Graduate Lecture at the University of Maryland (August 2012). Learning Objective: Identify and explain how future regulatory applications of BCS may be realized in the context of ‘Quality by Design’.
Updated July 2013.
I wish to thank all the viewers of my Slideshare presentation of the development and application of the US FDA’s BCS Guidance 2000. Over 11K views have been recorded making this the 2nd highest viewed presentation. FDA is expected to issue a revised BCS draft guidance in the next few weeks. Expected changes include the following:
1. Addition of ‘very rapid’ dissolution criteria (>85% in 15 minutes)
2. Change permeability boundary from 90% to 85%
3. Change the pH solubility range from 1 – 7.5 to 1 – 6.8
4. Possibility of changing paddle speed from 50 to 75 rpm.
5. Additional topics / clarification on FDCs (Fixed Dose Combinations), ODTs (Orally Disintegrating Tablets), MR (Modified Release) products.
6. Update the list of model drugs.
7. Strengthen GI stability requirement.
Bioavailability and bioequivalence – problems and pitfallsinemet
PharmaCon2007 Congress, Dubrovnik, Croatia "New Technologies and Trends in Pharmacy, Pharmaceutical Industry and Education" http://www.pharmacon2007.com
Abstract is available at http://www.pharmaconnectme.com
In this presentation I have mentioned whatever the possible relevant content/guidelines require for biowaiver application.
Citation Is done at the end of slide.
Content is up to date & true to my belief.
Thanks & Best Regards.
Anurag Pandey
B.Pharm (FACULTY OF PHARMACY, INVERTIS UNIVERSITY)
M.Pharm (INSTITUTE OF PHARMACY, NIRMA UNIVERSITY)
Email :- anurag.dmk05@gmail.com
Bioavailability and bioequivalence – problems and pitfallsinemet
PharmaCon2007 Congress, Dubrovnik, Croatia "New Technologies and Trends in Pharmacy, Pharmaceutical Industry and Education" http://www.pharmacon2007.com
Abstract is available at http://www.pharmaconnectme.com
In this presentation I have mentioned whatever the possible relevant content/guidelines require for biowaiver application.
Citation Is done at the end of slide.
Content is up to date & true to my belief.
Thanks & Best Regards.
Anurag Pandey
B.Pharm (FACULTY OF PHARMACY, INVERTIS UNIVERSITY)
M.Pharm (INSTITUTE OF PHARMACY, NIRMA UNIVERSITY)
Email :- anurag.dmk05@gmail.com
drug execipent compatibilty studies is of prime importance for the better formulation of the new drug and also for reducing cost by verfication of the data at the earlier atage.
this presentation will give the brief explanation of the goal, importance, dteps involve to studi the drug execient compatibility studies with different examples suitable accordiingly.
Friable: “ A friable substance is any substance that can be reduced to finer particles by the action of a small pressure or friction, such as rubbing or inadvertently brushing up against the substance”.
Friability test: Defined as the % of weight loss by tablets due to mechanical action during the test. Tablets are weighing before & after testing & friability is expressed as a percentage loss on pre-test tablet weight. & Friability test is done to check the ability of the compressed tablet to avoid fracture & breaking during the transport.
This testing involves repeatedly dropping a sample of tablets over a fixed time, using a rotating wheel with a baffle. The result is inspected for broken tablets, and the percentage of tablet mass lost through chipping.
If the average weight of the tablet is 0.65gm or less. Take 10 times of the whole weight i.e., 6.5 gm
2. Carefully deducts the tablets & weight required numbers of tablets.
Initial weight = 6.536gm
3. Set the Time duration for 4min
4. Set number of counts to 100
5. Make sure the drum is cleaned with no contaminates ,
add the initial weighted tables carefully & close the lid
6. Click Start button
Drum diameter : 283 -291mm
Depth: 36-40mm
Inner radius of the curve projection : 75.5mm – 85.5mm
Outer diameter of the central ring : 24.5mm – 25.5mm
Rotation Speed : 25 +/_ 1 cycle
Time Set: 4 min
After 4min automatically it stops ,
7. Take out the tablets & take out the dust from the tablets using brush /crumps
8. Take the After weight of the tablets
Total weight of after rotation= 6.443gm
Interpretation :
Value of friability should not be more than 1% for most of tablets.
If the value of friability for the first is greater than 1%, then repeat the test twice & mean of three values is taken.
If the mean value of three tests is less than 1% tablets passes the friability test,
otherwise tablet fails the test.
If the tablets are broken , chipped or cracked during the test, the tablets fails the friability test.
By ArcImBioCLinica (AIBC)
This guideline is a revised of the ICHQ1A –stability data package for new drug substance /DRUG PRODUCT .The [urpose of guideline to define stability data package that sufficient for a registration application within the 3 regions of EU ,JAPAN & USA & to maintain the quality of drug products, in relation to safety , efficacy & acceptability throughout the propose shelf life.
United State Pharmacopoeia (USP)The establishment of a rational relationship between a biological property, or a parameter derived from a biological property produced by a dosage form, and a physicochemical property or characteristic of the same dosage form.
Food and Drug Administration (FDA) definitionIVIVC is a predictive mathematical model describing the relationship between an in vitro property of a dosage form and a relevant in vivo response. Generally, the in vitro property is the rate or extent of drug dissolution or release while the in vivo response is the plasma drug concentration or amount of drug absorbed.
