseptically filled into a previously sterilized container. The selection of the filter
used should ensure that it is compatible with the product and as described in the marketing
authorization (refer to paragraph 8.125).
Shows what should be considered during sterilizing filter qualification but no
definition of “compatible”
8.82 “Due to the potential additional risks of a sterile filtration process, as compared with
other sterilization processes, a second filtration through a sterile sterilizing grade filter,
immediately prior to filling, should be considered as part of an overall CCS.”
Replaces term “microorganism retentive” in old annex – now MORE SPECIFIC
Example of Additional Specific Recommendations in Draft
Annex 1 Revision – Choice of Product Sterilization
25. Traditional Style Sterile Filtration System with Bioburden
Reduction Filter and EMA/PIC/S Draft Annex 1 Compliant
8.82 “Due to the potential additional risks of a sterile filtration process, as compared
with other sterilization processes, a second filtration through a sterile sterilizing grade
filter, immediately prior to filling, should be considered as part of an overall CCS.”
Aseptic Filler
Sterile Hold
Tank
Vent
Filter
Vent
Filter
Sterilizing
Filter
Bioburden
Reduction
Filter
Sterilizing
Filter
Prefiltered
Formulation
NOT Redundant Filtration
26. 8.83 The selection of components for the filtration system and their
interconnection and arrangement within the filtration system, including
pre-filters, should be based on the critical quality attributes of the
product, justified and documented. The filtration system should minimize
the generation of fibres and particulates, not cause or contribute to
unacceptable levels of impurities, or possess characteristics that otherwise
alter the quality and efficacy of the product. Similarly, the filter
characteristics should be compatible with the fluid and not be adversely
affected by the product to be filtered. Adsorption of product components
and extraction/leaching of filter components should be evaluated (refer to
paragraph 8.125).
Component selection is Drug Manufacturer’s responsibility
Prefilter needs to be part of the validated system (8 elements)
Greater focus on target quality product profile / QbD
Reference point is the final sterile medicinal drug product safety
and patient protection
Example of Additional Specific Recommendations in Draft
Annex 1 Revision – Filtration & prefilters
27. 8.84 The filtration system should be designed to:
i. Allow operation within validated process parameters.
ii. Maintain the sterility of the filtrate.
iii. Minimize the number of aseptic connections required between the
sterilizing filter and the final filling of the product.
iv. Allow cleaning procedures to be conducted as necessary.
v. Allow sterilization procedures, including sterilization in place, to be
conducted as necessary.
vi. Permit in-place integrity testing, of the 0.22 μm sterilizing filter, preferably
as a closed system, prior to filtration as necessary. In-place integrity
testing methods should be selected to avoid any adverse impact on
the quality of the product.
Open for interpretation – “in-place”
Example of Additional Specific Recommendations in Draft
Annex 1 Revision – Filtration System Design
28. 8.85 Sterile filtration of liquids should be validated in accordance with European (or other
relevant) Pharmacopeia requirements. Validation can be grouped by different strengths or
variations of a product but should be done under worst case conditions. The rationale for
grouping should be justified and documented.
The filter vendor can and should provide this – but the user must understand this
8.86 During filter validation, wherever possible, the product to be filtered should be used
for bacterial retention testing of the sterilizing filter. Where the product to be filtered is not
suitable for use in bacterial retention testing, a suitable surrogate product should be
justified for use in the test. The challenge organism used in the bacterial retention test
should be justified.
Environmental monitoring and bioburden studies are vital
Example of Additional Specific Recommendations in Draft
Annex 1 Revision – Sterilizing Filter Validation
29. 8.87 Filtration parameters that should be
considered in validation and routine processing
should include but are not limited to:
a) If the system is flushed or integrity tested in-
situ with a fluid other than the product, then
flushing with the product should be part of the
process.
b) The wetting fluid used for filter integrity testing
based on filter manufacturer’s recommendation or
the fluid to be filtered. For the latter, the
appropriate integrity test value specification
should be established.
29
Example of Additional Specific
Recommendations in Draft Annex 1
Revision – Filter Validation (FIT)
Regulators want to see water flushing study information and
product based integrity testing studies and filter integrity test
result trending
30. 30
Example of Additional Specific Recommendations in Draft
Annex 1 Revision – Filtration Process Condition
8.87 c) Filtration process conditions including:
i. Fluid prefiltration holding time and effect on bioburden.
ii. Filter conditioning, with fluid if necessary.
iii. Maximum filtration time/total time filter is in contact with fluid.
iv. Flow rate.
v. Filtration volume.
vi. Temperature.
vii. The time taken to filter a known volume of bulk solution and the pressure difference
to be used across the filter.
Note: Results of these checks should be included in the batch record. Any significant
difference in parameters from those validated to those observed during routine
manufacturing should be noted and investigated.
