Each section within P2 can have an impact on the other P2 sections and similarly other sections of a submission and to CGMP’s By recognizing this as a complex design system that involves multiple attributes, goals, constraints, multidisciplinary design teams (subsystems), different degrees of uncertainty, risk tolerance, etc., we wish to find opportunities to identify robust designs and design space that provides a sound basis for risk assessment and mitigation
Design is to do good not just be and look good: Bad Design is Smoke, Good Des...Ajaz Hussain
Design is to do good not just be and look good. "Design means being good, not just looking good." ~ Clement Mok. "A small change at the beginning of the design process defines an entirely different product at the end." ~ Jonathan Ive. "User-centered design means understanding what your users need, how they think, and how they behave - and incorporating that understanding into every aspect of your process." ~ Jesse James Garrett.
Compared to “one factor at a time” experiments, increased experimental efficiency, accounting interactions, multivariate predictive capability, minimization, maximization, optimization, graphical illustration for enhanced communication of complex topics.
"Design is intelligence made visible." -- Alina Wheeler
Equivalence Assessment and Maturity of Quality Management SystemsAjaz Hussain
Challenge: As a system or cohort, we can do more to adequately appreciate that “systems” proficiency is a stage in adult development that most struggle to achieve.
Repurposing in the Chaos of 2020 and Validity of Scientific EvidenceAjaz Hussain
Having been focused on manufacturing challenges for most of 2020, taking a time out to think about how best to garner "new prior knowledge" needed to facilitate development of evidence for repurposing option for the SARS-COV-2 cases and COVID-19 disease.
Sustain and Build a Quality Culture in Today's RealitiesAjaz Hussain
What is quality, what is culture? Culture, quality, and assurance are just a few of the many abstract words in our lexicon. The meaning we make evolves with our development and maturity. Our education and training are necessary but insufficient for our development and maturity. Learning from experience is essential, and experiential learning is highly variable. Some continue to develop, but at different rates; others do not. In this presentation, I share why and how a connect-the-dots framework was developed and what it offers to individuals and organizations. Building refers to a process by which a source code guides software coding programs for a stand-alone computer or an enterprise-wide system. The context of this presentation is experiential. The content is derived from experiencing the real world via an intentional journey beginning in 2015 across the globe; since 2020, this journey has been searching for the source code to what is good. In my imagination and thought experiments, the building is a process, as in the context of software development. Coding for a stand-alone computer is similar but not interchangeable or automatically substitutable for writing and executing a personal or individualized continuous professional development plan. I speak about quality culture to ease the process of continuous learning, development, and maturity in professionals and management systems. To improve feedback and encourage backpropagation of errors of omission and commission to learn how to prevent mistakes and improve continually, I remind that it is increasingly relevant today to begin asking - how might we assess suitability, capability, and comparability of humans and AI in the context of CGMP compliance and maturity of a pQMS. I implicitly use the lexicon of biosimilars, interchangeable biosimilar products, and automatic generic substitution for brand products to help us make sense of our suitability and capability to know the difference in the maturity stages we call professional and good practitioners to appreciate the differences in the regulatory and social expectation of validation and assurance broadly and specifically as in the validation of computer and pharmaceutical systems.
Sharpen your Unique Sensing Proclivity: Dissolution is a process in mind and ...Ajaz Hussain
Self-authorship bridging the Academia to Industry (A2I) Gap. The challenge in our systems asking why signifies ignorance. Perhaps until a correction is needed. But after corrective and preventive actions (CAPA) often nothing changes. Errors reoccur and we acquire an “immunity to change.”
Chemometrics, Pharmacometrics and Econometrics Dimensions_of_QualityAjaz Hussain
25 May 2012 Basel, Switzerland. A philosophical exploration - Scientific understanding and risk-based regulatory decisions on Quality by Design. How good are the scientific explanations in regulatory submissions? Scientific explanations yield understanding; quality of explanations differ.What role can Chemometrics, Pharmacometics and Econometrics play? Understanding multidisciplinary (cGMP, CMC, Clin. Pharm., Tox., Clinical, Public Health) perspectives on risk is important. Opportunities; only when the disciplinary divides are bridged. Within the regulatory realm how we set specifications and assess risk have progressed incrementally; at this rate the Vision 2020 may be expected to be visible broadly over time, by 2020?
Design is to do good not just be and look good: Bad Design is Smoke, Good Des...Ajaz Hussain
Design is to do good not just be and look good. "Design means being good, not just looking good." ~ Clement Mok. "A small change at the beginning of the design process defines an entirely different product at the end." ~ Jonathan Ive. "User-centered design means understanding what your users need, how they think, and how they behave - and incorporating that understanding into every aspect of your process." ~ Jesse James Garrett.
Compared to “one factor at a time” experiments, increased experimental efficiency, accounting interactions, multivariate predictive capability, minimization, maximization, optimization, graphical illustration for enhanced communication of complex topics.
"Design is intelligence made visible." -- Alina Wheeler
Equivalence Assessment and Maturity of Quality Management SystemsAjaz Hussain
Challenge: As a system or cohort, we can do more to adequately appreciate that “systems” proficiency is a stage in adult development that most struggle to achieve.
Repurposing in the Chaos of 2020 and Validity of Scientific EvidenceAjaz Hussain
Having been focused on manufacturing challenges for most of 2020, taking a time out to think about how best to garner "new prior knowledge" needed to facilitate development of evidence for repurposing option for the SARS-COV-2 cases and COVID-19 disease.
Sustain and Build a Quality Culture in Today's RealitiesAjaz Hussain
What is quality, what is culture? Culture, quality, and assurance are just a few of the many abstract words in our lexicon. The meaning we make evolves with our development and maturity. Our education and training are necessary but insufficient for our development and maturity. Learning from experience is essential, and experiential learning is highly variable. Some continue to develop, but at different rates; others do not. In this presentation, I share why and how a connect-the-dots framework was developed and what it offers to individuals and organizations. Building refers to a process by which a source code guides software coding programs for a stand-alone computer or an enterprise-wide system. The context of this presentation is experiential. The content is derived from experiencing the real world via an intentional journey beginning in 2015 across the globe; since 2020, this journey has been searching for the source code to what is good. In my imagination and thought experiments, the building is a process, as in the context of software development. Coding for a stand-alone computer is similar but not interchangeable or automatically substitutable for writing and executing a personal or individualized continuous professional development plan. I speak about quality culture to ease the process of continuous learning, development, and maturity in professionals and management systems. To improve feedback and encourage backpropagation of errors of omission and commission to learn how to prevent mistakes and improve continually, I remind that it is increasingly relevant today to begin asking - how might we assess suitability, capability, and comparability of humans and AI in the context of CGMP compliance and maturity of a pQMS. I implicitly use the lexicon of biosimilars, interchangeable biosimilar products, and automatic generic substitution for brand products to help us make sense of our suitability and capability to know the difference in the maturity stages we call professional and good practitioners to appreciate the differences in the regulatory and social expectation of validation and assurance broadly and specifically as in the validation of computer and pharmaceutical systems.