Myself Omkar B. Tipugade ,M-Pharm Sem II, Department of Pharmaceutics , Today I upload the presentation on Artificial Intelligene , In that I discuss about the definition of AI as well as their important in Pharmaceutical field . Also give brief information about the Neural networking & fuzzy logic with diagrammatic presentation And also application of AI in product formulation. I highlight the important words.
Bio pharmaceutical classification System [BCS]Sagar Savale
The Biopharmaceutical Classification System was first developed by in 1995, by Amidon et al & his colleagues.
Definition:
“The Biopharmaceutical Classification System is a scientific framework for classifying a drug substance based on its aqueous solubility & intestinal permeability & dissolution rate”.
To saved time fast screening is required so drug substances are classified on basis of solubility and permeability. This classification is called Biopharmaceutical Classification System
drug execipent compatibilty studies is of prime importance for the better formulation of the new drug and also for reducing cost by verfication of the data at the earlier atage.
this presentation will give the brief explanation of the goal, importance, dteps involve to studi the drug execient compatibility studies with different examples suitable accordiingly.
Friable: “ A friable substance is any substance that can be reduced to finer particles by the action of a small pressure or friction, such as rubbing or inadvertently brushing up against the substance”.
Friability test: Defined as the % of weight loss by tablets due to mechanical action during the test. Tablets are weighing before & after testing & friability is expressed as a percentage loss on pre-test tablet weight. & Friability test is done to check the ability of the compressed tablet to avoid fracture & breaking during the transport.
This testing involves repeatedly dropping a sample of tablets over a fixed time, using a rotating wheel with a baffle. The result is inspected for broken tablets, and the percentage of tablet mass lost through chipping.
If the average weight of the tablet is 0.65gm or less. Take 10 times of the whole weight i.e., 6.5 gm
2. Carefully deducts the tablets & weight required numbers of tablets.
Initial weight = 6.536gm
3. Set the Time duration for 4min
4. Set number of counts to 100
5. Make sure the drum is cleaned with no contaminates ,
add the initial weighted tables carefully & close the lid
6. Click Start button
Drum diameter : 283 -291mm
Depth: 36-40mm
Inner radius of the curve projection : 75.5mm – 85.5mm
Outer diameter of the central ring : 24.5mm – 25.5mm
Rotation Speed : 25 +/_ 1 cycle
Time Set: 4 min
After 4min automatically it stops ,
7. Take out the tablets & take out the dust from the tablets using brush /crumps
8. Take the After weight of the tablets
Total weight of after rotation= 6.443gm
Interpretation :
Value of friability should not be more than 1% for most of tablets.
If the value of friability for the first is greater than 1%, then repeat the test twice & mean of three values is taken.
If the mean value of three tests is less than 1% tablets passes the friability test,
otherwise tablet fails the test.
If the tablets are broken , chipped or cracked during the test, the tablets fails the friability test.
By ArcImBioCLinica (AIBC)
This guideline is a revised of the ICHQ1A –stability data package for new drug substance /DRUG PRODUCT .The [urpose of guideline to define stability data package that sufficient for a registration application within the 3 regions of EU ,JAPAN & USA & to maintain the quality of drug products, in relation to safety , efficacy & acceptability throughout the propose shelf life.
United State Pharmacopoeia (USP)The establishment of a rational relationship between a biological property, or a parameter derived from a biological property produced by a dosage form, and a physicochemical property or characteristic of the same dosage form.
Food and Drug Administration (FDA) definitionIVIVC is a predictive mathematical model describing the relationship between an in vitro property of a dosage form and a relevant in vivo response. Generally, the in vitro property is the rate or extent of drug dissolution or release while the in vivo response is the plasma drug concentration or amount of drug absorbed.
Myself Omkar B. Tipugade ,M-Pharm Sem II, Department of Pharmaceutics , Today I upload the presentation on Artificial Intelligene , In that I discuss about the definition of AI as well as their important in Pharmaceutical field . Also give brief information about the Neural networking & fuzzy logic with diagrammatic presentation And also application of AI in product formulation. I highlight the important words.
Bio pharmaceutical classification System [BCS]Sagar Savale
The Biopharmaceutical Classification System was first developed by in 1995, by Amidon et al & his colleagues.
Definition:
“The Biopharmaceutical Classification System is a scientific framework for classifying a drug substance based on its aqueous solubility & intestinal permeability & dissolution rate”.
To saved time fast screening is required so drug substances are classified on basis of solubility and permeability. This classification is called Biopharmaceutical Classification System
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?
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
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
Need for an Integrated approach to Formulation Research and Knowledge ManagementAjaz Hussain
1. Confidence in Generics: Need for an Integrated
approach to Formulation Research and Knowledge
Management (Ajaz Hussain)
2. Mechanism for an integrated approach to Formulation
Research, Knowledge Management, & Knowledge
sharing with FDA & Industry (Steve Byrn)
3. Integrated approach for evolving standards for
formulation design - case example NTI's (Ken Morris)
4. Integrated approach for evolving standard for analytical
characterization - case example excipient variability
(Eric Munson)
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)
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.
Pharmaceutical 6 Sigma and QbD May 2005 Ball State UniversityAjaz Hussain
Pharmaceutical product and process quality – what is the current “sigma”?