So much of this
is the basis of
QbD and of user
requirement
specifications
31. 31
Examples of Key Differences in Draft Annex 1 Revision –
Filter Integrity Testing
8.88 The integrity of the sterilized filter assembly should be verified by integrity testing before use, to
check for damage and loss of integrity caused by the filter preparation prior to use. A sterilizing grade
filter that is used to sterilize a fluid should be subject to a non-destructive integrity test post-use prior
to removal of the filter from its housing.
“assembly” is stated rather than “system” – may implication for SUS assemblies
“on-line” testing may immediately require risk assessment due to lack of liquid at POU
It is recognized that pre-use post sterilization integrity testing (PUPSIT) may not always be possible
after sterilization due to process constraints (e.g. the filtration of very small volumes of solution). In these
cases, an alternative approach may be taken providing that a thorough risk assessment has been
performed and compliance is achieved by the implementation of appropriate controls to mitigate any
risk of non-sterility. Points to consider in such a risk assessment should include but are not be limited to:
i. In depth knowledge and control of the sterilization process to ensure that the potential for damage to the filter is
minimized.
ii. In depth knowledge and control of the supply chain – sterilization facility, transportation & packaging validation
iii. In depth process knowledge such as – product type, particle content that could mask/plug the filter
First time have mentioned on risk assessment for PUPSIT
32. 32
Example of Additional Specific Recommendations in Draft
Annex 1 Revision – Old vs Revised – Compressed Gas
“7.19 Compressed gases that come in direct contact with the product/container primary
surfaces should be of appropriate chemical, particulate and microbiological purity . . .
Compressed gases must be filtered through a sterilizing filter (with a nominal pore size of a
maximum of 0.22μm) at the point of use. Where used for aseptic manufacturing,
confirmation of the integrity of the final sterilization gas filter should be
considered as part of the batch release process.”
“8.89-91 The integrity of critical sterile gas and air vent filters in the filter assembly
should be verified by testing after use. The integrity of non-critical air or gas vent filters
should be confirmed and recorded at appropriate intervals. For gas filtration, attention
should be paid to avoiding unintended moistening or wetting of the filter or filter equipment.
This can be achieved by the use of hydrophobic filters.”
Post-use testing requirement has not changed HOWEVER 7.19 is specific as to the
more specific requirements for critical gas filtration
33. 8.92 If the sterilizing filtration process has been validated
as a system consisting of multiple filters to achieve the
sterility for a given fluid, the filtration system is considered
to be a single sterilizing unit and all filters within the
system should satisfactorily pass integrity testing after
use.
8.93 In a redundant filtration system (where a second
filter is present as a backup but the sterilizing process is
validated as only requiring one filter), post-use integrity
test of the primary sterilizing filter should be performed
and if demonstrated to be integral, then a post-use
integrity test of the secondary filter is not necessary.
However, in the event of a failure of the post-use integrity
test on the primary filter, a risk assessment should be
carried out to determine the acceptability of performing a
post-use integrity test on the secondary (redundant)
filter.
33
Examples of Key Differences in Draft Annex 1 Revision -
Serial and Redundant Filtration
First time serial and redundant filtration mentioned in EU GMP guidelines
BUT no guidance as to when to use redundant filtration. Potential conflict
with PDA redundant FIT recommendations Bioburden sampling risk
34. Aseptic Filler
Sterile Hold
Tank
Vent
Filter
Vent
Filter
Bioburden
Reduction
Filter
Sterilizing
Filter
Sterilizing
Filter
Formulation
Aseptic Filler
Sterile Hold
Tank
Vent
Filter
Vent
Filter
Bioburden
Reduction
Filter
Sterilizing
Filter
Sterilizing
Filter
Vent
Filter
Sterilizing
Filter
Formulation
Sampling point
Potential Sampling Influence on Sterility in Current and in
Redundant Filtration Systems
8.94 Bioburden samples should
be taken from the bulk product
and immediately prior to the
final sterile filtration. Systems
for taking samples should be
designed so as not to introduce
contamination.
35. Draft Annex 1 - Impact of
Proposed Additional
Sections & Key Differences
Single-use Systems
36. “A Process that ensures that biological material does not come into
contact with external environment. Closed processing enables grey
space or Controlled Not Classified (CNC) processing and is
sometimes referred to as being conducted in a “ballroom”.”
According to ISPE:
“A Process condition when the product, materials, critical
components or container/closure surfaces are contained and
separated from the immediate process equipment within
closed/sealed process equipment. A process step (or system) in
which the product and product contact surfaces are not exposed to
the immediate room environment.”
BioPhorum: “The key factor for industry acceptance was the
Pharmaceutical Inspection Cooperation Scheme (PIC/S)
determination that clean room requirements for Biomanufacturing
can be relaxed/eliminated if your process is closed”
ISPE Baseline Guide: “The strategy of using uncontrolled
or unclassified spaces for closed piping system has
always been accepted by the regulatory agencies as
an acceptable risk.”
36
What is Closed Processing about?
Isolating a product
from the
environment and
vice versa
37. 8.116 Closed systems can be single use systems (i.e. disposable
systems) and fixed systems (such as vessels with fixed pipework).