Sharpen your Unique Sensing Proclivity: Dissolution is a process in mind and ...Ajaz Hussain
Self-authorship bridging the Academia to Industry (A2I) Gap. The challenge in our systems asking why signifies ignorance. Perhaps until a correction is needed. But after corrective and preventive actions (CAPA) often nothing changes. Errors reoccur and we acquire an “immunity to change.”
Chemometrics, Pharmacometrics and Econometrics Dimensions_of_QualityAjaz Hussain
25 May 2012 Basel, Switzerland. A philosophical exploration - Scientific understanding and risk-based regulatory decisions on Quality by Design. How good are the scientific explanations in regulatory submissions? Scientific explanations yield understanding; quality of explanations differ.What role can Chemometrics, Pharmacometics and Econometrics play? Understanding multidisciplinary (cGMP, CMC, Clin. Pharm., Tox., Clinical, Public Health) perspectives on risk is important. Opportunities; only when the disciplinary divides are bridged. Within the regulatory realm how we set specifications and assess risk have progressed incrementally; at this rate the Vision 2020 may be expected to be visible broadly over time, by 2020?
Visioning the Next Decade: NIPTE-FDA CollaborationAjaz Hussain
NIPTE Seminar at US FDA, 16 March 2016.
QBR as an Organizing Principle for the Proposed NIPTE Center of Excellence for Pharmaceutical Formulations (CEPF)
On FDA’s Guidance on Pharmaceutical Process Validation (2011)lAjaz Hussain
Connectors between Culture – Metrics – Continued Process Verification in Process Validation?
Confidence is a critical quality attribute. CGMP violations erode confidence and increase nocebo effects. Currently – “breaches in assurance of data integrity” is a global concern. Have exposed the prevailing ‘regulator heterogeneity’. Re-building ‘epistemic trust” is difficult generally; more so with US FDA. Some thoughts on how to ....
Behavioral Economics and Managment of Pharmaceutical QbD 25 August 2016Ajaz Hussain
Pharmaceutical knowledge pyramid can be toppled easily!
Serendipitous intersection of Behavioral Economics & CGMP.
Why attention to Behavioral Economics can improve management of QbD work-streams?
How? What (benefits)?
Between regulatory query and response there is Design Space. In that space is our comparability protocol…
Question Based Development to Quality by Design to Continued Process Verification
Does your QbD program delivery confidence in CQA’s?
Does it reduce the risk of development failure?
Does it provide a process which is stable and ‘in control’?
Does it reduce risk of GMP noncompliance?
Are we asking the right question and at the right time?
Totality of Evidence & Theraputic Equivalence 15 October 2016Ajaz Hussain
Put R back in R&D & recognize It is a “complex” product and process!
Invest smartly in analytics, mathematics & statistics, and large sample sizes; and in systems/integrative thinking and data integration
Get to know the RLD – multiple lots; open the door with large sample size
Build capability to justify measured RLD variability is relevant to development of the proposed generic/biosimilar
Exquisite regulatory communication strategy
This is not a ‘complicated process’ for which typical “good practices” will work seamlessly (e.g., typical project management approach); this is a complex process – with multiple interactions and “emergent properties”
Treat it as it is - a complex process and plan; anticipate and address “emergent issues” - in technical, regulatory and legal dimensions; at a certain point be prepared for stakeholder (payers, patient groups,..) communications
We are defining the problem too narrowly. Our paradigm of pharmaceutical quality sifted long-ago. We have harmonized on a regulatory methodology for QbD (e.g., ICH Q8). However, with the prevailing ontological gaps (for example as illustrated in the continuing challenges posed with the current FDA’s Inactive Ingredient Database) - How good are the scientific explanations in regulatory submissions? Is quality risk-assessment - metaphysical or an epistemological category?
Pharmaceutical quality decisions are made by multidisciplinary teams (a range of maturity), at different times and in various organizations; understanding of the QbD paradigm and methodology is derived experientially -One Quality Voice is hard to achieve!
Legacy challenges, various ontological assumptions, and weak epistemology curtails knowledge sharing, delays consensus and keeps us trapped in a reactive mode (3rd Order)
The risk of irrational decision making needs to be accounted. ”Cut-paste” or “check-the-box” practices are reminders that we are not achieving an optimal integration or practicing systems thinking.
A reactive approach (3rd Order) to filling the noted gaps poses risk of continued erosion in the confidence the public should have in our assurance of pharmaceutical quality
We need a thoughtful, planned approach to filling these gaps –NIPTE should take on this challenge! Will it?
CHIR Best Brains Exchange 22 January 2016Ajaz Hussain
Quality of drugs manufactured in emerging economies: Are cost containment strategies heightening the likelihood of substandard drugs in Canada?
What regulatory, policy, and/ or governance changes are needed to address new and increased risks?
How can Canada prevent and reduce health risks that emerge when the pharmaceutical industry adopts globalized production strategies?
Part 1: FDA Trends
Background: The little secret – swept under the rug? No more!
Challenge or opportunity: Unprecedented juxtaposition – at the Tipping Point!
Questions: What consideration are needed for building your validation roadmap? Three options: Pathfinder, Standard or Emergency; what will you choose?
Part II: A higher level of confidence in quality assurance : State of Control (stability, capability with statistical confidence)
Case example: Challenges of implementing a roadmap to process capability for some currently commercialized products.
IGPA Building a Culture of Quality Ajaz Hussain_5 Sept 2015_Rferences minAjaz Hussain
Improving Confidence in Quality of Medicines . We make two products – medicine and evidence (documents) but many forget this and do not pay attention to documentation.
Level of attention to documentation is a “canary in a coal mine”
Breaches are irrational –”System 1 thinking” and cognitive biases.
Culture of Quality is familiar to all of us – a framework proposed
Quality Metrics – great idea – very much needed; but we are not yet ready for an FDA Guidance.
We must first address our collective blind spots; be confident that process validation truly ensures complexity is sufficiently reduced and that outcomes are predictable.
We are on a journey to make quality medicines affordable to all. In the 21st Century, this journey will be successful to the extent we recognize that quality has to be built-in by design and that it cannot be tested into products, utilize and improve a global Quality Management System (QMS), and implement science based risk assessment in our decision making. Pharmacopoeias are an integral part of this global QMS and have been setting public or market standards for medical products for many centuries. In the 21st Century, Pharmacopoeias can and should be a champion for the practice of quality by design. To do so most effectively it would be useful to recognize how, in the 21st Century, human factors help and hinder optimal development, and correct interpretation, of public or market standards in design, development, control and manufacturing decisions. To explore this aspect in this presentation, cognitive biases – blind spots or alleys – are collected and organized on topics relevant to this workshop: (a) Impurities & Contaminants, (b) Analytical Method Validation, and (c) Public/market standards and Release Testing. How to confront these biases will be discussed. Steps to help in maximally leveraging the Pharmacopoeias on the 21st Century journey will be highlighted.