Challenges in moving towards “6-sigma” levels?
What are the steps necessary for the pharmaceutical continuous improvement journey in the 21st Century?
Sharing my learning in dealing with complexity and uncertainty and shed some light on:
(a) Understanding the ‘biosimilar paradox’
(b) Accelerating our “QbD” Journey – focusing on ‘from Generics to Biosimilars’
(c) In preparing this talk, collect my thoughts to help NIPTE consider ways for developing its program on Biosimilars to help the Nation improve assurance of quality with confidence and lower costs
(D) Invite the audience to get to know NIPTE and provide us ways to collaborate with industry
21CFR 320- BIO AVAILABILITY AND BIO EQUIVALENCE REQUIREMENTSPallavi Christeen
this presentation describes briefly about Bioavailability and Bioequivalence requirements as per US FDA Code of Federal Regulations under title 21 and chapter 320
Regulatory Compliance in Clinical Research: Navigating the FDA and Other Agen...ClinosolIndia
Regulatory compliance is a crucial aspect of conducting clinical research, ensuring that studies meet the requirements and standards set by regulatory agencies such as the U.S. Food and Drug Administration (FDA) and other relevant bodies. Here are some key points to navigate regulatory compliance in clinical research:
Familiarize Yourself with Applicable Regulations: Stay updated on the relevant regulations and guidelines that govern clinical research, including FDA regulations, International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines, and local regulatory requirements. Understand the specific regulations that apply to your study, such as those related to investigational new drugs (IND) or investigational device exemptions (IDE).
Obtain Institutional Review Board (IRB) Approval: IRBs play a crucial role in ensuring the protection of human subjects in research. Before initiating a clinical trial, obtain IRB approval by submitting a detailed study protocol, informed consent documents, and other required materials. IRBs review the study's scientific merit, ethical considerations, and compliance with regulations.
Investigational New Drug (IND) or Investigational Device Exemption (IDE) Application: If your clinical research involves the use of investigational drugs or devices, you may need to submit an IND or IDE application to the FDA. These applications provide detailed information on the investigational product, its safety, efficacy, manufacturing processes, and proposed study design.
Good Clinical Practice (GCP) Guidelines: GCP guidelines provide a framework for the conduct of clinical research to ensure data integrity and participant protection. Adhere to GCP principles, including informed consent, protocol adherence, accurate documentation, and appropriate monitoring and reporting of adverse events.
Adverse Event Reporting: Monitor and report adverse events occurring during the study promptly. Follow the FDA's requirements for safety reporting, including expedited reporting of serious and unexpected adverse events. Maintain accurate and complete records of adverse events and their follow-up actions.
Data Integrity and Documentation: Ensure the integrity, accuracy, and traceability of study data. Implement robust data management practices, including proper documentation, source data verification, and secure storage of study documents. Follow regulatory requirements for data retention, including archiving study records for the required period.
Audits and Inspections: Be prepared for audits and inspections by regulatory agencies. Maintain organized and easily accessible study documentation, including study protocols, informed consent forms, case report forms, and correspondence with IRBs and regulatory agencies. Cooperate with auditors or inspectors and address any identified deficiencies or findings promptly.
Did you know 40-65% of all clinical trials involving FDA-regulated products are being conducted overseas? Time, reduced costs, and easier subject recruitment are the factors that make life science companies to conduct clinical trials overseas.
This SlideShare gives an overview on how a drug is discovered, researched, developed, tested and reviewed for approval. It follows the current standard of approval set by the Food and Drug Administration (FDA), a federal agency of the United States Department of Health and Human Services. The process is generally divided into 4 Stages: Pre-Clinical, Clinical, New Drug Application (NDA) Review & Post-Marketing.
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
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.
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”?
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
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.
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.
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?
Embracing GenAI - A Strategic ImperativePeter Windle
Artificial Intelligence (AI) technologies such as Generative AI, Image Generators and Large Language Models have had a dramatic impact on teaching, learning and assessment over the past 18 months. The most immediate threat AI posed was to Academic Integrity with Higher Education Institutes (HEIs) focusing their efforts on combating the use of GenAI in assessment. Guidelines were developed for staff and students, policies put in place too. Innovative educators have forged paths in the use of Generative AI for teaching, learning and assessments leading to pockets of transformation springing up across HEIs, often with little or no top-down guidance, support or direction.
This Gasta posits a strategic approach to integrating AI into HEIs to prepare staff, students and the curriculum for an evolving world and workplace. We will highlight the advantages of working with these technologies beyond the realm of teaching, learning and assessment by considering prompt engineering skills, industry impact, curriculum changes, and the need for staff upskilling. In contrast, not engaging strategically with Generative AI poses risks, including falling behind peers, missed opportunities and failing to ensure our graduates remain employable. The rapid evolution of AI technologies necessitates a proactive and strategic approach if we are to remain relevant.
Unit 8 - Information and Communication Technology (Paper I).pdfThiyagu K
This slides describes the basic concepts of ICT, basics of Email, Emerging Technology and Digital Initiatives in Education. This presentations aligns with the UGC Paper I syllabus.
Macroeconomics- Movie Location
This will be used as part of your Personal Professional Portfolio once graded.
Objective:
Prepare a presentation or a paper using research, basic comparative analysis, data organization and application of economic information. You will make an informed assessment of an economic climate outside of the United States to accomplish an entertainment industry objective.
