This document provides guidance for the Pharmaceutical Development section of regulatory submissions for drug products. It describes the objective to provide a comprehensive understanding of the product and manufacturing process. Key aspects addressed include: components of the drug product; formulation, manufacturing process, container closure, and control strategy development; use of quality risk management; establishment of a design space; and submission organization. The degree of regulatory flexibility is based on the level of scientific knowledge provided regarding pharmaceutical and manufacturing sciences.
The document provides guidelines on pharmaceutical development as described in ICH Q8(R2). It discusses the objective to design a quality product and manufacturing process. Key points covered include critical quality attributes, design space, control strategies, flexibility opportunities, and examples of QbD application. The annex to ICH Q8(R1) further explains quality by design principles and their application in practice.
This document provides guidance on the content of the Pharmaceutical Development section (3.2.P.2) of regulatory submissions for drug products. It describes the components and attributes of drug products and manufacturing processes that should be discussed, including drug substances, excipients, formulations, manufacturing methods, and controls. The level of scientific knowledge provided in the submission forms the basis for flexible regulatory approaches. The guidance aims to facilitate a comprehensive understanding of products and processes for regulatory review and inspection.
This document provides a guideline for an effective pharmaceutical quality system across the product lifecycle. It describes a model quality system that achieves product quality objectives, establishes process control, and facilitates continual improvement. Key elements include management commitment, quality planning, resource management, communication, and management reviews. Quality risk management and knowledge management are important enablers. The quality system extends to outsourced activities and materials. Implementation of this guideline will help companies strengthen the link between development and manufacturing to enhance quality and availability of medicines.
This document provides guidance on quality risk management principles and tools that can be applied throughout the lifecycle of pharmaceutical products, including development, manufacturing, distribution, and regulatory processes. It describes a general quality risk management process involving risk assessment, risk control, communication, and review. Potential applications of quality risk management are also outlined for various aspects of pharmaceutical quality. The goal is to facilitate more effective risk-based decisions by both regulators and industry regarding pharmaceutical quality and consistency with clinical data.
This document provides guidance for reporting and controlling degradation products in new drug products. It recommends identifying degradation products present above specified thresholds in stability studies. Analytical methods must be validated to detect and quantify degradation products. Degradation products observed during development and manufacturing should be summarized, along with identification of those above thresholds and efforts to identify unknown peaks.
The document provides guidelines on pharmaceutical development as described in ICH Q8(R2). It discusses the objective to design a quality product and manufacturing process. Key points covered include critical quality attributes, design space, control strategies, flexibility opportunities, and examples of QbD application. The annex to ICH Q8(R1) further explains quality by design principles and their application in practice.
This document provides guidance on the content of the Pharmaceutical Development section (3.2.P.2) of regulatory submissions for drug products. It describes the components and attributes of drug products and manufacturing processes that should be discussed, including drug substances, excipients, formulations, manufacturing methods, and controls. The level of scientific knowledge provided in the submission forms the basis for flexible regulatory approaches. The guidance aims to facilitate a comprehensive understanding of products and processes for regulatory review and inspection.
This document provides a guideline for an effective pharmaceutical quality system across the product lifecycle. It describes a model quality system that achieves product quality objectives, establishes process control, and facilitates continual improvement. Key elements include management commitment, quality planning, resource management, communication, and management reviews. Quality risk management and knowledge management are important enablers. The quality system extends to outsourced activities and materials. Implementation of this guideline will help companies strengthen the link between development and manufacturing to enhance quality and availability of medicines.
This document provides guidance on quality risk management principles and tools that can be applied throughout the lifecycle of pharmaceutical products, including development, manufacturing, distribution, and regulatory processes. It describes a general quality risk management process involving risk assessment, risk control, communication, and review. Potential applications of quality risk management are also outlined for various aspects of pharmaceutical quality. The goal is to facilitate more effective risk-based decisions by both regulators and industry regarding pharmaceutical quality and consistency with clinical data.
This document provides guidance for reporting and controlling degradation products in new drug products. It recommends identifying degradation products present above specified thresholds in stability studies. Analytical methods must be validated to detect and quantify degradation products. Degradation products observed during development and manufacturing should be summarized, along with identification of those above thresholds and efforts to identify unknown peaks.
This document provides an overview of Quality by Design (QbD) in pharmaceutical development based on ICH Q8 guidelines. It discusses key QbD concepts like critical quality attributes, risk assessment, design space and control strategy. It also presents two case studies applying QbD approaches - one on developing controlled-release felodipine tablets using polymeric surfactants and another on starch-based nanocapsules for topical drug delivery. The document outlines the various elements of pharmaceutical development as defined in ICH Q8 like quality target product profile, critical quality attributes, risk assessment, design space and product lifecycle management.
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 provides guidance for registration applications on reporting and controlling degradation products in new drug products. Any degradation product observed above the identification threshold in stability studies should be identified. Analytical procedures must be validated to detect and quantify degradation products. Results should be reported for batches used in testing and batches representative of the commercial process. Degradation products present below identification thresholds usually do not need identification, unless they are unusually potent or toxic.
ICH Q10/WHO TRS provides a regulatory perspective on quality guidelines. It discusses the history of WHO GMP guidelines and introduces ICH Q10, which describes a pharmaceutical quality system to ensure product quality over the lifecycle. ICH Q10 complements GMPs and facilitates continual improvement. It has been adopted by various regulatory agencies and provides a comprehensive approach to quality management.
This document provides a summary of an evaluation of dissolution test methods from three pharmacopoeias - the European Pharmacopoeia, Japanese Pharmacopoeia, and United States Pharmacopoeia. It was determined that the basket apparatus, paddle apparatus, and flow-through cell methods can be considered interchangeable between the three regions, with some clarifications and conditions. Product-specific parameters need to be defined in applications. The timing of implementing this interchangeability may differ by region depending on regulatory processes. Considerations for implementation include validation requirements and compendial change procedures.
This document discusses quality by design (QbD), a new quality paradigm for pharmaceutical development and manufacturing proposed by regulatory agencies. It provides background on QbD, describing how the FDA and ICH have advocated for a more systematic, science-based approach focusing on identifying and controlling critical quality attributes. The key aspects of QbD include establishing a quality target product profile, identifying potential critical quality attributes, selecting appropriate manufacturing processes and controls, and taking a lifecycle approach to validation. The document compares traditional and QbD approaches and explains how QbD involves building quality into processes from the start through tools like risk management and multivariate experimentation.
The document summarizes the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines. The ICH was established in 1990 and brings together regulatory authorities and the pharmaceutical industry from Europe, Japan, and the United States to discuss product registration and improve efficiency. The ICH has developed over 50 harmonized guidelines on quality, safety, efficacy, and other topics to eliminate duplication in the drug development and approval process. The guidelines cover areas like stability testing, analytical validation methods, impurities, biotechnological products, and good manufacturing practices.
This document provides guidance for assessing the comparability of biotechnological products before and after changes to the manufacturing process. It aims to assist manufacturers in collecting relevant technical information to demonstrate that manufacturing changes will not adversely impact quality, safety or efficacy. The guidelines cover analytical techniques, characterization, specifications, stability and other quality, nonclinical and clinical considerations for evaluating comparability. The goal is to ensure the quality, safety and efficacy of products produced by changed processes through evaluating relevant data. A finding of comparability does not require identical quality attributes but highly similar attributes without adverse impacts on safety or efficacy.
This document provides an overview of WHO good manufacturing practices (GMP) for pharmaceutical products. It discusses key concepts like quality assurance, GMP, and quality control as interrelated aspects of quality management in the pharmaceutical industry. The document defines important terms and outlines 17 main principles of GMP, including quality management, personnel, premises, equipment, materials, documentation, production processes, and quality control. It emphasizes that GMP aims to ensure pharmaceutical products are consistently produced and controlled according to quality standards appropriate for their intended use.
The document summarizes guidelines for pharmacovigilance planning from the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH). It recommends summarizing the important identified and potential risks of a drug in a Safety Specification and developing a Pharmacovigilance Plan to address ongoing safety issues and monitor risks in the post-approval period. The plan should include routine pharmacovigilance practices as well as additional actions to evaluate specific risks, and be revised as new safety information emerges. Pharmacovigilance planning aims to improve risk communication and the benefit-risk assessment of drugs over their lifecycle.
This document provides guidance on setting specifications for biotechnological and biological products. It outlines principles for characterizing products and establishing acceptance criteria based on physicochemical properties, biological activity, immunogenicity, purity, and impurities. Specifications should be justified based on data from lots used in clinical studies and manufacturing consistency lots. The document provides appendices on characterization techniques and types of impurities to consider.