Good Regulators of Pharmaceuticals (GRP) 22 October 2014Ajaz Hussain
Sharing thoughts on what makes a Good Regulator of Pharmaceuticals with pharmacy students at the Universities of Minnesota and Iowa. A point of emphasis on "we all are regulators" is explained and three areas for learning - (a) Systems and Integrative Thinking, (b) Argumentation and (c) Behavioral Economics described.
I hope you, the viewers, will also find some value in reviewing these slides. If you are a student and have some questions please feel free to drop me a email (a2zpharmsci@msn.com).
Emergency: “No-pain No-gain”
Standard: “Plan Do Check & Act”
Pathfinders: B1: “Don’t Use & Don’t Tell”; no more!
B2: Every vertex can be a Tipping Point
G1: Same and Similar
G2: Synthesis & Analysis
The IFPAC Session: Controlling excipient impact during the product lifecycle.
Excipients enable the delivery of actives as a pharmaceutical product. Quality by Design requires that the impact of excipient variability on finished product quality be minimized, or, as paraphrased by Tobyn: - What matters doesn’t vary, and what varies doesn’t matter.
This parallels the current practice of categorizing excipients into critical vs non-critical, the assumption being that the latter do not impact the finished product Critical Quality Attributes. This binary classification of criticality has been criticized as too simple and it is not uncommon to observe excursions in finished product quality correlating with variability of a so-called non-critical excipient. The complexity of the excipients, and the products into which they are formulated, contributes to this uncertainty. For excipients, what varies may not have mattered prior to approval, but may come to matter later in the product lifecycle, especially for continuously manufactured products with real time release.
Excipients, even if fully compliant and manufactured under GMP, represent a reservoir of special cause variability in finished product quality. By definition this can only be addressed via the Control Strategy. Risk management requires continuous multivariate monitoring of finished product and raw materials to maintain quality and model fidelity.
Regulatory Aspects of Continuous Pharmaceutical ManufacturingAjaz Hussain
Digital Pharma Manufacturing RoundtableKronberg, Germany, March 17 2017
A story about manufacturing two products, medicinal product and documented data, and a “little secret”
Strengthening the National System for Excipient Risk Mitigation Ajaz Hussain
Today the assurance of continual supply, authenticity, quality, and functionality of pharmaceutical materials active and so-called "inactive" excipients is at risk that needs to be mitigated. This presentation seeks to bring attention to the prevalent "inactive" mindset that is so difficult to change. At the precipice, we do change. Are we there yet?
QbD and CoQ IDMA Mumbai 24 March 2015 slideshareAjaz Hussain
IDMA – UL SUMMIT 24 March 2015, Mumbai
"Evolving Quality Culture in Indian Pharmaceutical Industry“: Strengthening Our Culture of Quality
Organizational Culture, Good or Bad?
Dr Venkateswarlu Memorial Lecture 2015Ajaz Hussain
Purpose of this talk is to request you to consider the following 4 Steps
1. Strengthening the ‘Culture of Quality’ – the focus of this talk
2. Improve efficiency with confidence in controls by integrating India’s engineering and statistical know-how and technologies
3. Working together – ‘One Quality for All’ to say proudly – Made in India: Pharmaceutical Factory to the World
4. Leverage India’s Wisdom Traditions to provide leadership in setting the standards for Integrative Medicine so as to deliver a model of ‘Health Care for All’: Pharmacy to the World.
Visioning the Next Decade: NIPTE-FDA CollaborationAjaz Hussain
NIPTE Seminar at US FDA, 16 March 2016.
QBR as an Organizing Principle for the Proposed NIPTE Center of Excellence for Pharmaceutical Formulations (CEPF)
On FDA’s Guidance on Pharmaceutical Process Validation (2011)lAjaz Hussain
Connectors between Culture – Metrics – Continued Process Verification in Process Validation?
Confidence is a critical quality attribute. CGMP violations erode confidence and increase nocebo effects. Currently – “breaches in assurance of data integrity” is a global concern. Have exposed the prevailing ‘regulator heterogeneity’. Re-building ‘epistemic trust” is difficult generally; more so with US FDA. Some thoughts on how to ....
Behavioral Economics and Managment of Pharmaceutical QbD 25 August 2016Ajaz Hussain
Pharmaceutical knowledge pyramid can be toppled easily!
Serendipitous intersection of Behavioral Economics & CGMP.
Why attention to Behavioral Economics can improve management of QbD work-streams?
How? What (benefits)?
Between regulatory query and response there is Design Space. In that space is our comparability protocol…
Question Based Development to Quality by Design to Continued Process Verification
Does your QbD program delivery confidence in CQA’s?
Does it reduce the risk of development failure?
Does it provide a process which is stable and ‘in control’?
Does it reduce risk of GMP noncompliance?
Are we asking the right question and at the right time?
Totality of Evidence & Theraputic Equivalence 15 October 2016Ajaz Hussain
Put R back in R&D & recognize It is a “complex” product and process!
Invest smartly in analytics, mathematics & statistics, and large sample sizes; and in systems/integrative thinking and data integration
Get to know the RLD – multiple lots; open the door with large sample size
Build capability to justify measured RLD variability is relevant to development of the proposed generic/biosimilar
Exquisite regulatory communication strategy
This is not a ‘complicated process’ for which typical “good practices” will work seamlessly (e.g., typical project management approach); this is a complex process – with multiple interactions and “emergent properties”
Treat it as it is - a complex process and plan; anticipate and address “emergent issues” - in technical, regulatory and legal dimensions; at a certain point be prepared for stakeholder (payers, patient groups,..) communications
We are defining the problem too narrowly. Our paradigm of pharmaceutical quality sifted long-ago. We have harmonized on a regulatory methodology for QbD (e.g., ICH Q8). However, with the prevailing ontological gaps (for example as illustrated in the continuing challenges posed with the current FDA’s Inactive Ingredient Database) - How good are the scientific explanations in regulatory submissions? Is quality risk-assessment - metaphysical or an epistemological category?
Pharmaceutical quality decisions are made by multidisciplinary teams (a range of maturity), at different times and in various organizations; understanding of the QbD paradigm and methodology is derived experientially -One Quality Voice is hard to achieve!
Legacy challenges, various ontological assumptions, and weak epistemology curtails knowledge sharing, delays consensus and keeps us trapped in a reactive mode (3rd Order)
The risk of irrational decision making needs to be accounted. ”Cut-paste” or “check-the-box” practices are reminders that we are not achieving an optimal integration or practicing systems thinking.
A reactive approach (3rd Order) to filling the noted gaps poses risk of continued erosion in the confidence the public should have in our assurance of pharmaceutical quality
We need a thoughtful, planned approach to filling these gaps –NIPTE should take on this challenge! Will it?
CHIR Best Brains Exchange 22 January 2016Ajaz Hussain
Quality of drugs manufactured in emerging economies: Are cost containment strategies heightening the likelihood of substandard drugs in Canada?
What regulatory, policy, and/ or governance changes are needed to address new and increased risks?
How can Canada prevent and reduce health risks that emerge when the pharmaceutical industry adopts globalized production strategies?
Part 1: FDA Trends
Background: The little secret – swept under the rug? No more!