Read| The latest issue of The Challenger is here! We are thrilled to announce that our school paper has qualified for the NATIONAL SCHOOLS PRESS CONFERENCE (NSPC) 2024. Thank you for your unwavering support and trust. Dive into the stories that made us stand out!
How to Make a Field invisible in Odoo 17Celine George
It is possible to hide or invisible some fields in odoo. Commonly using “invisible” attribute in the field definition to invisible the fields. This slide will show how to make a field invisible in odoo 17.
Honest Reviews of Tim Han LMA Course Program.pptxtimhan337
Personal development courses are widely available today, with each one promising life-changing outcomes. Tim Han’s Life Mastery Achievers (LMA) Course has drawn a lot of interest. In addition to offering my frank assessment of Success Insider’s LMA Course, this piece examines the course’s effects via a variety of Tim Han LMA course reviews and Success Insider comments.
The Roman Empire A Historical Colossus.pdfkaushalkr1407
The Roman Empire, a vast and enduring power, stands as one of history's most remarkable civilizations, leaving an indelible imprint on the world. It emerged from the Roman Republic, transitioning into an imperial powerhouse under the leadership of Augustus Caesar in 27 BCE. This transformation marked the beginning of an era defined by unprecedented territorial expansion, architectural marvels, and profound cultural influence.
The empire's roots lie in the city of Rome, founded, according to legend, by Romulus in 753 BCE. Over centuries, Rome evolved from a small settlement to a formidable republic, characterized by a complex political system with elected officials and checks on power. However, internal strife, class conflicts, and military ambitions paved the way for the end of the Republic. Julius Caesar’s dictatorship and subsequent assassination in 44 BCE created a power vacuum, leading to a civil war. Octavian, later Augustus, emerged victorious, heralding the Roman Empire’s birth.
Under Augustus, the empire experienced the Pax Romana, a 200-year period of relative peace and stability. Augustus reformed the military, established efficient administrative systems, and initiated grand construction projects. The empire's borders expanded, encompassing territories from Britain to Egypt and from Spain to the Euphrates. Roman legions, renowned for their discipline and engineering prowess, secured and maintained these vast territories, building roads, fortifications, and cities that facilitated control and integration.
The Roman Empire’s society was hierarchical, with a rigid class system. At the top were the patricians, wealthy elites who held significant political power. Below them were the plebeians, free citizens with limited political influence, and the vast numbers of slaves who formed the backbone of the economy. The family unit was central, governed by the paterfamilias, the male head who held absolute authority.
Culturally, the Romans were eclectic, absorbing and adapting elements from the civilizations they encountered, particularly the Greeks. Roman art, literature, and philosophy reflected this synthesis, creating a rich cultural tapestry. Latin, the Roman language, became the lingua franca of the Western world, influencing numerous modern languages.
Roman architecture and engineering achievements were monumental. They perfected the arch, vault, and dome, constructing enduring structures like the Colosseum, Pantheon, and aqueducts. These engineering marvels not only showcased Roman ingenuity but also served practical purposes, from public entertainment to water supply.
1.4 modern child centered education - mahatma gandhi-2.pptx
Biopharmaceutics Classification System (BCS) & Waiver of Bioequivalence
1. BIOPHARMACEUTICSCLASSIFICATION SYSTEM: A
BASIS FOR REGULATORYWAIVER OF IN VIVO BA/BE
STUDIES
Ajaz | Insight
7/11/2013 1Ajaz | Insight
Graduate lecture at University of Maryland: on 17 August 2012
Update: 11 July 2013
http://www.ajazhussain.com
2. Update
ViroPharma Suit Against FDA Over Generic Vancocin Tossed
[Bloomberg. By Andrew Zajac & Tom Schoenberg - Jan 9, 2013]
The company failed to produce new evidence following rejection in April of its request
for a court order to block FDA approval of three generic versions of Vancocin
• U.S. District Judge Ellen Segal Huvelle in Washington said today in her ruling.
• The case is ViroPharma Inc. v. Hamburg, 12-cv-00584, U.S. District Court, District of Columbia(Washington)
7/11/2013 Ajaz | Insight 2
4. WhatisBCS?
A
paradigm
shift
• 𝑀 𝑡 = 0
𝑡
𝑃𝐶(
𝑑𝐴
𝑑𝑡
)
• 𝐾 𝑎 = (
𝑆
𝑉
)𝑃𝑒𝑓𝑓
• 𝐴𝑏𝑠𝑜𝑟𝑝𝑡𝑖𝑜𝑛 𝑛𝑢𝑚𝑏𝑒𝑟 𝐴 𝑛 =
𝑃𝑒𝑓𝑓
𝑅
.< 𝑇𝑠𝑖 >
• 𝐷𝑖𝑠𝑠𝑜𝑙𝑢𝑡𝑖𝑜𝑛 𝑛𝑢𝑚𝑏𝑒𝑟𝐷 𝑛 =
3𝐷
𝑟2
𝐶 𝑠
. < 𝑇𝑠𝑖>
• If the Peff of a drug is less than2•10–4 cm/s, then
drug absorption will be incomplete
• Class I—high solubility, high permeability:
generallyvery well-absorbedcompounds
• Class II—low solubility, high permeability:exhibit
dissolution rate-limitedabsorption
• Class III—high solubility, low permeability:exhibit
permeabilityrate-limitedabsorption
• Class IV—low solubility, low permeability:very
poor oral bioavailability
7/11/2013 4
http://www.fda.gov/ohr
ms/dockets/ac/04/slides
/2004-
4078S2_10_Amidon_files/
frame.htm
Journal of Clinical Pharmacology, 2002;42:620-643
Ajaz | Insight
5. RegulatoryApplications?
• Types of dissolution test comparisons for
manufacturing and formulation changes
Initial applicationin
SUPAC-IR (1995)
• Methods to classify per BCS and criteria
for biowaiver
Waiver of In vivo BA/BE
…BCS Guidance (2000)
• Several workshops and reportsEfforts to extend
biowaivers (beyond 2000)
• Debate and court case
A relativelyrecent
applicationto a ‘locally
acting’ drug
• BCS a foundational element of QbDOpportunities for Quality
by Design
7/11/2013 5Ajaz | Insight
6. Learningobjectives
(1). Considerations
for developing the
FDA guidance
“Waiver of In Vivo
Bioavailability and
Bioequivalence
Studies for
Immediate-Release
Solid Oral Dosage
Forms Based on a
Biopharmaceutics
ClassificationSystem”
(August 2000)
Broadly, gain an
understandingof
considerationsfor
translating
scientific
knowledgeinto
regulatorypolicy
(2) What questions
should you ask?
(3) What
assumptions
should you accept?
(4) How precise
should your
answers be?
Develop a basis to
critically evaluate
considerations
utilized for
developmentof
the FDA guidance
document
(5) How should you
‘connect the dots’:
CMC – BA/BE?
Can you justify new
applications of BCS
(i.e., beyond the
2000 guidance)?
Identify and
explain how
future regulatory
applicationsof
BCS may be
realized in the
context of ‘Quality
by Design’
7/11/2013 Ajaz | Insight 6
8. VIROPHARMAINC., PLAINTIFF, VS.
(FDA) MARGARETA. HAMBURG,M.D., ET AL.,
DEFENDANTS.
IN THE UNITED STATES DISTRICT COURT FOR THE DISTRICT OF COLUMBIA
Civil Action No. 12-cv-00584-ESH
Filed 04/17/12
7/11/2013 Ajaz | Insight 8
9. 13April2012PlaintiffssuedFDA
Issue
• Agency’s 9 April 9 2012 approval of three
ANDAs of the company’s Vancocin®
(vancomycin hydrochloride).
They alleged
that:
• FDA impermissiblyinterpretedthe Food, Drug, and
CosmeticAct when it denied the company three-year
exclusivity for its NDA supplement (“sNDA”)
(“exclusivityclaim”);and
• FDA violated its own regulations—andchanged
established policy withoutthe procedure requiredby
law—whenit chose to accept in vitro bioequivalence
data for oral vancomycin (“bioequivalenceclaim”).
7/11/2013 Ajaz | Insight 9
http://www.fdalawblog.net/fda_law_blog_hyman_phelps/2012/04/court-denies-viropharmas-motion-for-tropi-in-
vancomycin-caseleaves-generics-on-the-market.html
10. 23 April2012Memorandumof Opinion
7/11/2013 Ajaz | Insight 10
http://en.wiki
pedia.org/wiki
/Ellen_Segal_H
uvelle#Early_li
fe_and_career
Memorandum Opinion issued on April 23, 2012
The Judge
11. TITLE 21--FOOD AND DRUGS
CHAPTER I--FOODAND DRUGADMINISTRATION
SUBCHAPTER D--DRUGS FORHUMAN USE
• PART 320 BIOAVAILABILITY AND BIOEQUIVALENCE REQUIREMENTS
• Subpart A--General Provisions
§ 320.1 - Definitions.
• Subpart B--Procedures for Determining the Bioavailability or Bioequivalence of Drug Products
§ 320.21 - Requirements for submission of bioavailability and bioequivalence data.
§ 320.22 - Criteria for waiver of evidence of in vivo bioavailability or bioequivalence.
§ 320.23 - Basis for measuring in vivobioavailability or demonstrating bioequivalence.
§ 320.24 - Types of evidence to measure bioavailability or establish bioequivalence.
§ 320.25 - Guidelines for the conduct of an in vivobioavailability study.
§ 320.26 - Guidelines on the design of a single-dose in vivobioavailability or bioequivalence study.
§ 320.27 - Guidelines on the design of a multiple-dose in vivo bioavailability study.
§ 320.28 - Correlation of bioavailability with an acute pharmacological effect or clinical evidence.
§ 320.29 - Analytical methods for an in vivobioavailability or bioequivalence study.
§ 320.30 - Inquiries regarding bioavailability and bioequivalence requirements and review of protocols by the Food and Drug Administration.
§ 320.31 - Applicability of requirements regarding an "Investigational New Drug Application."
§ 320.32 - Procedures for establishing or amending a bioequivalence requirement.
§ 320.33 - Criteria and evidence to assess actual or potential bioequivalence problems.
§ 320.34 - Requirements for batch testing and certification by the Food and Drug Administration.
§ 320.35 - Requirements for in vitro testing of each batch.
§ 320.36 - Requirements for maintenance of records of bioequivalence testing.