This document provides guidelines for validating analytical procedures used in pharmaceutical registration applications. It discusses four common types of analytical procedures: identification tests, impurity tests, limit tests for impurities, and quantitative assays. The guidelines describe key validation characteristics such as accuracy, precision, specificity, detection limit, quantitation limit, linearity, range, and robustness. It provides a table summarizing which characteristics are most important to evaluate for each type of analytical procedure. The document also includes definitions for validation terminology and methodology recommendations for demonstrating various validation characteristics.
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 guidelines for registration applications regarding impurities in new drug substances produced through chemical synthesis. It discusses classification of impurities, rationale for reporting and controlling impurities, analytical procedures, reporting impurity content in batches, listing impurities in specifications, and qualification of impurities. The guidelines are intended to address impurities from both a chemistry and safety perspective for new drug substances not previously registered in a region.
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.
The document summarizes information from the International Council for Harmonisation (ICH) website. ICH is an international body that brings together regulatory authorities and the pharmaceutical industry to discuss guidelines for drug development and regulation. The document outlines ICH's history, mission, members and observers, processes for harmonizing guidelines, and categories of guidelines related to quality, safety, efficacy, and multidisciplinary topics. It provides details on ICH guidelines for stability testing, analytical validation, impurities, and other quality-related topics.
This document provides guidelines for good manufacturing practices for active pharmaceutical ingredients intended for human use. It acknowledges previous guidelines from various organizations and countries. The guidelines are intended to ensure active ingredients are manufactured under a quality assurance system suitable for their intended use in medicines. The guidelines apply from the stage in production where analytical specifications alone are sufficient to ensure quality, and include requirements for organization, facilities, equipment, documentation, validation, change control, materials management, and quality management.
Phenomics assisted breeding in crop improvementIshaGoswami9
As the population is increasing and will reach about 9 billion upto 2050. Also due to climate change, it is difficult to meet the food requirement of such a large population. Facing the challenges presented by resource shortages, climate
change, and increasing global population, crop yield and quality need to be improved in a sustainable way over the coming decades. Genetic improvement by breeding is the best way to increase crop productivity. With the rapid progression of functional
genomics, an increasing number of crop genomes have been sequenced and dozens of genes influencing key agronomic traits have been identified. However, current genome sequence information has not been adequately exploited for understanding
the complex characteristics of multiple gene, owing to a lack of crop phenotypic data. Efficient, automatic, and accurate technologies and platforms that can capture phenotypic data that can
be linked to genomics information for crop improvement at all growth stages have become as important as genotyping. Thus,
high-throughput phenotyping has become the major bottleneck restricting crop breeding. Plant phenomics has been defined as the high-throughput, accurate acquisition and analysis of multi-dimensional phenotypes
during crop growing stages at the organism level, including the cell, tissue, organ, individual plant, plot, and field levels. With the rapid development of novel sensors, imaging technology,
and analysis methods, numerous infrastructure platforms have been developed for phenotyping.
This document provides an overview of Quality by Design (QbD) in pharmaceutical development based on ICH Q8 guidelines. It discusses key QbD concepts like critical quality attributes, risk assessment, design space and control strategy. It also presents two case studies applying QbD approaches - one on developing controlled-release felodipine tablets using polymeric surfactants and another on starch-based nanocapsules for topical drug delivery. The document outlines the various elements of pharmaceutical development as defined in ICH Q8 like quality target product profile, critical quality attributes, risk assessment, design space and product lifecycle management.
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 provides guidance for registration applications on reporting and controlling degradation products in new drug products. Any degradation product observed above the identification threshold in stability studies should be identified. Analytical procedures must be validated to detect and quantify degradation products. Results should be reported for batches used in testing and batches representative of the commercial process. Degradation products present below identification thresholds usually do not need identification, unless they are unusually potent or toxic.
ICH Q10/WHO TRS provides a regulatory perspective on quality guidelines. It discusses the history of WHO GMP guidelines and introduces ICH Q10, which describes a pharmaceutical quality system to ensure product quality over the lifecycle. ICH Q10 complements GMPs and facilitates continual improvement. It has been adopted by various regulatory agencies and provides a comprehensive approach to quality management.
This document provides a summary of an evaluation of dissolution test methods from three pharmacopoeias - the European Pharmacopoeia, Japanese Pharmacopoeia, and United States Pharmacopoeia. It was determined that the basket apparatus, paddle apparatus, and flow-through cell methods can be considered interchangeable between the three regions, with some clarifications and conditions. Product-specific parameters need to be defined in applications. The timing of implementing this interchangeability may differ by region depending on regulatory processes. Considerations for implementation include validation requirements and compendial change procedures.
This document discusses quality by design (QbD), a new quality paradigm for pharmaceutical development and manufacturing proposed by regulatory agencies. It provides background on QbD, describing how the FDA and ICH have advocated for a more systematic, science-based approach focusing on identifying and controlling critical quality attributes. The key aspects of QbD include establishing a quality target product profile, identifying potential critical quality attributes, selecting appropriate manufacturing processes and controls, and taking a lifecycle approach to validation. The document compares traditional and QbD approaches and explains how QbD involves building quality into processes from the start through tools like risk management and multivariate experimentation.
The document summarizes the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines. The ICH was established in 1990 and brings together regulatory authorities and the pharmaceutical industry from Europe, Japan, and the United States to discuss product registration and improve efficiency. The ICH has developed over 50 harmonized guidelines on quality, safety, efficacy, and other topics to eliminate duplication in the drug development and approval process. The guidelines cover areas like stability testing, analytical validation methods, impurities, biotechnological products, and good manufacturing practices.
This document provides guidance for assessing the comparability of biotechnological products before and after changes to the manufacturing process. It aims to assist manufacturers in collecting relevant technical information to demonstrate that manufacturing changes will not adversely impact quality, safety or efficacy. The guidelines cover analytical techniques, characterization, specifications, stability and other quality, nonclinical and clinical considerations for evaluating comparability. The goal is to ensure the quality, safety and efficacy of products produced by changed processes through evaluating relevant data. A finding of comparability does not require identical quality attributes but highly similar attributes without adverse impacts on safety or efficacy.
This document provides an overview of WHO good manufacturing practices (GMP) for pharmaceutical products. It discusses key concepts like quality assurance, GMP, and quality control as interrelated aspects of quality management in the pharmaceutical industry. The document defines important terms and outlines 17 main principles of GMP, including quality management, personnel, premises, equipment, materials, documentation, production processes, and quality control. It emphasizes that GMP aims to ensure pharmaceutical products are consistently produced and controlled according to quality standards appropriate for their intended use.
The document summarizes guidelines for pharmacovigilance planning from the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH). It recommends summarizing the important identified and potential risks of a drug in a Safety Specification and developing a Pharmacovigilance Plan to address ongoing safety issues and monitor risks in the post-approval period. The plan should include routine pharmacovigilance practices as well as additional actions to evaluate specific risks, and be revised as new safety information emerges. Pharmacovigilance planning aims to improve risk communication and the benefit-risk assessment of drugs over their lifecycle.
This document provides guidance on setting specifications for biotechnological and biological products. It outlines principles for characterizing products and establishing acceptance criteria based on physicochemical properties, biological activity, immunogenicity, purity, and impurities. Specifications should be justified based on data from lots used in clinical studies and manufacturing consistency lots. The document provides appendices on characterization techniques and types of impurities to consider.
This document provides guidelines for validating analytical procedures used in pharmaceutical registration applications. It discusses four common types of analytical procedures: identification tests, impurity tests, limit tests for impurities, and quantitative assays. The guidelines describe key validation characteristics such as accuracy, precision, specificity, detection limit, quantitation limit, linearity, range, and robustness. It provides a table summarizing which characteristics are most important to evaluate for each type of analytical procedure. The document also includes definitions for validation terminology and methodology recommendations for demonstrating various validation characteristics.
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 guidelines for registration applications regarding impurities in new drug substances produced through chemical synthesis. It discusses classification of impurities, rationale for reporting and controlling impurities, analytical procedures, reporting impurity content in batches, listing impurities in specifications, and qualification of impurities. The guidelines are intended to address impurities from both a chemistry and safety perspective for new drug substances not previously registered in a region.
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.
The document summarizes information from the International Council for Harmonisation (ICH) website. ICH is an international body that brings together regulatory authorities and the pharmaceutical industry to discuss guidelines for drug development and regulation. The document outlines ICH's history, mission, members and observers, processes for harmonizing guidelines, and categories of guidelines related to quality, safety, efficacy, and multidisciplinary topics. It provides details on ICH guidelines for stability testing, analytical validation, impurities, and other quality-related topics.