Challenge or opportunity: Unprecedented juxtaposition – at the Tipping Point!
Questions: What consideration are needed for building your validation roadmap? Three options: Pathfinder, Standard or Emergency; what will you choose?
Part II: A higher level of confidence in quality assurance : State of Control (stability, capability with statistical confidence)
Case example: Challenges of implementing a roadmap to process capability for some currently commercialized products.
IGPA Building a Culture of Quality Ajaz Hussain_5 Sept 2015_Rferences minAjaz Hussain
Improving Confidence in Quality of Medicines . We make two products – medicine and evidence (documents) but many forget this and do not pay attention to documentation.
Level of attention to documentation is a “canary in a coal mine”
Breaches are irrational –”System 1 thinking” and cognitive biases.
Culture of Quality is familiar to all of us – a framework proposed
Quality Metrics – great idea – very much needed; but we are not yet ready for an FDA Guidance.
We must first address our collective blind spots; be confident that process validation truly ensures complexity is sufficiently reduced and that outcomes are predictable.
We are on a journey to make quality medicines affordable to all. In the 21st Century, this journey will be successful to the extent we recognize that quality has to be built-in by design and that it cannot be tested into products, utilize and improve a global Quality Management System (QMS), and implement science based risk assessment in our decision making. Pharmacopoeias are an integral part of this global QMS and have been setting public or market standards for medical products for many centuries. In the 21st Century, Pharmacopoeias can and should be a champion for the practice of quality by design. To do so most effectively it would be useful to recognize how, in the 21st Century, human factors help and hinder optimal development, and correct interpretation, of public or market standards in design, development, control and manufacturing decisions. To explore this aspect in this presentation, cognitive biases – blind spots or alleys – are collected and organized on topics relevant to this workshop: (a) Impurities & Contaminants, (b) Analytical Method Validation, and (c) Public/market standards and Release Testing. How to confront these biases will be discussed. Steps to help in maximally leveraging the Pharmacopoeias on the 21st Century journey will be highlighted.
Good Regulators of Pharmaceuticals (GRP) 22 October 2014Ajaz Hussain
Sharing thoughts on what makes a Good Regulator of Pharmaceuticals with pharmacy students at the Universities of Minnesota and Iowa. A point of emphasis on "we all are regulators" is explained and three areas for learning - (a) Systems and Integrative Thinking, (b) Argumentation and (c) Behavioral Economics described.
I hope you, the viewers, will also find some value in reviewing these slides. If you are a student and have some questions please feel free to drop me a email (a2zpharmsci@msn.com).
Emergency: “No-pain No-gain”
Standard: “Plan Do Check & Act”
Pathfinders: B1: “Don’t Use & Don’t Tell”; no more!
B2: Every vertex can be a Tipping Point
G1: Same and Similar
G2: Synthesis & Analysis
The IFPAC Session: Controlling excipient impact during the product lifecycle.
Excipients enable the delivery of actives as a pharmaceutical product. Quality by Design requires that the impact of excipient variability on finished product quality be minimized, or, as paraphrased by Tobyn: - What matters doesn’t vary, and what varies doesn’t matter.
This parallels the current practice of categorizing excipients into critical vs non-critical, the assumption being that the latter do not impact the finished product Critical Quality Attributes. This binary classification of criticality has been criticized as too simple and it is not uncommon to observe excursions in finished product quality correlating with variability of a so-called non-critical excipient. The complexity of the excipients, and the products into which they are formulated, contributes to this uncertainty. For excipients, what varies may not have mattered prior to approval, but may come to matter later in the product lifecycle, especially for continuously manufactured products with real time release.
Excipients, even if fully compliant and manufactured under GMP, represent a reservoir of special cause variability in finished product quality. By definition this can only be addressed via the Control Strategy. Risk management requires continuous multivariate monitoring of finished product and raw materials to maintain quality and model fidelity.
Regulatory Aspects of Continuous Pharmaceutical ManufacturingAjaz Hussain
Digital Pharma Manufacturing RoundtableKronberg, Germany, March 17 2017
A story about manufacturing two products, medicinal product and documented data, and a “little secret”
Strengthening the National System for Excipient Risk Mitigation Ajaz Hussain
Today the assurance of continual supply, authenticity, quality, and functionality of pharmaceutical materials active and so-called "inactive" excipients is at risk that needs to be mitigated. This presentation seeks to bring attention to the prevalent "inactive" mindset that is so difficult to change. At the precipice, we do change. Are we there yet?
QbD and CoQ IDMA Mumbai 24 March 2015 slideshareAjaz Hussain
IDMA – UL SUMMIT 24 March 2015, Mumbai
"Evolving Quality Culture in Indian Pharmaceutical Industry“: Strengthening Our Culture of Quality
Organizational Culture, Good or Bad?
Dr Venkateswarlu Memorial Lecture 2015Ajaz Hussain
Purpose of this talk is to request you to consider the following 4 Steps
1. Strengthening the ‘Culture of Quality’ – the focus of this talk
2. Improve efficiency with confidence in controls by integrating India’s engineering and statistical know-how and technologies
3. Working together – ‘One Quality for All’ to say proudly – Made in India: Pharmaceutical Factory to the World
4. Leverage India’s Wisdom Traditions to provide leadership in setting the standards for Integrative Medicine so as to deliver a model of ‘Health Care for All’: Pharmacy to the World.
ICH Guidelines Effective for Regulating Quality of Medicines?Ajaz Hussain
ICH Guidelines: Effective tools for regulating the quality of medicines? Enabling regulatory considerations – the ICH Q8 – 12 are such considerations. Effective implementation of enabling regulatory considerations is a challenge. The challenge is what we know and what we can implement are two different things. Education, training, and experience linked to measures of professional development, as it relates to PQS, should bridge what we know and what we implement. What are such measures? Some corporations are already focused on making their PQS effective (e.g., Amgen) but most are not. In a global supply chain (with ~ 90% of Rx being generics) this can pose a major challenge to deliver assurance patients need. Why? #education #medicine #assurance #regulations #globalization #corporations #bridging #measurements
Protocol Design & Development: What You Need to Know to Ensure a Successful S...Brook White, PMP
Solid protocol design is critical to clinical development. No matter how well executed a clinical study is, if the underlying design is flawed, it wasn’t worth doing. In this presentation, Dr. David Shoemaker, SVP R&D, and Dr. Karen Kesler, AVP Operations, will walk through the process of developing a protocol, explain the major considerations, and point out common mistakes and challenges.
Drug Development Life Cycle - Costs and RevenueRobert Sturm
Presentation explains the Drug Development Process in terms of time/costs from initial research to final manufacturing. It presents strategies for increasing profits/decreasing costs, shows the impact of generics and details how Information Technology fits into this equation. It uses research from DiMasi and Grabowski to identify drug costs and product revenue.
How and When to Kill a Program in New Product PlanningAnthony Russell
Presented at the 4th New Product Planning Summit in Boston (Dec 2 -3 , 2019). Presentation covers why weak programs should be cut from pharmaceutical and biotech pipelines, what defines a "weak" program, and describes objective methods to evaluate programs to help prioritize assets.