§ 320.38 - Retention of bioavailability samples.
§ 320.63 - Retention of bioequivalence samples
7/11/2013 Ajaz | Insight 11
http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=320.22
12. DraftGuidance onVancomycin Hydrochloride(2008)
• Vancomycin acts locally in the lower GI tract
• The dosage form is expected to be in contact with a
relatively large fluid volume, vancomycin is
expected to be in solution long (e.g., hours) before it
reaches the site of action in the lower GI tract.
VancomycinHCl Capsules
are administeredorally for
treatmentof enterocolitis
• Equivalent release of vancomycin,
• The high solubility of vancomycin drug substance,
• The effect of inactive ingredients on the transport of
vancomycin drug through the GI tract and/or the
effectiveness of drug at the site of action
The BE of two capsule
formulationsof oral
vancomycin HCl is
determinedby?
• Formulations are Q1 and Q2 the same as the RLD
• Dissolution: Basket, 100 rpm, 0.1N HCl (or 0.1N
HCl with NaCl at pH 1.2), pH 4.5 Acetate buffer, and
pH 6.8 Phosphate buffer; 900 mL; 37ºC
• An f2 test of similarity
In Vitro BE
7/11/2013 Ajaz | Insight 12
http://www.fda.gov/OHRMS/DOCKETS/98fr/FDA-2008-D-0626-gdl.pdf
13. Plaintiffs’ArgumentPriorto theCourtCase
30 June 2009,
Plaintiffs’
briefing
document FDA
Advisory
Committee for
Pharmaceutical
Science and
Clinical
Pharmacology
“Is essentially the
Biopharmaceutics
Classification System
(BCS)-based biowaiver,
which was developed
using healthy GI
parameters to predict the
absorption of
systemically acting drugs
from the healthy gut and
was not intended for use
in predicting the in vivo
performance of locally
acting GI drugs”
Healthy GI physiological parameters may not
be an appropriate in vitro model for assessing
BE with locally acting GI drugs used to treat
serious GI disease
Oral Vancomycin is Systemically Absorbed in
Some Patients and has Been Linked with
Systemic Toxicity. Does a Biowaiver Ensure
Safety or Should In VivoTesting be Considered
for this Drug?
Extension of a Biowaiver to a New Class of
Drug Should be Evidence-Based and Data-
Driven.
Evaluation of Inactive Ingredients
http://www.fda.gov/downloads/AdvisoryCom
mittees/CommitteesMeetingMaterials/Drugs/
AdvisoryCommitteeforPharmaceuticalSciencea
ndClinicalPharmacology/UCM173159.pdf
7/11/2013 Ajaz | Insight 13
www.fda.gov/downloads/AdvisoryCommittees/.../UCM179424.pdf (FDA ACPS Transcripts)
14. Plaintiffs, In-Part,BasedtheirArgumentsona PreviousACPS
Discussion(October20,2004)
Bioequivalence
Testing for Locally
Acting
Gastrointestinal
ACPS presentations:
Prof. Amidon
http://www.fda.gov/ohrms/docke
ts/ac/04/slides/2004-
4078S2_10_Amidon_files/frame.ht
m
and OGD
(Lionberger)
http://www.fda.gov/ohrms/docke
ts/ac/04/slides/2004-
4078S2_11_Lionberger_files/frame
.htm
As the Deputy Director of FDA’s
Office of Pharmaceutical
Science Dr. Ajaz Hussain
summarized in his concluding
remarks, “I don’t want to sort of
jump in and say all right” and
simply apply the BCS approach
to locally acting GI drugs, in
part because issues relating to
“volume” and “hydrodynamics”
merited close attention.
Consequently, he said, “we have
to give some thought to how we
would approach that, so it is
not a trivial matter.”
(http://www.fda.gov/downloads/AdvisoryCommittees
/CommitteesMeetingMaterials/Drugs/AdvisoryCommit
teeforPharmaceuticalScienceandClinicalPharmacology/
UCM173159.pdf)
My comments (cited) related to broad
policy decision; not relevant to specific
case example as in this case.
FDA ‘point-to-point’ response to the
Citizen Petition addressed the questions
posed
http://www.regulations.gov/#!documentDetail;D=FDA-2006-P-
0007-0051
Congressional Record - Senate (S5649-
5650), May 7, 2007 - [D. Robertson -
Comment]
http://www.regulations.gov/#!documentDetail;D=FDA-2006-P-0007-
0014
7/11/2013 Ajaz | Insight 14
http://www.fda.gov/ohrms/dockets/ac/04/transcripts/2004-4078T2.pdf (ACPS 2004 transcripts)
http://www.regulations.gov/#!documentDetail;D=FDA-2006-P-0007-0051 (FDA CP response)
15. Re-capandNextSteps
Application
of BCS
beyond the
2000
Guidance?
54321
7/11/2013 Ajaz | Insight 15
A successful application of BCS principles to a
particular “locally acting” drugs (low to no
permeability). FDA willing to make ‘case-by-case’
decision. Broad policy recommendation yet to be
formulated.
(5) How should
you ‘connect the
dots’: CMC –
BA/BE? (QbD)
(2) What
questions should
you ask?
(4) How precise
should your
answers be?
(3) What
assumptions
should you
accept?