This document provides guidelines for good manufacturing practices for active pharmaceutical ingredients intended for human use. It acknowledges previous guidelines from various organizations and countries. The guidelines are intended to ensure active ingredients are manufactured under a quality assurance system suitable for their intended use in medicines. The guidelines apply from the stage in production where analytical specifications alone are sufficient to ensure quality, and include requirements for organization, facilities, equipment, documentation, validation, change control, materials management, and quality management.
Phenomics assisted breeding in crop improvementIshaGoswami9
As the population is increasing and will reach about 9 billion upto 2050. Also due to climate change, it is difficult to meet the food requirement of such a large population. Facing the challenges presented by resource shortages, climate
change, and increasing global population, crop yield and quality need to be improved in a sustainable way over the coming decades. Genetic improvement by breeding is the best way to increase crop productivity. With the rapid progression of functional
genomics, an increasing number of crop genomes have been sequenced and dozens of genes influencing key agronomic traits have been identified. However, current genome sequence information has not been adequately exploited for understanding
the complex characteristics of multiple gene, owing to a lack of crop phenotypic data. Efficient, automatic, and accurate technologies and platforms that can capture phenotypic data that can
be linked to genomics information for crop improvement at all growth stages have become as important as genotyping. Thus,
high-throughput phenotyping has become the major bottleneck restricting crop breeding. Plant phenomics has been defined as the high-throughput, accurate acquisition and analysis of multi-dimensional phenotypes
during crop growing stages at the organism level, including the cell, tissue, organ, individual plant, plot, and field levels. With the rapid development of novel sensors, imaging technology,
and analysis methods, numerous infrastructure platforms have been developed for phenotyping.
hematic appreciation test is a psychological assessment tool used to measure an individual's appreciation and understanding of specific themes or topics. This test helps to evaluate an individual's ability to connect different ideas and concepts within a given theme, as well as their overall comprehension and interpretation skills. The results of the test can provide valuable insights into an individual's cognitive abilities, creativity, and critical thinking skills
Unlocking the mysteries of reproduction: Exploring fecundity and gonadosomati...AbdullaAlAsif1
The pygmy halfbeak Dermogenys colletei, is known for its viviparous nature, this presents an intriguing case of relatively low fecundity, raising questions about potential compensatory reproductive strategies employed by this species. Our study delves into the examination of fecundity and the Gonadosomatic Index (GSI) in the Pygmy Halfbeak, D. colletei (Meisner, 2001), an intriguing viviparous fish indigenous to Sarawak, Borneo. We hypothesize that the Pygmy halfbeak, D. colletei, may exhibit unique reproductive adaptations to offset its low fecundity, thus enhancing its survival and fitness. To address this, we conducted a comprehensive study utilizing 28 mature female specimens of D. colletei, carefully measuring fecundity and GSI to shed light on the reproductive adaptations of this species. Our findings reveal that D. colletei indeed exhibits low fecundity, with a mean of 16.76 ± 2.01, and a mean GSI of 12.83 ± 1.27, providing crucial insights into the reproductive mechanisms at play in this species. These results underscore the existence of unique reproductive strategies in D. colletei, enabling its adaptation and persistence in Borneo's diverse aquatic ecosystems, and call for further ecological research to elucidate these mechanisms. This study lends to a better understanding of viviparous fish in Borneo and contributes to the broader field of aquatic ecology, enhancing our knowledge of species adaptations to unique ecological challenges.
Current Ms word generated power point presentation covers major details about the micronuclei test. It's significance and assays to conduct it. It is used to detect the micronuclei formation inside the cells of nearly every multicellular organism. It's formation takes place during chromosomal sepration at metaphase.
ESR spectroscopy in liquid food and beverages.pptxPRIYANKA PATEL
With increasing population, people need to rely on packaged food stuffs. Packaging of food materials requires the preservation of food. There are various methods for the treatment of food to preserve them and irradiation treatment of food is one of them. It is the most common and the most harmless method for the food preservation as it does not alter the necessary micronutrients of food materials. Although irradiated food doesn’t cause any harm to the human health but still the quality assessment of food is required to provide consumers with necessary information about the food. ESR spectroscopy is the most sophisticated way to investigate the quality of the food and the free radicals induced during the processing of the food. ESR spin trapping technique is useful for the detection of highly unstable radicals in the food. The antioxidant capability of liquid food and beverages in mainly performed by spin trapping technique.
The use of Nauplii and metanauplii artemia in aquaculture (brine shrimp).pptxMAGOTI ERNEST
Although Artemia has been known to man for centuries, its use as a food for the culture of larval organisms apparently began only in the 1930s, when several investigators found that it made an excellent food for newly hatched fish larvae (Litvinenko et al., 2023). As aquaculture developed in the 1960s and ‘70s, the use of Artemia also became more widespread, due both to its convenience and to its nutritional value for larval organisms (Arenas-Pardo et al., 2024). The fact that Artemia dormant cysts can be stored for long periods in cans, and then used as an off-the-shelf food requiring only 24 h of incubation makes them the most convenient, least labor-intensive, live food available for aquaculture (Sorgeloos & Roubach, 2021). The nutritional value of Artemia, especially for marine organisms, is not constant, but varies both geographically and temporally. During the last decade, however, both the causes of Artemia nutritional variability and methods to improve poorquality Artemia have been identified (Loufi et al., 2024).
Brine shrimp (Artemia spp.) are used in marine aquaculture worldwide. Annually, more than 2,000 metric tons of dry cysts are used for cultivation of fish, crustacean, and shellfish larva. Brine shrimp are important to aquaculture because newly hatched brine shrimp nauplii (larvae) provide a food source for many fish fry (Mozanzadeh et al., 2021). Culture and harvesting of brine shrimp eggs represents another aspect of the aquaculture industry. Nauplii and metanauplii of Artemia, commonly known as brine shrimp, play a crucial role in aquaculture due to their nutritional value and suitability as live feed for many aquatic species, particularly in larval stages (Sorgeloos & Roubach, 2021).
Authoring a personal GPT for your research and practice: How we created the Q...Leonel Morgado
Thematic analysis in qualitative research is a time-consuming and systematic task, typically done using teams. Team members must ground their activities on common understandings of the major concepts underlying the thematic analysis, and define criteria for its development. However, conceptual misunderstandings, equivocations, and lack of adherence to criteria are challenges to the quality and speed of this process. Given the distributed and uncertain nature of this process, we wondered if the tasks in thematic analysis could be supported by readily available artificial intelligence chatbots. Our early efforts point to potential benefits: not just saving time in the coding process but better adherence to criteria and grounding, by increasing triangulation between humans and artificial intelligence. This tutorial will provide a description and demonstration of the process we followed, as two academic researchers, to develop a custom ChatGPT to assist with qualitative coding in the thematic data analysis process of immersive learning accounts in a survey of the academic literature: QUAL-E Immersive Learning Thematic Analysis Helper. In the hands-on time, participants will try out QUAL-E and develop their ideas for their own qualitative coding ChatGPT. Participants that have the paid ChatGPT Plus subscription can create a draft of their assistants. The organizers will provide course materials and slide deck that participants will be able to utilize to continue development of their custom GPT. The paid subscription to ChatGPT Plus is not required to participate in this workshop, just for trying out personal GPTs during it.
Immersive Learning That Works: Research Grounding and Paths ForwardLeonel Morgado
We will metaverse into the essence of immersive learning, into its three dimensions and conceptual models. This approach encompasses elements from teaching methodologies to social involvement, through organizational concerns and technologies. Challenging the perception of learning as knowledge transfer, we introduce a 'Uses, Practices & Strategies' model operationalized by the 'Immersive Learning Brain' and ‘Immersion Cube’ frameworks. This approach offers a comprehensive guide through the intricacies of immersive educational experiences and spotlighting research frontiers, along the immersion dimensions of system, narrative, and agency. Our discourse extends to stakeholders beyond the academic sphere, addressing the interests of technologists, instructional designers, and policymakers. We span various contexts, from formal education to organizational transformation to the new horizon of an AI-pervasive society. This keynote aims to unite the iLRN community in a collaborative journey towards a future where immersive learning research and practice coalesce, paving the way for innovative educational research and practice landscapes.
The technology uses reclaimed CO₂ as the dyeing medium in a closed loop process. When pressurized, CO₂ becomes supercritical (SC-CO₂). In this state CO₂ has a very high solvent power, allowing the dye to dissolve easily.