Pharmaceutical Quality by Design (QBD) is a concept introduced by the International Conference on Harmonization (ICH) Q8 guideline, as a systematic approach to development that begins with predetermined objectives and emphasizes the understanding of production and processes and process control, based on sound science and quality risk management.
The basic concept of QBD is “The Quality cannot be tested into the product, but it should be built into it.”
Get Your Development Program Started on the Right FootBrook White, PMP
You think you have a potential pharmaceutical or biotechnology product based on animal or in vitro data—what is the next step? Two documents you need at an early stage are the Target Product Profile (TPP) which defines expectations for your potential medicine and an Integrated Product Development Plan (IPDP) which describes the activities required through approval of your marketing application.
Pharmaceutical Quality - The Office ofAjaz Hussain
The keynote address at the Fall meeting of the CPPR Industrial Advisory Board and the Site Directors held yesterday (27 October 2014) at Purdue University. The talk provides a perspective on the recent organizational changes announced by FDA CDER - the Office of Pharmaceutical Quality.
The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) is unique in bringing together the regulatory authorities and pharmaceutical industry to discuss scientific and technical aspects of drug registration. Since its inception in 1990, ICH has gradually evolved, to respond to the increasingly global face of drug development. ICH’s mission is to achieve greater harmonisation worldwide to ensure that safe, effective, and high quality medicines are developed and registered in the most resource-efficient manner. On 23 October 2015, ICH announced organisational changes as it marks 25 years of successful harmonisation.
Root cause Analysis (RCA) & Corrective and Preventive action (CAPA) in MRCT d...Bhaswat Chakraborty
This presentation describes Identification & differentiation of Protocol deviation & violation; Different methods of RCA & best suitable method for Multiregional Clinical Trial; CAPA management and CAPA application to other trial sites/CRO/SMO/ Country that is involved in same trial (Strategic Management and application of CAPA in MRCT)
A Leapfrog Need and Opportunity for mAbsAjaz Hussain
Leapfrogging on reforming mAbs policies makes sense, and doing so can be a principled duty of care.
SMART Technology, SMART Professionals, SMART Services, SMART Organization.
SMART Quality by Design Applications Not Submissions in 2024Ajaz Hussain
Many generic pharma companies seeking regulatory approval uncritically follow “past” practices and prior knowledge. Few, if any, correct errors and innovate to improve past expertise and techniques. The idea of SMART "QbD in ANDApplications" (not “submission”) builds on this observation.
Intuitively Moving Institutions Towards Global Regulatory Resilience Ajaz Hussain
From my experience, how can I describe an intuitive and self-organizing social force around "attractors" patients' value to be assured of therapeutic equivalence?
Critical Importance of Pharmaceutical Traceability in the Experience.pdfAjaz Hussain
From a narrow viewpoint, serialization is just a process of printing an identifying number on products and shipping cases.
From a long-term view, the integration of serialization numbering systems with the production line as well as the quality control procedures required to maintain the integrity of the numbers.
Validation 4 for Credible Pharma 4 a Keynote for Valconnect 2023.pdfAjaz Hussain
The notion of Validation 4.0 in the title of this keynote relates to the development and maturity of people and professionals, which I will elaborate on in the context of the ValGenesis experiences [of its users and service providers].
Validation 4.0 in this talk is about internal assurance, self-assurance, and self-authoring policies, plans, and procedures, ideally without the need [to wait] for FDA guidance.
SMART Triaxial Compaction, Social Form 483 and VAI or OAI to an Avenger.pdfAjaz Hussain
Why did the company not design and formulate a tablet that did not “cap”? Why wouldn’t NIH fund my proposal for CAFD? Why did the FDA [discount] Pharmaceutical Development Reports, while in the EU and Japan, is it an essential part of the regulatory review?
Under a hypothetical social inspection scheme, a report submitted in 2010 is imagined as PM 483 in the spirit of FDA Form 483 of “Inspectional Observations.”
What do the noted observations suggest about my professional maturity or state of mind at that event in 2010? What would be an appropriate “feedback” response?
Statistical Thinking and Pharmaceutical Professional Development, a keynote b...Ajaz Hussain
In adulthood, to keep maturing, one must acknowledge the elephant in the room – the emotions we feel. To feel is to experience. Experience complements our scientific training. But do we pay attention to the Integrity of our experience? A tonic for wiser statistical thinking to inform the development of pharmaceuticals and professionals.
An Updating Perspective on BAD I in March Madness 2023.pdfAjaz Hussain
Why does it take decades to acknowledge the obvious? Something to ponder and write about. How do you suggest we keep moving closer to the truth? Can we simultaneously personalize our minds, machines, and medicines to develop continuously? How? I am sharing a slide deck of thoughts to discuss meaning-making and the Federal Food, Drug, and Cosmetic Act (FD&C Act) in the context of the post-truth world, which I collected to populate two invited lectures at the University of Minnesota, College of Pharmacy. The slides I am uploading here are in reverse order, 2nd lecture followed by the first. It is, to begin with, a journey to 2020+ to note that the root cause of BAD-I is I and to pose a challenging premise that beyond the age of majority, few adults continue to develop and mature. What evidence warrants this premise, and why? Then how to develop and mature continuously as an adult and a professional.
Mature Managers and Management of Pharmaceutical Quality and QuantitiesAjaz Hussain
We live in a post-truth world, and we like to think we are good. Are we? Do we not need ALCOA for the integrity of our experience?
Remember: Experience means to feel; how you feel determines what you learn! Honoring my grandmother’s advice, keeping intentions clean, इरादों को साफ रखें to begin to recognize a pattern of interactions between how I feel, what I think to explain why I behaved in a certain way.
Some of my thoughts on SMART Objective negotiations and to be better at SMART Experiencing than SMART Machines. The content describes insights from observing the immaturity of political, regulating, and management systems. Why does “immature” claim “I am mature” when it shouldn't?
I-SMART Internal Validation for Continuous Professional Development.pdfAjaz Hussain
i-SMART: Internal validation [is] continuous [professional development]. It is a journey within and without. In the growing chaos, it is urgent and essential that we must be the change we seek in the world. Be I-SMART! #Validaiton #good
S.M.A.R.T Pharmaceuticals 2021 -2030: AI or Human?Ajaz Hussain
Take a smart “development stance” to prepare for 2022 and beyond, envision your journey to 2030. Spiral high and wide like a migratory bird. Recall, Reflect, Research, Remember, Reset and Rebuild: Recycling necessary but not sufficient.
https://www.linkedin.com/pulse/recall-reflect-research-remember-reset-rebuild-ajaz-hussain-ph-d-/?trackingId=aF5BbJF0T5%2B036rQ7Zw3gA%3D%3D
Managing Pharmaceutical Quality in Traditional Paradigm and in the Emerging “...Ajaz Hussain
The epistemic crisis has deepened; multiple systems are now chaotic, fear and anxiety unabated and as expected the dominant response to the crisis is procrustean. Scenarios to consider managing pharmaceutical quality design space in traditional paradigm and in the emerging “SMARTness”?