(1). Considerations
for developing the
FDA guidance
16. CONSIDERATIONSFOR DEVELOPING THE FDA
GUIDANCE:QUESTIONS, ASSUMPTIONS, AND NEEDED
PRECISION
Reflecting back to 1995-2000
Note: A number of data slides to follow have been taken from a
previous presentation available at:
www.fda.gov/ohrms/dockets/ac/05/.../2005-4137S2_02_Hussain.ppt
7/11/2013 Ajaz | Insight 16
17. NeedtoReduceOurRelianceon In VivoBEStudies:Why?
7/11/2013 Ajaz | Insight 17
• 21 CFR 320.25(a)“… no unnecessary human
researchshould be done.”Ethical reasons
• “building quality into products”
• “right first time”
Focus on
prevention
• Sciencecontinuesto provide new methodsto
identifyand eliminateunnecessary in vivo BE
studies; reduce time and cost of drug
developmentand review
Efficiency
18. TherapeuticEquivalence
7/11/2013 Ajaz | Insight 18
Reference Test
PharmaceuticalEquivalent
Products
Possible Differences
Drug particlesize, ..
Excipients
Manufacturingprocess
Equipment
Site of manufacture
Batch size ….
Documented Bioequivalence
= Therapeutic Equivalence
(Note: Generally, same dissolution spec.)
Normalhealthy subjects
Crossover design
Overnight fast
Glass of water
90% CI within 80-125%
of Ref. (Cmax& AUC)
19. RegulatoryBioequivalence:A Summary
7/11/2013 Ajaz | Insight 19
In Vivo BE
Pre-1962 DESI Drugs: In Vivo
evaluation for “bio-problem”
drugs (TI, PK, P-Chem)
Post-1962 Drugs: Generally
In Vivo - some exceptions
(IVIVC..)
SUPAC-IR
(1995)
Dissolution-IR
BCS
(pre-/post
approval
“Self-evident” - Biowaivers granted
Condition- excipients do not alter absorption
(historical data)
Solutions
Suspensions
Chewable, etc.
Conventional
Tablets
Capsules
MR Products SUPAC – MR;
IVIVC
Quality by Design & Design Space
IVIVC = In vitro to in vivo correlation
21. Dissolutiontests:Debates
Dissolution tests are “over
discriminating”
Products that dissolve about
70% in 45 minutes have no
medically relevant
bioequivalence problems
Dissolution tests are not sufficientto
assure bioequivalence
Demonstrationof IVIVC is necessary
IVIVC’s are “Product Specific”
7/11/2013 Ajaz | Insight 21
24. DissolutionTestProblems:False+ivesand -ives
7/11/2013
Ajaz | Insight
24
15 min 30 min 45 min AUC Cmax
Ref 95 96 98 100 100
B 96 97 97 104 95
C 62 84 92 84 55
D 82 94 95 88 87
E 103 103 103 112 120
F 13 35 53 100 102
Test/Ref.Mean
I. J. MacGilvery. Bioequivalence: A Canadian Regulatory
Perspective. In, Pharmaceutical Bioequivalence
. Eds. Welling, Tse, and Dighe. Marcel Dekker, Inc., New York, (1992)).
24
25. “FormulationSpecific”IVIVC
7/11/2013 Ajaz | Insight 25
Peak Concentration Vs. % Dissolved in vitro
Clarke et al. J. Pharm. Sci. 66: 1429, 1977
% Dissolved in 40 minutes
20 40 60 80 100
PeakConcentration(ug/100ml)
12
14
16
18
20
22
24
26
28
30
A
B
H
I
D
F
J
C
G
E
27. TypicalPhysiologicParameters:
SingleDoseFasting BE Study
7/11/2013 Ajaz | Insight 27
Volume = Gastric fluid + 8 oz water (~300 ml)
pH of gastric fluid = 1-3
Res. time (fasting)= variable; T50%=15 min.
Permeability - Low , compared to Small Intestine.
Surface tension lower than water, ….
Volume (fasting)= what gets emptied + SI vol.(500 ml?)
pH = 3-8, surface tension low,...
Res. time (fasting): 2-4 hours
Permeability - high compared to other parts
Hydrodynamics?
28. Whenyouchangethe wayyoulookata thing….
The
paradigm
shifts
• 𝑀 𝑡 = 0
𝑡
𝑃𝐶(
𝑑𝐴
𝑑𝑡
)
• 𝐾 𝑎 = (
𝑆
𝑉
)𝑃𝑒𝑓𝑓
• 𝐴𝑏𝑠𝑜𝑟𝑝𝑡𝑖𝑜𝑛 𝑛𝑢𝑚𝑏𝑒𝑟 𝐴 𝑛 =
𝑃𝑒𝑓𝑓
𝑅
.< 𝑇𝑠𝑖 >
• 𝐷𝑖𝑠𝑠𝑜𝑙𝑢𝑡𝑖𝑜𝑛 𝑛𝑢𝑚𝑏𝑒𝑟𝐷 𝑛 =
3𝐷
𝑟2
𝐶 𝑠
. < 𝑇𝑠𝑖>
• If the Peff of a drug is less than2•10–4 cm/s, then
drug absorption will be incomplete
• Class I—high solubility, high permeability:
generallyvery well-absorbedcompounds
• Class II—low solubility, high permeability:exhibit
dissolution rate-limitedabsorption
• Class III—high solubility, low permeability:exhibit
permeabilityrate-limitedabsorption
• Class IV—low solubility, low permeability:very
poor oral bioavailability
7/11/2013 Ajaz | Insight 28
http://www.fda.gov/ohr
ms/dockets/ac/04/slides
/2004-
4078S2_10_Amidon_files/
frame.htm
Journal of Clinical Pharmacology, 2002;42:620-643
29. SUPAC-IR/BCS:Forsome‘Level2’ Changes
7/11/2013 Ajaz | Insight 29
HS/HP LS/HP HS/LP LS/LP
Critical Process Gastric
Emptying
Dissolution Permeability D/P
IVIVC Not likely Likely Not likely (?)