ESPP presentation to EU Waste Water Network, 4th June 2024 “EU policies driving nutrient removal and recycling
and the revised UWWTD (Urban Waste Water Treatment Directive)”
2. ICH guideline Q8 (R2) on pharmaceutical development
EMA/CHMP/ICH/167068/2004 Page 2/24
Document History
First
Codification
History Date
Parent Guideline: Pharmaceutical Development
Q8 Approval of the Guideline by the Steering Committee under Step 2
and release for public consultation.
18
November
2004
Q8 Approval of the Guideline by the Steering Committee under Step 4
and recommendation for adoption to the three ICH regulatory bodies.
10
November
2005
Annex to the Parent Guideline: Pharmaceutical Development
Annex to Q8 Approval of the Annex by the Steering Committee under Step 2 and
release for public consultation.
1 November
2007
Annex to Q8 Approval of the Annex by the Steering Committee under Step 4 and
recommendation for adoption to the three ICH regulatory bodies.
13
November
2008
Addition of Annex to the Parent Guideline
Q8(R1) The parent guideline “Pharmaceutical Development” was recoded
Q8(R1) following the addition of the Annex to the parent guideline.
November
2008
Current Step 4 version
Q8(R2) Corrigendum to titles of “Figure 2a” and “Figure 2b” of “Example 2” on
page 23.
August
2009
3. ICH guideline Q8 (R2) on pharmaceutical development
EMA/CHMP/ICH/167068/2004 Page 3/24
ICH guideline Q8 (R2) on pharmaceutical development
Table of contents
Part I: Pharmaceutical Development ........................................................... 5
1. Introduction ............................................................................................ 5
1.1. Objective of the Guideline .....................................................................................5
1.2. Scope .................................................................................................................5
2. Pharmaceutical development .................................................................. 5
2.1. Components of the drug product ............................................................................6
2.1.1. Drug Substance.................................................................................................6
2.1.2. Excipients.........................................................................................................7
2.2. Drug product .......................................................................................................7
2.2.1. Formulation development ...................................................................................7
2.2.2. Overages..........................................................................................................8
2.2.3. Physicochemical and biological properties .............................................................8
2.3. Manufacturing process development .......................................................................8
2.4. Container closure system ......................................................................................9
2.5. Microbiological Attributes.....................................................................................10
2.6. Compatibility .....................................................................................................10
3. Glossary ................................................................................................ 10
Part II:Pharmaceutical development - Annex............................................ 12
1. Introduction .......................................................................................... 12
2. Elements of pharmaceutical development ............................................. 13
2.1. Quality target product profile ...............................................................................13
2.2. Critical quality attributes .....................................................................................13
2.3. Risk assessment: linking material attributes and process parameters to drug product
CQAs.......................................................................................................................14
2.4. Design space .....................................................................................................14
2.4.1. Selection of variables .......................................................................................14
2.4.2. Describing a design space in a submission ..........................................................15
2.4.3. Unit operation design space(s) ..........................................................................15
2.4.4. Relationship of design space to scale and equipment............................................15
2.4.5. Design space versus proven acceptable ranges ...................................................15
2.4.6. Design space and edge of failure .......................................................................15
2.5. Control strategy .................................................................................................16
2.6. Product lifecycle management and continual improvement ......................................17
3. Submission of pharmaceutical development and related information in
common technical documents (CTD) format.............................................. 17
3.1. Quality risk management and product and process development ..............................17
3.2. Design space .....................................................................................................17
3.3. Control strategy .................................................................................................18
3.4. Drug substance related information ......................................................................18
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4. Glossary ................................................................................................ 18
Appendix 1. Differing approaches to pharmaceutical development ........... 19
Appendix 2. illustrative examples.............................................................. 20
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Part I: Pharmaceutical Development
1. Introduction
1.1. Objective of the Guideline
This guideline describes the suggested contents for the 3.2.P.2 (Pharmaceutical Development) section
of a regulatory submission in the ICH M4 Common Technical Document (CTD) format.
The Pharmaceutical Development section provides an opportunity to present the knowledge gained
through the application of scientific approaches and quality risk management (for definition, see ICH
Q9) to the development of a product and its manufacturing process. It is first produced for the original
marketing application and can be updated to support new knowledge gained over the lifecycle* of a
product. The Pharmaceutical Development section is intended to provide a comprehensive
understanding of the product and manufacturing process for reviewers and inspectors. The guideline
also indicates areas where the demonstration of greater understanding of pharmaceutical and
manufacturing sciences can create a basis for flexible regulatory approaches. The degree of regulatory
flexibility is predicated on the level of relevant scientific knowledge provided.
1.2. Scope
This guideline is intended to provide guidance on the contents of Section 3.2.P.2 (Pharmaceutical
Development) for drug products as defined in the scope of Module 3 of the Common Technical
Document (ICH guideline M4). The guideline does not apply to contents of submissions for drug
products during the clinical research stages of drug development. However, the principles in this
guideline are important to consider during those stages as well. This guideline might also be
appropriate for other types of products. To determine the applicability of this guideline to a particular
type of product, applicants can consult with the appropriate regulatory authorities.
2. Pharmaceutical development
The aim of pharmaceutical development is to design a quality product and its manufacturing process to
consistently deliver the intended performance of the product. The information and knowledge gained
from pharmaceutical development studies and manufacturing experience provide scientific
understanding to support the establishment of the design space*, specifications, and manufacturing
controls.
Information from pharmaceutical development studies can be a basis for quality risk management. It is
important to recognize that quality* cannot be tested into products; i.e., quality should be built in by
design. Changes in formulation and manufacturing processes during development and lifecycle
management should be looked upon as opportunities to gain additional knowledge and further support
establishment of the design space. Similarly, inclusion of relevant knowledge gained from experiments
giving unexpected results can also be useful. Design space is proposed by the applicant and is subject
to regulatory assessment and approval. Working within the design space is not considered as a
change. Movement out of the design space is considered to be a change and would normally initiate a
regulatory post approval change process.
* See Glossary for definition
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The Pharmaceutical Development section should describe the knowledge that establishes that the type
of dosage form selected and the formulation proposed are suitable for the intended use. This section
should include sufficient information in each part to provide an understanding of the development of
the drug product and its manufacturing process. Summary tables and graphs are encouraged where
they add clarity and facilitate review.
At a minimum, those aspects of drug substances, excipients, container closure systems, and
manufacturing processes that are critical to product quality should be determined and control
strategies justified. Critical formulation attributes and process parameters are generally identified
through an assessment of the extent to which their variation can have impact on the quality of the
drug product.
In addition, the applicant can choose to conduct pharmaceutical development studies that can lead to
an enhanced knowledge of product performance over a wider range of material attributes, processing
options and process parameters. Inclusion of this additional information in this section provides an
opportunity to demonstrate a higher degree of understanding of material attributes, manufacturing
processes and their controls. This scientific understanding facilitates establishment of an expanded
design space. In these situations, opportunities exist to develop more flexible regulatory approaches,
for example, to facilitate:
risk-based regulatory decisions (reviews and inspections);
manufacturing process improvements, within the approved design space described in the dossier,
without further regulatory review;
reduction of post-approval submissions;
real-time quality control, leading to a reduction of end-product release testing.
To realise this flexibility, the applicant should demonstrate an enhanced knowledge of product
performance over a range of material attributes, manufacturing process options and process
parameters. This understanding can be gained by application of, for example, formal experimental
designs*, process analytical technology (PAT)*, and/or prior knowledge. Appropriate use of quality risk
management principles can be helpful in prioritising the additional pharmaceutical development studies
to collect such knowledge.
The design and conduct of pharmaceutical development studies should be consistent with their
intended scientific purpose. It should be recognized that the level of knowledge gained, and not the
volume of data, provides the basis for science-based submissions and their regulatory evaluation.
2.1. Components of the drug product
2.1.1. Drug substance
The physicochemical and biological properties of the drug substance that can influence the
performance of the drug product and its manufacturability, or were specifically designed into the drug
substance (e.g., solid state properties), should be identified and discussed. Examples of
physicochemical and biological properties that might need to be examined include solubility, water
content, particle size, crystal properties, biological activity, and permeability. These properties could be
inter-related and might need to be considered in combination.
* See Glossary for definition
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To evaluate the potential effect of drug substance physicochemical properties on the performance of
the drug product, studies on drug product might be warranted. For example, the ICH Q6A
Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and New Drug
Products: Chemical Substances describes some of the circumstances in which drug product studies are
recommended (e.g., Decision Tree #3 and #4 (Part 2)). This approach applies equally for the ICH Q6B
Specifications: Test Procedures and Acceptance Criteria for Biotechnology/Biological Products. The
knowledge gained from the studies investigating the potential effect of drug substance properties on
drug product performance can be used, as appropriate, to justify elements of the drug substance
specification (3.2.S.4.5).