Pharmaceutical Quality in the 21st Century, Current Status of PAT & QbDAjaz Hussain
What we know is not what we implement in practice is the shadow in our development—walking a tight rope across the precipice with an elephant on my back. Is an Elephant on My Back the apt metaphor to replace the Six Blind Men and an Elephant and an Elephant in the Dark?
Meaning making measurement maturity and management mokshaAjaz Hussain
Power without wisdom is a recipe for disaster. “Your problem is not technology. The problem is you. You lack the will to change” (The Day the Earth Stood Still (2008). “I think we need to do some very serious soul searching,” Woodcock (2020). Adequate, well-controlled, qualified by training and experience, fairly, responsibly (FD&C Act). “Only at the precipice do we evolve.” Is this our moment? Profiteers learn to be patient. Exploitation & Exploration: Bottom and Toplines, the ambidextrous. Quality is integral; warrant connects quantitative evidence with claims. Cease dependence on inspection via maturity of self, systems, & societies. You can find the way forward [to maturity] in the heart. Sense within to awaken. Dil Se! By heart.
Professionals and human experience: Ex[CI]perience Lessons in Excipients Ajaz Hussain
Alone together, civil war, same difference, unbiased opinion, and the "hindsight is always 20/20" feels oxymoronic. What space will excipients occupy in our consciousness in the next decade?
Industrial Policy and NIPTE: Goodbye NIPTE Ajaz Hussain
1. Grab a chair when the music stops
2. Formulate Pharmaceutical Science Evidence in the Real-World
3. Personalize consequence of the systemic, harmful, societal underappreciation of pharmaceutics, industrial pharmacy, and pharmaceutical engineering
4. I am off to find a jungle to write my first novel
Uncertainty Management: Chaos to Continual ImprovementAjaz Hussain
In its 19th century origin, the current US pharmaceutical regulatory system underestimates the inherent complexity in making pharmaceutical products. Recurring errors, shortages, and warning letters serve as a “red flag,” reminding us that some assumptions we hold as “truths to be self-evident” are not. From an oxymoron to a discipline, pharmaceutical regulatory science is unfolding a fascinating journey from chaos to continual improvement.
How to Prepare for the New World of Pharmaceutical Development and Manufactu...Ajaz Hussain
An unprecedented level of uncertainty, erosion of trust, and the increasing likelihood of multiple systems crumbling – CAHOS!
Information is not knowledge, and information not processed carefully is infectious and, perhaps, poses a higher risk than COVID-19.
Self is "being-whole" (mind and body, conscious and unconscious, to know and to believe), and self-authoring is a measure and a stage of development.
Pharma professionals have a duty of care to assure others; they do so when they are self-assured. This webinar is to continue building a "community of knowledge."
Knowledge, Risk and Satisfaction Management 21 Century Pharmaceuticals, Octo...Ajaz Hussain
Chaos is not “disorder,” and in drawing this distinction, I posit chaos to continual improvement is a path forward, which the pharmaceutical sector should consider. How is this path different, and what steps would we need to take, for example, to leave behind unpredictability and move towards predictability.
Strategies for Effective Upskilling is a presentation by Chinwendu Peace in a Your Skill Boost Masterclass organisation by the Excellence Foundation for South Sudan on 08th and 09th June 2024 from 1 PM to 3 PM on each day.
June 3, 2024 Anti-Semitism Letter Sent to MIT President Kornbluth and MIT Cor...Levi Shapiro
Letter from the Congress of the United States regarding Anti-Semitism sent June 3rd to MIT President Sally Kornbluth, MIT Corp Chair, Mark Gorenberg
Dear Dr. Kornbluth and Mr. Gorenberg,
The US House of Representatives is deeply concerned by ongoing and pervasive acts of antisemitic
harassment and intimidation at the Massachusetts Institute of Technology (MIT). Failing to act decisively to ensure a safe learning environment for all students would be a grave dereliction of your responsibilities as President of MIT and Chair of the MIT Corporation.
This Congress will not stand idly by and allow an environment hostile to Jewish students to persist. The House believes that your institution is in violation of Title VI of the Civil Rights Act, and the inability or
unwillingness to rectify this violation through action requires accountability.
Postsecondary education is a unique opportunity for students to learn and have their ideas and beliefs challenged. However, universities receiving hundreds of millions of federal funds annually have denied
students that opportunity and have been hijacked to become venues for the promotion of terrorism, antisemitic harassment and intimidation, unlawful encampments, and in some cases, assaults and riots.
The House of Representatives will not countenance the use of federal funds to indoctrinate students into hateful, antisemitic, anti-American supporters of terrorism. Investigations into campus antisemitism by the Committee on Education and the Workforce and the Committee on Ways and Means have been expanded into a Congress-wide probe across all relevant jurisdictions to address this national crisis. The undersigned Committees will conduct oversight into the use of federal funds at MIT and its learning environment under authorities granted to each Committee.
• The Committee on Education and the Workforce has been investigating your institution since December 7, 2023. The Committee has broad jurisdiction over postsecondary education, including its compliance with Title VI of the Civil Rights Act, campus safety concerns over disruptions to the learning environment, and the awarding of federal student aid under the Higher Education Act.
• The Committee on Oversight and Accountability is investigating the sources of funding and other support flowing to groups espousing pro-Hamas propaganda and engaged in antisemitic harassment and intimidation of students. The Committee on Oversight and Accountability is the principal oversight committee of the US House of Representatives and has broad authority to investigate “any matter” at “any time” under House Rule X.
• The Committee on Ways and Means has been investigating several universities since November 15, 2023, when the Committee held a hearing entitled From Ivory Towers to Dark Corners: Investigating the Nexus Between Antisemitism, Tax-Exempt Universities, and Terror Financing. The Committee followed the hearing with letters to those institutions on January 10, 202
How to Add Chatter in the odoo 17 ERP ModuleCeline George
In Odoo, the chatter is like a chat tool that helps you work together on records. You can leave notes and track things, making it easier to talk with your team and partners. Inside chatter, all communication history, activity, and changes will be displayed.
A review of the growth of the Israel Genealogy Research Association Database Collection for the last 12 months. Our collection is now passed the 3 million mark and still growing. See which archives have contributed the most. See the different types of records we have, and which years have had records added. You can also see what we have for the future.
Normal Labour/ Stages of Labour/ Mechanism of LabourWasim Ak
Normal labor is also termed spontaneous labor, defined as the natural physiological process through which the fetus, placenta, and membranes are expelled from the uterus through the birth canal at term (37 to 42 weeks
Delivering Micro-Credentials in Technical and Vocational Education and TrainingAG2 Design
Explore how micro-credentials are transforming Technical and Vocational Education and Training (TVET) with this comprehensive slide deck. Discover what micro-credentials are, their importance in TVET, the advantages they offer, and the insights from industry experts. Additionally, learn about the top software applications available for creating and managing micro-credentials. This presentation also includes valuable resources and a discussion on the future of these specialised certifications.