Guidance in this section is equally applicable to both systems.
8.117 The use of closed systems can reduce the risk of extraneous
contamination such as microbial, particulate and chemical from the
adjacent environment. Closed systems should always be designed to
reduce the need for, and complexity of manual interventions.
8.118 It is critical to ensure the sterility of all product contact
surfaces of closed systems used for aseptic processing. The design and
selection of any closed system used for aseptic processing should ensure
maintenance of sterility. Connection of sterile equipment (e.g. tubing /
pipework) to the sterilized product pathway after the final sterilizing filter
should be designed to be connected aseptically (e.g. by intrinsic
aseptic connectors or fusion systems).
37
Key References to Single-use Systems in Draft Annex 1
Revision – Closed Systems
1) Aseptic connections qualified on regular basis as part of routine
sterility assurance policy
2) Supplier assessment should include the collation of data in
relation to potential failure modes that may lead to a loss of
system sterility.
38. 8.121 SUS are those technologies used in manufacture of
sterile products which are used as an alternative to
reusable equipment. SUS can be individual components
or made up of multiple components such as bags,
filters, tubing, connectors, valves, storage bottles
and sensors.
8.123 Sterilization processes for SUS should be validated
and shown to have no adverse impact on system
performance.
8.124 Assessment of suppliers of disposable systems
including sterilization is critical to the selection and use of
these systems. For sterile SUS, verification of sterility
should be performed as part of the supplier
qualification and on receipt and use of each unit.
38
Key References to Single-use Systems in Draft Annex 1
Revision – SUS Relevance
39. 8.122 There are some specific risks associated with SUS
which should be assessed as part of the CCS.
These risks include but are not limited to:
i) The interaction between the product and product
contact surface (such as adsorption, or the formation of
leachables and extractables).
ii) The fragile nature of the system compared to fixed
reusable systems.
iii) The increase in the number and complexity of manual operations
(including inspection and handling of the system) and connections made.
iv) The complexity of the assembly.
v) The performance of the pre-use integrity test for sterilizing grade filters
(refer to paragraph 8.88).
vi) The risk of holes and leakage.
vii) The potential for compromising the system at the point of opening the outer packaging.
viii. The risk of particulate contamination.
39
Key References to Single-use Systems in
Draft Annex 1 Revision – SUS Relevance
40. 8.125 The adsorption and reactivity of the product with product contact surfaces should
be evaluated under process conditions.
8.126 The extractable and leachable profile of the SUS and any impact on the quality of
the product especially where the system is made from polymer-based materials should be
evaluated. An assessment should be carried out for each component to evaluate the
applicability of the extractable profile data. For components considered to be at high risk
from leachables, including those that may absorb processed materials or those with
extended material contact times, an assessment of leachable profile studies, including
safety concerns, should be taken into consideration. If applying simulated processing
conditions, these should accurately reflect the actual processing conditions and be based on
a scientific rationale.
Consider USP 665 draft guidance & BioPhorum E&L protocol.
Vendors should be able to provide critical help
Key References to Single-use Systems in Draft Annex 1
Revision – SUS Interaction with Product
42. 42
8.127 SUS should be designed to maintain
integrity throughout processing under the
intended operational conditions. Attention to the
structural integrity of the single use components
is necessary where these may be exposed to
more extreme conditions (e.g. freezing and
thawing processes) either during routine
processing or transportation. This should include
certification that intrinsic aseptic connections
(both heat sealed and mechanically sealed)
remain integral under these conditions.
8.129 Critical manual handling operations of SUS
such as assembly and connections should be
subject to appropriate controls and verified
during the APS.
Key References to Single-
use Systems in Draft Annex
1 Revision – SUS Relevance
Transport studies should be
included in the OQ studies
Media fills are still required
following same rules as used for
fixed SS equipment
43. 43
8.128 Acceptance criteria should be established and
implemented for SUS corresponding to the risks or
criticality of the products and its processes. On
receipt, each piece of SUS should be checked to
ensure that they have been manufactured, supplied
and delivered in accordance with the approved
specification.
A visual inspection of the outer packaging (e.g.
appearance of exterior carton, product pouches),
label printing, and review of attached documents
(e.g. certificate of conformance and proof of
sterilization) should be carried out and documented
prior to use.
Key References to Single-use
Systems in Draft Annex 1 Revision
– SUS Acceptance Criteria
1) Vendor’s sterilisation validation should be included in audit requirements
and on-going performance and consistency should be confirmed regularly (e.g.
quarterly dose audit reports
2) Vendor’s change notification process should be included in vendor quality
agreements
3) Training is vital across all departments and should be conducted by SMEs
44. Regulatory framework – understand the risk and
manage it
Industry associations facilitate implementation
of regulatory guidelines
Contamination Control Strategy (CCS) is key
PUPSIT is still emphasized – exceptions through
risk assessment
For the first time, redundant sterilizing filtration
has been mentioned in EU guideline
Single-use systems enable closed processing
44
Conclusion