The compatibility of the drug substance with excipients listed in 3.2.P.1 should be evaluated. For
products that contain more than one drug substance, the compatibility of the drug substances with
each other should also be evaluated.
2.1.2. Excipients
The excipients chosen, their concentration, and the characteristics that can influence the drug product
performance (e.g., stability, bioavailability) or manufacturability should be discussed relative to the
respective function of each excipient. This should include all substances used in the manufacture of the
drug product, whether they appear in the finished product or not (e.g., processing aids). Compatibility
of excipients with other excipients, where relevant (for example, combination of preservatives in a dual
preservative system), should be established. The ability of excipients (e.g., antioxidants, penetration
enhancers, disintegrants, release controlling agents) to provide their intended functionality, and to
perform throughout the intended drug product shelf life, should also be demonstrated. The information
on excipient performance can be used, as appropriate, to justify the choice and quality attributes of the
excipient, and to support the justification of the drug product specification (3.2.P.5.6).
Information to support the safety of excipients, when appropriate, should be cross-referenced
(3.2.P.4.6).
2.2. Drug product
2.2.1. Formulation development
A summary should be provided describing the development of the formulation, including identification
of those attributes that are critical to the quality of the drug product, taking into consideration
intended usage and route of administration. Information from formal experimental designs can be
useful in identifying critical or interacting variables that might be important to ensure the quality of the
drug product.
The summary should highlight the evolution of the formulation design from initial concept up to the
final design. This summary should also take into consideration the choice of drug product components
(e.g., the properties of the drug substance, excipients, container closure system, any relevant dosing
device), the manufacturing process, and, if appropriate, knowledge gained from the development of
similar drug product(s).
Any excipient ranges included in the batch formula (3.2.P.3.2) should be justified in this section of the
application; this justification can often be based on the experience gained during development or
manufacture.
A summary of formulations used in clinical safety and efficacy and in any relevant bioavailability or
bioequivalence studies should be provided. Any changes between the proposed commercial formulation
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and those formulations used in pivotal clinical batches and primary stability batches should be clearly
described and the rationale for the changes provided.
Information from comparative in vitro studies (e.g., dissolution) or comparative in vivo studies (e.g.,
bioequivalence) that links clinical formulations to the proposed commercial formulation described in
3.2.P.1 should be summarized and a cross-reference to the studies (with study numbers) should be
provided. Where attempts have been made to establish an in vitro/in vivo correlation, the results of
those studies, and a cross-reference to the studies (with study numbers), should be provided in this
section. A successful correlation can assist in the selection of appropriate dissolution acceptance
criteria, and can potentially reduce the need for further bioequivalence studies following changes to the
product or its manufacturing process.
Any special design features of the drug product (e.g., tablet score line, overfill, anti-counterfeiting
measure as it affects the drug product) should be identified and a rationale provided for their use.
2.2.2. Overages
In general, use of an overage of a drug substance to compensate for degradation during manufacture
or a product’s shelf life, or to extend shelf life, is discouraged.
Any overages in the manufacture of the drug product, whether they appear in the final formulated
product or not, should be justified considering the safety and efficacy of the product. Information
should be provided on the 1) amount of overage, 2) reason for the overage (e.g., to compensate for
expected and documented manufacturing losses), and 3) justification for the amount of overage. The
overage should be included in the amount of drug substance listed in the batch formula (3.2.P.3.2).
2.2.3. Physicochemical and biological properties
The physicochemical and biological properties relevant to the safety, performance or manufacturability
of the drug product should be identified and discussed. This includes the physiological implications of
drug substance and formulation attributes. Studies could include, for example, the development of a
test for respirable fraction of an inhaled product. Similarly, information supporting the selection of
dissolution vs. disintegration testing, or other means to assure drug release, and the development and
suitability of the chosen test, could be provided in this section. See also ICH Q6A Specifications: Test
Procedures And Acceptance Criteria For New Drug Substances And New Drug Products: Chemical
Substances; Decision Tree #4 (Part 3) and Decision Tree #7 (Part 1) or ICH Q6B Specifications: Test
Procedures and Acceptance Criteria for Biotechnology/Biological Products. The discussion should cross-
reference any relevant stability data in 3.2.P.8.3.
2.3. Manufacturing process development
The selection, the control, and any improvement of the manufacturing process described in 3.2.P.3.3
(i.e., intended for commercial production batches) should be explained. It is important to consider the
critical formulation attributes, together with the available manufacturing process options, in order to
address the selection of the manufacturing process and confirm the appropriateness of the
components. Appropriateness of the equipment used for the intended products should be discussed.
Process development studies should provide the basis for process improvement, process validation,
continuous process verification* (where applicable), and any process control requirements. Where
appropriate, such studies should address microbiological as well as physical and chemical attributes.
* See Glossary for definition
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The knowledge gained from process development studies can be used, as appropriate, to justify the
drug product specification (3.2.P.5.6).
The manufacturing process development programme or process improvement programme should
identify any critical process parameters that should be monitored or controlled (e.g., granulation end
point) to ensure that the product is of the desired quality.
For those products intended to be sterile an appropriate method of sterilization for the drug product
and primary packaging material should be chosen and the choice justified.
Significant differences between the manufacturing processes used to produce batches for pivotal
clinical trials (safety, efficacy, bioavailability, bioequivalence) or primary stability studies and the
process described in 3.2.P.3.3 should be discussed. The discussion should summarise the influence of
the differences on the performance, manufacturability and quality of the product. The information
should be presented in a way that facilitates comparison of the processes and the corresponding batch
analyses information (3.2.P.5.4). The information should include, for example, (1) the identity (e.g.,
batch number) and use of the batches produced (e.g., bioequivalence study batch number), (2) the
manufacturing site, (3) the batch size, and (4) any significant equipment differences (e.g., different
design, operating principle, size).
In order to provide flexibility for future process improvement, when describing the development of the
manufacturing process, it is useful to describe measurement systems that allow monitoring of critical
attributes or process end-points. Collection of process monitoring data during the development of the
manufacturing process can provide useful information to enhance process understanding. The process
control strategies that provide process adjustment capabilities to ensure control of all critical attributes
should be described.
An assessment of the ability of the process to reliably produce a product of the intended quality (e.g.,
the performance of the manufacturing process under different operating conditions, at different scales,
or with different equipment) can be provided. An understanding of process robustness* can be useful
in risk assessment and risk reduction (see ICH Q9 Quality Risk Management glossary for definition)
and to support future manufacturing and process improvement, especially in conjunction with the use
of risk management tools (see ICH Q9 Quality Risk Management).
2.4. Container closure system
The choice and rationale for selection of the container closure system for the commercial product
(described in 3.2.P.7) should be discussed. Consideration should be given to the intended use of the
drug product and the suitability of the container closure system for storage and transportation
(shipping), including the storage and shipping container for bulk drug product, where appropriate.
The choice of materials for primary packaging should be justified. The discussion should describe
studies performed to demonstrate the integrity of the container and closure. A possible interaction
between product and container or label should be considered.
The choice of primary packaging materials should consider, e.g., choice of materials, protection from
moisture and light, compatibility of the materials of construction with the dosage form (including
sorption to container and leaching), and safety of materials of construction. Justification for secondary
packaging materials should be included, when relevant.
* See Glossary for definition
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If a dosing device is used (e.g., dropper pipette, pen injection device, dry powder inhaler), it is
important to demonstrate that a reproducible and accurate dose of the product is delivered under
testing conditions which, as far as possible, simulate the use of the product.
2.5. Microbiological attributes
Where appropriate, the microbiological attributes of the drug product should be discussed in this
section (3.2.P.2.5). The discussion should include, for example:
The rationale for performing or not performing microbial limits testing for non sterile drug products
(e.g., Decision Tree #8 in ICH Q6A Specifications: Test Procedures and Acceptance Criteria for New
Drug Substances and New Drug Products: Chemical Substances and ICH Q6B Specifications: Test
Procedures and Acceptance Criteria for Biotechnology/Biological Products);
The selection and effectiveness of preservative systems in products containing antimicrobial
preservative or the antimicrobial effectiveness of products that are inherently antimicrobial;
For sterile products, the integrity of the container closure system as it relates to preventing
microbial contamination.
Although chemical testing for preservative content is the attribute normally included in the drug
product specification, antimicrobial preservative effectiveness should be demonstrated during
development. The lowest specified concentration of antimicrobial preservative should be demonstrated
to be effective in controlling micro-organisms by using an antimicrobial preservative effectiveness test.