For more detailed information on delivering micro-credentials in TVET, visit this https://tvettrainer.com/delivering-micro-credentials-in-tvet/
How to Build a Module in Odoo 17 Using the Scaffold MethodCeline George
Odoo provides an option for creating a module by using a single line command. By using this command the user can make a whole structure of a module. It is very easy for a beginner to make a module. There is no need to make each file manually. This slide will show how to create a module using the scaffold method.
Biological screening of herbal drugs: Introduction and Need for
Phyto-Pharmacological Screening, New Strategies for evaluating
Natural Products, In vitro evaluation techniques for Antioxidants, Antimicrobial and Anticancer drugs. In vivo evaluation techniques
for Anti-inflammatory, Antiulcer, Anticancer, Wound healing, Antidiabetic, Hepatoprotective, Cardio protective, Diuretics and
Antifertility, Toxicity studies as per OECD guidelines
A workshop hosted by the South African Journal of Science aimed at postgraduate students and early career researchers with little or no experience in writing and publishing journal articles.
South African Journal of Science: Writing with integrity workshop (2024)
Critical Path Initiative Challenges: FDA ACPS Meeting 19 October 2004
1. Critical Path Initiative:
Challenges and
Opportunities
Ajaz S. Hussain, Ph.D.
Deputy Director, Office of Pharmaceutical
Science, CDER, FDA
19 October 2004 ACPS Meeting
3. What is Critical Path?
A serious attempt to examine and
improve the techniques and
methods used to evaluate the
safety, efficacy and quality of
medical products as they move from
product selection and design to
mass manufacture.
State of CDER 2004; Steven Galson & Doug Throckmorton October 6, 2004
5. Critical Path Document
(March 2004)
The drug development process – the
“critical path,” is becoming a serious
bottleneck to delivery of new
medical products
State of CDER 2004; Steven Galson & Doug Throckmorton October 6, 2004
7. NMEs Filed by Fiscal Year
0
10
20
30
40
50
1983
1984
1985
1986
1987
1988
1989
1990
1991
1992
1993
1994
1995
1996
1997
1998
1999
2000
2001
2002
2003
NumberFiled
Priority Standard
* for NMEs submitted prior to 1992, type A and type B applications are counted as Priority review and type C
applications are counted as Standard review.
But, New Product Submissions
Have Remained Flat
8. Why FDA Concern?
FDA Statutory Mission -- Not only to
protect but also to advance public
health by improving availability of
safe and effective new medical
products
State of CDER 2004; Steven Galson & Doug Throckmorton October 6, 2004
9. FDA Has Unique Role in
Addressing the Problem
FDA scientists are involved in review during
product development -- they see the successes,
failures, and missed opportunities
FDA not a competitor, can serve a crucial
convening and coordinating role for consensus
development between industry, academia and
government
FDA sets the standards that innovators must
meet. New knowledge and applied science tools
needed not only by innovators – must also be
incorporated into agency review
State of CDER 2004; Steven Galson & Doug Throckmorton October 6, 2004
10. How to Proceed: Science-Driven
Shared Effort
Drawing on available data, need to target
specific, deliverable projects that will
improve drug development efficiency
Not just an FDA effort – we can identify
problems & propose solutions – solutions
themselves require efforts of all
stakeholders
• CMS, NIH, CDC
• Federal Register Notice requesting comments,
Well over 100 written responses to date.
State of CDER 2004; Steven Galson & Doug Throckmorton October 6, 2004
11. CDER/ FDA Next Steps
on Critical Path
HHS Medical Technologies
Innovation Taskforce providing
broad leadership
• Chaired by Dr. Crawford
• Includes CDC, CMS, NIH and FDA
Work on addition funding….
Meetings with external stakeholders
to identify opportunities, enlist allies
State of CDER 2004; Steven Galson & Doug Throckmorton October 6, 2004
12. Critical Path Summary
Present state of drug development not
sustainable
FDA must lead effort to question any
assumptions that limit or slow new
product development:
• Are they justified?
• Are there more efficient alternatives?
• If so, why are the alternatives not being
utilized?
State of CDER 2004; Steven Galson & Doug Throckmorton October 6, 2004
13. Three Dimensions of the Critical
Path
Assessment of Safety – how to predict if
a potential product will be harmful?
Assessing Efficacy -- how to determine if
a potential product will have medical
benefit?
Industrialization – how to manufacture a
product at commercial scale with
consistently high quality?
State of CDER 2004; Steven Galson & Doug Throckmorton October 6, 2004
14. Applied Science Needed to Better Evaluate and
Predict on 3 Key Dimensions on 'Critical Path' of
Development
15. OPS Programs & Critical Path
Initiative
The discussion today is to seek input and
advise from ACPS on:
• Aligning and prioritizing current OPS regulatory
assessment and research programs
Note that all research and laboratory programs are
not intended to be focused on the “Critical Path”
• Identify gaps in the current programs
• Identify opportunities for addressing the needs
identified by the Critical Path Initiative
16. Planned Project in the OPS
Immediate Office
An immediate need is to ensure
appropriate support
• Generic Drugs - the growing volume and
complexity of applications
• New Drug Chemistry - their new paradigm for
review assessment and efforts to support
innovation and continuous improvement goals
of the CGMP Initiative
• Biotechnology Products – complete integration
in OPS and the evolving concept of "Follow-on
Protein Products
• Alignment of research programs in OPS
17. OPS IO: Critical Path Initiative
Project Proposal
To develop a common regulatory
decision framework for addressing
scientific uncertainty in the context
of complexity of products and
manufacturing processes in Offices of
New Drug Chemistry, Biotechnology
Products, and Generic Drugs
18. Motivation
Uncertainty (stochastic and epistemic) and
complexity are two important elements of
risk-based based regulatory decisions
A common scientific framework,
irrespective of the regulatory path or
process for these products, will provide a
basis for efficient and effective policy
development and regulatory assessment
to ensure timely availability of these
products.
19. Approach
There are no good methods available
for developing a standard approach
for addressing uncertainty; different
approaches will be required in
different assessment situations.
Therefore, a decision framework for
selecting an approach for addressing
uncertainty over the life cycle of
products is proposed.
20. Project #1
Create the "As Is" regulatory
decision process map for ONDC,
OBP, and OGD
a representative sample of product
applications will be selected for this
mapping process
21. Project #1: Steps
Determine regulatory process efficiency
and effectiveness (quality) using metrics
similar to that of manufacturing process
Identify and compare:
• Critical regulatory review decision points and
criteria
• Evaluate correlation and/or causal links
between review process efficacy metrics and
critical decisions criteria, and available
information (in submissions), and
• Evaluate the role of reviewer training and
experience
22. Project #1: Steps (Contd.)
Summarize available information on the selected
products
Collect and describe product and manufacturing
process complexity, post-approval change history,
and compliance history (including AER's)
Describe product and process complexity and
uncertainty with respect to
• Current scientific knowledge (mechanism of action,
critical variables, analytical methods, failure modes,
etc.)