The concentration used should be justified in terms of efficacy and safety, such that the minimum
concentration of preservative that gives the required level of efficacy throughout the intended shelf life
of the product is used. Where relevant, microbial challenge testing under testing conditions that, as far
as possible, simulate patient use should be performed during development and documented in this
section.
2.6. Compatibility
The compatibility of the drug product with reconstitution diluents (e.g., precipitation, stability) should
be addressed to provide appropriate and supportive information for the labelling. This information
should cover the recommended in-use shelf life, at the recommended storage temperature and at the
likely extremes of concentration. Similarly, admixture or dilution of products prior to administration
(e.g., product added to large volume infusion containers) might need to be addressed.
3. Glossary
Continuous process verification:
An alternative approach to process validation in which manufacturing process performance is
continuously monitored and evaluated.
Design space:
The multidimensional combination and interaction of input variables (e.g., material attributes) and
process parameters that have been demonstrated to provide assurance of quality. Working within the
design space is not considered as a change. Movement out of the design space is considered to be a
change and would normally initiate a regulatory post approval change process. Design space is
proposed by the applicant and is subject to regulatory assessment and approval.
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Formal experimental design:
A structured, organized method for determining the relationship between factors affecting a process
and the output of that process. Also known as “Design of Experiments”.
Lifecycle:
All phases in the life of a product from the initial development through marketing until the product’s
discontinuation.
Process Analytical Technology (PAT):
A system for designing, analyzing, and controlling manufacturing through timely measurements (i.e.,
during processing) of critical quality and performance attributes of raw and in-process materials and
processes with the goal of ensuring final product quality.
Process robustness:
Ability of a process to tolerate variability of materials and changes of the process and equipment
without negative impact on quality.
Quality:
The suitability of either a drug substance or drug product for its intended use. This term includes such
attributes as the identity, strength, and purity (from ICH Q6A Specifications: Test Procedures and
Acceptance Criteria for New Drug Substances and New Drug Products: Chemical Substances).
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Part II: Pharmaceutical development - Annex
1. Introduction
This guideline is an annex to ICH Q8 Pharmaceutical Development and provides further clarification of
key concepts outlined in the core guideline. In addition, this annex describes the principles of quality
by design1 (QbD). The annex is not intended to establish new standards or to introduce new
regulatory requirements; however, it shows how concepts and tools (e.g., design space1) outlined in
the parent Q8 document could be put into practice by the applicant for all dosage forms. Where a
company chooses to apply quality by design and quality risk management (ICH Q9, Quality Risk
Management), linked to an appropriate pharmaceutical quality system, opportunities arise to enhance
science- and risk-based regulatory approaches (see ICH Q10, Pharmaceutical Quality System).
Approaches to Pharmaceutical Development
In all cases, the product should be designed to meet patients’ needs and the intended product
performance. Strategies for product development vary from company to company and from product to
product. The approach to, and extent of, development can also vary and should be outlined in the
submission. An applicant might choose either an empirical approach or a more systematic approach to
product development, or a combination of both. An illustration of the potential contrasts of these
approaches is shown in Appendix 1. A more systematic approach to development (also defined as
quality by design) can include, for example, incorporation of prior knowledge, results of studies using
design of experiments, use of quality risk management, and use of knowledge management (see ICH
Q10) throughout the lifecycle1 of the product. Such a systematic approach can enhance achieving the
desired quality of the product and help the regulators to better understand a company’s strategy.
Product and process understanding can be updated with the knowledge gained over the product
lifecycle.
A greater understanding of the product and its manufacturing process can create a basis for more
flexible regulatory approaches. The degree of regulatory flexibility is predicated on the level of relevant
scientific knowledge provided in the registration application. It is the knowledge gained and submitted
to the authorities, and not the volume of data collected, that forms the basis for science- and risk-
based submissions and regulatory evaluations. Nevertheless, appropriate data demonstrating that this
knowledge is based on sound scientific principles should be presented with each application.
Pharmaceutical development should include, at a minimum, the following elements:
Defining the quality target product profile1 (QTPP) as it relates to quality, safety and efficacy,
considering e.g., the route of administration, dosage form, bioavailability, strength, and stability;
Identifying potential critical quality attributes1 (CQAs) of the drug product, so that those product
characteristics having an impact on product quality can be studied and controlled;
Determining the critical quality attributes of the drug substance, excipients etc., and selecting the
type and amount of excipients to deliver drug product of the desired quality1;
Selecting an appropriate manufacturing process ;
Defining a control strategy1.
1
See glossary
1
See glossary
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An enhanced, quality by design approach to product development would additionally include the
following elements:
A systematic evaluation, understanding and refining of the formulation and manufacturing process,
including;
Identifying, through e.g., prior knowledge, experimentation, and risk assessment, the material
attributes and process parameters that can have an effect on product CQAs;
Determining the functional relationships that link material attributes and process parameters to
product CQAs;
Using the enhanced product and process understanding in combination with quality risk
management to establish an appropriate control strategy which can, for example, include a
proposal for a design space(s) and/or real-time release testing1
.
As a result, this more systematic approach could facilitate continual improvement and innovation
throughout the product lifecycle (See ICH Q10).
2. Elements of pharmaceutical development
The section that follows elaborates on possible approaches to gaining a more systematic, enhanced
understanding of the product and process under development. The examples given are purely
illustrative and are not intended to create new regulatory requirements.
2.1. Quality target product profile
The quality target product profile forms the basis of design for the development of the product.
Considerations for the quality target product profile could include:
Intended use in clinical setting, route of administration, dosage form, delivery systems;
Dosage strength(s);
Container closure system;
Therapeutic moiety release or delivery and attributes affecting pharmacokinetic characteristics
(e.g., dissolution, aerodynamic performance) appropriate to the drug product dosage form being
developed;
Drug product quality criteria (e.g., sterility, purity, stability and drug release) appropriate for the
intended marketed product.
2.2. Critical quality attributes
A CQA is a physical, chemical, biological, or microbiological property or characteristic that should be
within an appropriate limit, range, or distribution to ensure the desired product quality. CQAs are
generally associated with the drug substance, excipients, intermediates (in-process materials) and
drug product.
CQAs of solid oral dosage forms are typically those aspects affecting product purity, strength, drug
release and stability. CQAs for other delivery systems can additionally include more product specific
aspects, such as aerodynamic properties for inhaled products, sterility for parenterals, and adhesion
properties for transdermal patches. For drug substances, raw materials and intermediates, the CQAs
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can additionally include those properties (e.g., particle size distribution, bulk density) that affect drug
product CQAs.
Potential drug product CQAs derived from the quality target product profile and/or prior knowledge are
used to guide the product and process development. The list of potential CQAs can be modified when
the formulation and manufacturing process are selected and as product knowledge and process
understanding increase. Quality risk management can be used to prioritize the list of potential CQAs
for subsequent evaluation. Relevant CQAs can be identified by an iterative process of quality risk
management and experimentation that assesses the extent to which their variation can have an impact
on the quality of the drug product.
2.3. Risk assessment: linking material attributes and process parameters
to drug product CQAs
Risk assessment is a valuable science-based process used in quality risk management (see ICH Q9)
that can aid in identifying which material attributes and process parameters potentially have an effect
on product CQAs. Risk assessment is typically performed early in the pharmaceutical development
process and is repeated as more information becomes available and greater knowledge is obtained.
Risk assessment tools can be used to identify and rank parameters (e.g., process, equipment, input
materials) with potential to have an impact on product quality, based on prior knowledge and initial
experimental data. For an illustrative example, see Appendix 2. The initial list of potential parameters
can be quite extensive, but can be modified and prioritized by further studies (e.g., through a
combination of design of experiments, mechanistic models). The list can be refined further through
experimentation to determine the significance of individual variables and potential interactions. Once
the significant parameters are identified, they can be further studied (e.g., through a combination of
design of experiments, mathematical models, or studies that lead to mechanistic understanding) to
achieve a higher level of process understanding.
2.4. Design space
The relationship between the process inputs (material attributes and process parameters) and the
critical quality attributes can be described in the design space (see examples in Appendix 2).
2.4.1. Selection of variables
The risk assessment and process development experiments described in Section 2.3 can lead to an
understanding of the linkage and effect of process parameters and material attributes on product
CQAs, and also help identify the variables and their ranges within which consistent quality can be
achieved. These process parameters and material attributes can thus be selected for inclusion in the
design space.
A description should be provided in the application of the process parameters and material attributes
considered for the design space, those that were included, and their effect on product quality. The
rationale for inclusion in the design space should be presented. In some cases it is helpful to provide
also the rationale as to why some parameters were excluded. Knowledge gained from studies should
be described in the submission. Process parameters and material attributes that were not varied
through development should be highlighted.
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2.4.2. Describing a design space in a submission
A design space can be described in terms of ranges of material attributes and process parameters, or
through more complex mathematical relationships. It is possible to describe a design space as a time
dependent function (e.g., temperature and pressure cycle of a lyophilisation cycle), or as a
combination of variables such as components of a multivariate model. Scaling factors can also be
included if the design space is intended to span multiple operational scales. Analysis of historical data
can contribute to the establishment of a design space. Regardless of how a design space is developed,
it is expected that operation within the design space will result in a product meeting the defined
quality.
Examples of different potential approaches to presentation of a design space are presented in Appendix
2.
2.4.3. Unit operation design space(s)
The applicant can choose to establish independent design spaces for one or more unit operations, or to
establish a single design space that spans multiple operations. While a separate design space for each
unit operation is often simpler to develop, a design space that spans the entire process can provide
more operational flexibility. For example, in the case of a drug product that undergoes degradation in
solution before lyophilisation, the design space to control the extent of degradation (e.g.,
concentration, time, temperature) could be expressed for each unit operation or as a sum over all unit
operations.
2.4.4. Relationship of design space to scale and equipment
When describing a design space, the applicant should consider the type of operational flexibility
desired. A design space can be developed at any scale. The applicant should justify the relevance of a
design space developed at small or pilot scale to the proposed production scale manufacturing process
and discuss the potential risks in the scale-up operation.
If the applicant proposes the design space to be applicable to multiple operational scales, the design
space should be described in terms of relevant scale-independent parameters. For example, if a
product was determined to be shear sensitive in a mixing operation, the design space could include
shear rate, rather than agitation rate. Dimensionless numbers and/or models for scaling can be
included as part of the design space description.
2.4.5. Design space versus proven acceptable ranges
A combination of proven acceptable ranges1
does not constitute a design space. However, proven
acceptable ranges based on univariate experimentation can provide useful knowledge about the
process.
2.4.6. Design space and edge of failure
It can be helpful to determine the edge of failure for process parameters or material attributes, beyond
which the relevant quality attributes cannot be met. However, determining the edge of failure or
demonstrating failure modes are not essential parts of establishing a design space.
1
See glossary
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2.5. Control strategy
A control strategy is designed to ensure that a product of required quality will be produced
consistently. The elements of the control strategy discussed in Section P.2 of the dossier should
describe and justify how in-process controls and the controls of input materials (drug substance and
excipients), intermediates (in-process materials), container closure system, and drug products
contribute to the final product quality. These controls should be based on product, formulation and
process understanding and should include, at a minimum, control of the critical process parameters1
and material attributes.
A comprehensive pharmaceutical development approach will generate process and product
understanding and identify sources of variability. Sources of variability that can impact product quality
should be identified, appropriately understood, and subsequently controlled. Understanding sources of
variability and their impact on downstream processes or processing, in-process materials, and drug
product quality can provide an opportunity to shift controls upstream and minimise the need for end
product testing. Product and process understanding, in combination with quality risk management (see
ICH Q9), will support the control of the process such that the variability (e.g., of raw materials) can be
compensated for in an adaptable manner to deliver consistent product quality.
This process understanding can enable an alternative manufacturing paradigm where the variability of
input materials could be less tightly constrained. Instead it can be possible to design an adaptive
process step (a step that is responsive to the input materials) with appropriate process control to
ensure consistent product quality.
Enhanced understanding of product performance can justify the use of alternative approaches to
determine that the material is meeting its quality attributes. The use of such alternatives could support
real time release testing. For example, disintegration could serve as a surrogate for dissolution for
fast-disintegrating solid forms with highly soluble drug substances. Unit dose uniformity performed in-
process (e.g., using weight variation coupled with near infrared (NIR) assay) can enable real time
release testing and provide an increased level of quality assurance compared to the traditional end-
product testing using compendial content uniformity standards. Real time release testing can replace
end product testing, but does not replace the review and quality control steps called for under GMP to
release the batch.
A control strategy can include, but is not limited to, the following:
Control of input material attributes (e.g., drug substance, excipients, primary packaging materials)
based on an understanding of their impact on processability or product quality;
Product specification(s);
Controls for unit operations that have an impact on downstream processing or product quality
(e.g., the impact of drying on degradation, particle size distribution of the granulate on
dissolution);
In-process or real-time release testing in lieu of end-product testing (e.g. measurement and
control of CQAs during processing);
A monitoring program (e.g., full product testing at regular intervals) for verifying multivariate
prediction models.
A control strategy can include different elements. For example, one element of the control strategy
could rely on end-product testing, whereas another could depend on real-time release testing. The
rationale for using these alternative approaches should be described in the submission.
17. ICH guideline Q8 (R2) on pharmaceutical development
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Adoption of the principles in this guideline can support the justification of alternative approaches to the
setting of specification attributes and acceptance criteria as described in Q6A and Q6B.
2.6. Product lifecycle management and continual improvement
Throughout the product lifecycle, companies have opportunities to evaluate innovative approaches to
improve product quality (see ICH Q10).
Process performance can be monitored to ensure that it is working as anticipated to deliver product
quality attributes as predicted by the design space. This monitoring could include trend analysis of the
manufacturing process as additional experience is gained during routine manufacture. For certain
design spaces using mathematical models, periodic maintenance could be useful to ensure the model’s
performance. The model maintenance is an example of activity that can be managed within a
company‘s own internal quality system provided the design space is unchanged.
Expansion, reduction or redefinition of the design space could be desired upon gaining additional
process knowledge. Change of design space is subject to regional requirements.
3. Submission of pharmaceutical development and related
information in common technical documents (CTD) format
Pharmaceutical development information is submitted in Section P.2 of the CTD. Other information
resulting from pharmaceutical development studies could be accommodated by the CTD format in a
number of different ways and some specific suggestions are provided below. However, the applicant
should clearly indicate where the different information is located. In addition to what is submitted in
the application, certain aspects (e.g., product lifecycle management, continual improvement) of this
guideline are handled under the applicant’s pharmaceutical quality system (see ICH Q10).
3.1. Quality risk management and product and process development
Quality risk management can be used at different stages during product and process development and
manufacturing implementation. The assessments used to guide and justify development decisions can
be included in the relevant sections of P.2. For example, risk analyses and functional relationships
linking material attributes and process parameters to product CQAs can be included in P.2.1, P.2.2,
and P.2.3. Risk analyses linking the design of the manufacturing process to product quality can be
included in P.2.3.
3.2. Design space
As an element of the proposed manufacturing process, the design space(s) can be described in the
section of the application that includes the description of the manufacturing process and process
controls (P.3.3). If appropriate, additional information can be provided in the section of the application
that addresses the controls of critical steps and intermediates (P.3.4). The product and manufacturing
process development sections of the application (P.2.1, P.2.2, and P.2.3) are appropriate places to
summarise and describe product and process development studies that provide the basis for the design
space(s). The relationship of the design space(s) to the overall control strategy can be discussed in the
section of the application that includes the justification of the drug product specification (P.5.6).
18. ICH guideline Q8 (R2) on pharmaceutical development
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3.3. Control strategy
The section of the application that includes the justification of the drug product specification (P.5.6) is
a good place to summarise the overall drug product control strategy. However, detailed information
about input material controls and process controls should still be provided in the appropriate CTD
format sections (e.g., drug substance section (S), control of excipients (P.4), description of
manufacturing process and process controls (P.3.3), controls of critical steps and intermediates
(P.3.4)).
3.4. Drug substance related information
If drug substance CQAs have the potential to affect the CQAs or manufacturing process of the drug
product, some discussion of drug substance CQAs can be appropriate in the pharmaceutical
development section of the application (e.g., P.2.1).
4. Glossary
Control strategy:
A planned set of controls, derived from current product and process understanding that ensures
process performance and product quality. The controls can include parameters and attributes related
to drug substance and drug product materials and components, facility and equipment operating
conditions, in-process controls, finished product specifications, and the associated methods and
frequency of monitoring and control. (ICH Q10)
Critical Process Parameter (CPP):
A process parameter whose variability has an impact on a critical quality attribute and therefore should
be monitored or controlled to ensure the process produces the desired quality.
Critical Quality Attribute (CQA):
A physical, chemical, biological or microbiological property or characteristic that should be within an
appropriate limit, range, or distribution to ensure the desired product quality.
Design space:
The multidimensional combination and interaction of input variables (e.g., material attributes) and
process parameters that have been demonstrated to provide assurance of quality. Working within the
design space is not considered as a change. Movement out of the design space is considered to be a
change and would normally initiate a regulatory post approval change process. Design space is
proposed by the applicant and is subject to regulatory assessment and approval (ICH Q8).