• Information available in the submissions,
• Reviewer expert opinions and perceptions
• If feasible/possible, seek similar information from
sponsor/company scientists on these same products
23. Project #1: Deliverables
Organize OPS Science Rounds to discuss and
debate the "As Is" process map and the
knowledge gained
• Identify "best regulatory practices" and opportunities for
improvement
Opportunities for improvement to include knowledge gaps
Develop a research agenda for OPS laboratories
• Develop a common scientific vocabulary to describe
uncertainty and complexity
• Develop an "ideal" scientific process map for addressing
uncertainty and complexity
• Adapt the "ideal" scientific process map to different
regulatory processes
24. Project #2: Background
Without a systems approach to the
entire regulatory process; from IND
to NDA (BLA, ANDA) review and
approval, to phase IV commitments
and CGMP inspections, the broad
FDA goals under the CGMP and the
Critical Path Initiatives will not be
optimally realized.
25. Project #2: Background
The team approach and systems perspective
under the CGMP Initiative only addressed a part
of the pharmaceutical system.
Quality by design and process understanding to a
large extent is achieved in a Research and
Development organization.
Pharmaceutical product development is a
complex and a creative design process that
involves many factors, many unknowns, many
disciplines, many decision-makers, and has
multiple iterations and long life-cycle
26. Project #2: Background
Significant uncertainty is created when a
particular disciplinary design team must try to
connect their subsystem to another disciplinary
subsystem (e.g., Clinical-CMC-CGMP).
Each subsystem can have its own goals and
constraints that must be satisfied along with the
system-level goals and constraints.
It is possible that goals of one subsystem may
not necessarily be satisfactory from the view of
other subsystem and design variables in one
subsystem may be controlled by other
disciplinary subsystem.
27. Project #2
Using ICH Q8 as the bridge between the
CGMP Initiative and the rest of the
regulatory system seek to develop a
knowledge management system to ensure
appropriate connectivity and synergy
between all regulatory disciplines
(Pharm/Tox, Clinical, Clinical
Pharmacology, Biopharmaceutics,
Bioequivalence, CMC, Compliance, CGMP
Inspections, Drug Safety,..)
28. Project #2: Approach
ICH Q8 CTD-Q Pharmaceutical
Development, P2 Section
• Each section within P2 can have an impact on
the other P2 sections and similarly other
sections of a submission and to CGMP’s
• By recognizing this as a complex design
system that involves multiple attributes, goals,
constraints, multidisciplinary design teams
(subsystems), different degrees of uncertainty,
risk tolerance, etc., we wish to find
opportunities to identify robust designs and
design space that provides a sound basis for
risk assessment and mitigation
29. Project #2: Approach
A significant body of knowledge exists (e.g., in
mechanical engineering - design of aircrafts) that
addresses this challenge; for example:
• Koor, I., Altus, S., Braun, R., Gage, P., and Sobieski, I.
Multidisciplinary Optimization Methods for Aircraft
Preliminary Desing. AIAA Paper 94-4325, 5th
AIAA/USAF/NASA/ISSMO Symposium, Sept. 1994
• Balling, R.J. and Sobieski, J. An Algorithm for Solving
System-Level Problem in Multilevel
Optimization.;Structural Optimization 9: 168-177 (1995)
• Kalsi, M., Hacker, K., Lewis, K. A Comprehensive Robust
Design Approach for Decision Trade-Offs in Complex
System Design. J. Mechanical Design. 123 (2001)
30. Project #2: Approach
The applicability of multidisciplinary optimization
methods for solving system level problems and
decisions trade-offs will be explored for the NDA
review process
• For example in the CDT-Q P2 section: Critical drug
substance variables that need to be considered in
section 2.2.1 Formulation Development are described in
section (P2.1.1.)
• P2.1.1. Drug Substance: “Key physicochemical and
biological characteristics of the drug substance that can
influence the performance of the drug product and its
manufacturability should be identified and discussed.
31. Project #2: Approach
Let f(2.1) be the objective function of section of
section P2.2.1. Formulation Development it
describes the desired quality and performance
attributes to be achieved by formulation
development program ( mean of the objective
function and its standard deviation)
Let g(2.1.) be the constraints placed on
formulation development
The subsystem optimization problem is then
defined as: Find X(2.1.) to achieve the objectives
of this subsystem as it relates to the overall
system
• Minimize [f, f]
• Subject to a given constraint g(1.1.,..2.1.,..)
32. X(2.1) = Design Variables for the P2 section (2.1)
Y(1.1)(2.1) = Linking variable that are evaluated in section (1.1)
and required in section (2.1) as the input
f(2.1) = Objective function addressed by section (2.1)
g(2.1) = Constraints in section (2.1)
f= Mean of objective function f
f= Standard deviation of objective function f
X= Deviation range of design solution (a design space
boundary)
2.1.1 Drug Substance
2.2.1 Formulation
Development
X(1.1) f(1.1) g(1.1)
Y(1.1)(2.1)
X(2.1) f(2.1) g(2.1)
Y(1.1.)(*.*)
Y(*.*.)(1.1.)
Y(2.1)(1.1)
Y(*.*)(2.1)Y(2.1.)(*.*)
API Manufacturing Process
or Quality control unit
33. Potential Deliverables
In conjunction with electronic submissions this
project can potentially provide a means to
• Link multidisciplinary information to improve regulatory
decisions (e.g., clinical relevance of CMC specifications)
• Creating a means for electronic review template and
collaboration between different disciplines
• Provide a common vocabulary for interdisciplinary
collaboration
• Create an objective "institutional memory' and
knowledge base
• A tool for new reviewer training
• A tool for FDA's Quality System
• Connect the CGMP Initiative to the Critical Path Initiative
34. Project #3
Explore the feasibility of a quantitative
Bayesian approach for addressing
uncertainty over the life cycle of products
• The most common tool for quantifying
uncertainties is probability. The frequentist's
(including classical statisticians) define
probability as a limiting frequency, which
applies only if one can identify a sample of
independent, identically distributed
observations of the phenomenon of interest.
35. Project #3
The Bayesian approach looks upon the concept of
probability as a degree of belief and include
statistical data, physical models and expert
opinions and it also provides methods for
updating probabilities when new data are
introduced.
The Bayesian approach may provide a more
comprehensive approach for regulatory decisions
process in dealing with CMC uncertainty over the
life cycle of a product.
• It may also provide a means to accommodate expert
opinions. The evolving CMC "peer review" process may
be a means to incorporate expert opinions.
Using the information collected in Project #1 seek
to develop quantitative Bayesian approaches for
risk-based regulatory CMC decisions in OPS
36. OPS Programs & Critical Path
Initiative
Other OPS programs – I/O, OBP, ONDC,
OGD, and OTR
The discussion today is to seek input and
advise from ACPS on:
• Aligning and prioritizing current OPS regulatory
assessment and research programs
Note that all research and laboratory programs are
not intended to be focused on the “Critical Path”
• Identify gaps in the current programs
• Identify opportunities for addressing the needs
identified by the Critical Path Initiative