Lifecycle:
All phases in the life of a product from the initial development through marketing until the product’s
discontinuation (ICH Q8).
Proven acceptable range:
A characterised range of a process parameter for which operation within this range, while keeping
other parameters constant, will result in producing a material meeting relevant quality criteria.
Quality:
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The suitability of either a drug substance or a drug product for its intended use. This term includes
such attributes as the identity, strength, and purity (ICH Q6A).
Quality by Design (QbD):
A systematic approach to development that begins with predefined objectives and emphasizes product
and process understanding and process control, based on sound science and quality risk management.
Quality Target Product Profile (QTPP):
A prospective summary of the quality characteristics of a drug product that ideally will be achieved to
ensure the desired quality, taking into account safety and efficacy of the drug product.
Real time release testing:
The ability to evaluate and ensure the quality of in-process and/or final product based on process data,
which typically include a valid combination of measured material attributes and process controls.
Appendix 1. Differing approaches to pharmaceutical
development
The following table has been developed to illustrate some potential contrasts between what might be
considered a minimal approach and an enhanced, quality by design approach regarding different
aspects of pharmaceutical development and lifecycle management. The comparisons are shown merely
to aid in the understanding of a range of potential approaches to pharmaceutical development and
should not be considered to be all-encompassing. The table is not intended to specifically define the
only approach a company could choose to follow. In the enhanced approach, establishing a design
space or using real time release testing is not necesserily expected. Current practices in the
pharmaceutical industry vary and typically lie between the two approaches presented in the table.
Aspect Minimal Approaches Enhanced, Quality by Design Approaches
Overall
Pharmaceutical
Development
Mainly empirical
Developmental research often
conducted one variable at a time
Systematic, relating mechanistic
understanding of material attributes and
process parameters to drug product CQAs
Multivariate experiments to understand
product and process
Establishment of design space
PAT tools utilised
Manufacturing
Process
Fixed
Validation primarily based on
initial full-scale batches
Focus on optimisation and
reproducibility
Adjustable within design space
Lifecycle approach to validation and, ideally,
continuous process verification
Focus on control strategy and robustness
Use of statistical process control methods
Process Controls In-process tests primarily for
go/no go decisions
Off-line analysis
PAT tools utilised with appropriate feed
forward and feedback controls
Process operations tracked and trended to
support continual improvement efforts post-
approval
Product
Specifications
Primary means of control
Based on batch data available at
Part of the overall quality control strategy
Based on desired product performance with
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Aspect Minimal Approaches Enhanced, Quality by Design Approaches
time of registration relevant supportive data
Control Strategy Drug product quality controlled
primarily by intermediates (in-
process materials) and end
product testing
Drug product quality ensured by risk-based
control strategy for well understood product
and process
Quality controls shifted upstream, with the
possibility of real-time release testing or
reduced end-product testing
Lifecycle
Management
Reactive (i.e., problem solving
and corrective action)
Preventive action
Continual improvement facilitated
Appendix 2. illustrative examples
A. Use of a risk assessment tool.
For example, a cross-functional team of experts could work together to develop an Ishikawa (fishbone)
diagram that identifies potential variables which can have an impact on the desired quality attribute.
The team could then rank the variables based on probability, severity, and detectability using failure
mode effects analysis (FMEA) or similar tools based on prior knowledge and initial experimental data.
Design of experiments or other experimental approaches could then be used to evaluate the impact of
the higher ranked variables, to gain greater understanding of the process, and to develop a proper
control strategy.
Ishikawa Diagram
Water
Content
Drying
Granulation
Raw
Materials
Compressing
Plant
Factors
Temp/RH
Precompressing
Main Compressing
Feeder Speed
Press Speed
Punch Penetration
Depth
Temp
RH
Air Flow
Shock Cycle
Drug
Substance
P.S.
Process Conditions
LOD
Diluents
P.S.
LOD
Other
Lubricant
Disintegrant
Binder
Water
Binder
Temp
Spray Rate
Spray Pattern
P.S.
Scrape Down
Chopper Speed
Mixer Speed
Endpoint
Power
Time
Age
Tooling
Operator
Training
Analytical
Method
Sampling
Feed
Frame
Tablet
Drying
Granulation
Raw
Materials
Compressing
Plant
Factors
Temp/RH
Precompressing
Main Compressing
Feeder Speed
Press Speed
Punch Penetration
Depth
Temp
RH
Air Flow
Shock Cycle
Drug
Substance
P.S.
Process Conditions
LOD
Diluents
P.S.
LOD
Other
Lubricant
Disintegrant
Binder
Water
Binder
Temp
Spray Rate
Spray Pattern
P.S.
Scrape Down
Chopper Speed
Mixer Speed
Endpoint
Power
Time
Age
Tooling
Operator
Training
Analytical
Method
Sampling
Feed
Frame
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B. Depiction of interactions
The figure below depicts the presence or absence of interactions among three process parameters on
the level of degradation product Y. The figure shows a series of two-dimensional plots showing the
effect of interactions among three process parameters (initial moisture content, temperature, mean
particle size) of the drying operation of a granulate (drug product intermediate) on degradation
product Y. The relative slopes of the lines or curves within a plot indicate if interaction is present. In
this example, initial moisture content and temperature are interacting; but initial moisture content and
mean particle size are not, nor are temperature and mean particle size.
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C. Presentations of design space
Example 1: Response graphs for dissolution are depicted as a surface plot (Figure 1a) and a contour
plot (Figure 1b). Parameters 1 and 2 are factors of a granulation operation that affect the dissolution
rate of a tablet (e.g., excipient attribute, water amount, granule size.)
Figure 1a: Response surface plot of
dissolution as a function of two parameters of
a granulation operation. Dissolution above
80% is desired.
Figure 1b: Contour plot of dissolution from
example 1a.
Figure 1c: Design space for granulation
parameters, defined by a non-linear combination
of their ranges, that delivers satisfactory
dissolution (i.e., >80%).
Figure 1d: Design space for granulation
parameters, defined by a linear combination of
their ranges, that delivers satisfactory dissolution
(i.e., >80%).
Two examples are given of potential design spaces. In Figure 1c, the design space is defined by a non-
linear combination of parameter ranges that delivers the dissolution critical quality attribute. In this
example, the design space is expressed by the response surface equation resolved at the limit for
satisfactory response (i.e.,80% dissolution). The acceptable range of one parameter is dependent on
the value of the other. For example:
If Parameter 1 has a value of 46, then Parameter 2 has a range of 0 and 1.5
If Parameter 2 has a value of 0.8, then Parameter 1 has a range of 43 and 54
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The approach in Figure 1c allows the maximum range of operation to achieve the desired dissolution
rate. In Figure 1d, the design space is defined as a smaller range, based on a linear combination of
parameters.
Parameter 1 has a range of 44 and 53
Parameter 2 has a range of 0 and 1.1
While the approach in Figure 1d is more limiting, the applicant may prefer it for operational simplicity.
This example discusses only two parameters and thus can readily be presented graphically. When
multiple parameters are involved, the design space can be presented for two parameters, in a manner
similar to the examples shown above, at different values (e.g., high, middle, low) within the range of
the third parameter, the fourth parameter, and so on. Alternatively, the design space can be explained
mathematically through equations describing relationships between parameters for successful
operation.
Example 2: Design space determined from the common region of successful operating ranges for
multiple CQAs. The relations of two CQAs, i.e., tablet friability and dissolution, to two process
parameters of a granulation operation are shown in Figures 2a and 2b. Parameters 1 and 2 are factors
of a granulation operation that affect the dissolution rate of a tablet (e.g., excipient attribute, water
amount, granule size). Figure 2c shows the overlap of these regions and the maximum ranges of the
proposed design space. The applicant can elect to use the entire region as the design space, or some
subset thereof.
Figure 2a: Contour plot of dissolution as a
function of Parameters 1 and 2.
Figure 2b: Contour plot of friability as a
function of Parameters 1 and 2.
> 80%
75-80%
70-75%
65-70%
60-65%
> 80%
75-80%
70-75%
65-70%
60-65%
4-5%
3-4%
2-3%
< 2%
4-5%
3-4%
2-3%
< 2%
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Figure 2c: Proposed design space,
comprised of the overlap region of
ranges for friability and or dissolution.
Example 3: The design space for a drying operation that is dependent upon the path of temperature
and/or pressure over time. The end point for moisture content is 1-2%. Operating above the upper
limit of the design space can cause excessive impurity formation, while operating below the lower limit
of the design space can result in excessive particle attrition.