Method 0.1 N HCl pH 1 - 7.4 App/Comp In Vivo BE
Acceptance
Criteria
Single point
85% in 15 min
Multiple
profiles
(f2 > or = 50)
Single profile
(f2 > or = 50)
AUC & Cmax
90% CI
80-125%
Note: NTI drugs excluded for some Level 2 Changes
31. BCS:ClassMembership
7/11/2013 Ajaz | Insight 31
• the highestdose strength is soluble in <250 mL
aqueous buffersover 1- 7.4 pH range of at 37oC.High Solubility
• extentof absorptionin humansis determinedto
be 90%
High
Permeability
• 85% dissolves within 30 minutesin 0.1 HCl (or
SGF), pH 4.5, and pH 6.8 buffers(or SIF) using
ApparatusI at 100 rpm or ApparatusII at 50 rpm.
Rapid
Dissolution
33. MetoprololIRTablets:Experimental&SimulationData
7/11/2013 Ajaz | Insight 33
RATIO (T/R) OF % DISSOLVED AT 10 MINUTES
0.2 0.4 0.6 0.8 1.0 1.2
0.5
0.6
0.7
0.8
0.9
1.0
1.1
1.2
AUC
Cmax
Plot 1 Regr
SOLUTION
T85%
~30min
invitro
0.1 0.2 0.3 0.4 0.5
0.0
0.5
1.0
1.5
2.0
0.0
0.5
1.0
1.5
2.0
0.75
0.80
0.85
0.90
0.95
0.70
0.75
0.80 0.85
0.90
0.95
Mean Intestinal Transit Time = 3.33 h
Mean Intestinal Transit Time = 1.67 h
85%
D
I
S
S
O
L
U
T
I
O
N
T
I
M
E
(h)
Gastric Emptying Half-Time (h)
Kaus LC, Gillespie WR, Hussain AS, Amidon GL. The effect of in
vivo dissolution, gastric emptying rate and intestinal transit time
on the peak concentrationand area-under-the-curve of drugs with
different gastrointestinal permeabilities. Pharm. Res. ,16, 272
(1999)
34. BCSClassMembership:RiskManagement
7/11/2013 Ajaz | Insight 34
Volume (ml) of water required to dissolve the highestdose
strength at the lowest solubility on the pH 1-7.5 range
JejunalPermeability
Peff(x10-4)cm/sec
1 10 100 1000 10000 100000
0.01
0.1
1
10
I
III
II
IV
Rapid Dissolution (in vivo & in vitro)
Likely Unlikely
Dissolution likely
to be “rate determining.”
Complex in vivo disso. and
solubilization process.
Dissolution in vivo
not likely to be rate
limiting - well
characterized excipients
Some hesitation with
the use of current
dissolution test
and concerns
with respect to
excipients.
Generally “problem” drugs
in vitro dissolution may
not be reliable
35. Re-capandNextSteps
Application
of BCS
beyond the
2000
Guidance?
54321
7/11/2013 Ajaz | Insight 35
A successful application of BCS principles to a
specific “locally acting” drugs (low to no
permeability). FDA willing to make ‘case-by-case’
decision. Broad policy recommendation yet to be
formulated.
(5) How should
you ‘connect the
dots’: CMC –
BA/BE? (QbD)
(2) What
questions should
you ask?
(4) How precise
should your
answers be?
(3) What
assumptions
should you
accept?
(1). Class
boundaries, rapid
dissolution
36. AssumptionsAcceptableto theSociety?
Therapeutic
Equivalence =
• Pharmaceutical
equivalence +
Bioequivalence
BE Self-evident
for solutions
• For solutions a
review of
historical use
of excipients
How precise is
this approach in
ensuring
therapeutic
equivalence?
Under the
umbrella of this
assumption, does
the FDA review
process focuses
on the ‘right
questions’?
7/11/2013 Ajaz | Insight 36
38. ExperimentalFormulation
Reference TEST formulation
Sucrose*
(high permeability)
5 g 0 g
Sorbitol
(low permeability)
0 g 5 g
Water 15 ml 15 ml
Drug 1 Ranitidine (low permeability)
Drug 2 Metoprolol (highpermeability)
7/11/2013 Ajaz | Insight 38
A Modern View of Excipient Effects on Bioequivalence: Case Study of Sorbitol
M.-L. Chen, A. B. Straughn, N. Sadrieh, M. Meyer, P. J. Faustino,A. B. Ciavarella,B. Meibohm, C. R. Yates and A. S. Hussain
Pharmaceutical Research, Volume 24, Number 1 (2007),73-80, DOI: 10.1007/s11095-006-9120-4
* Rapidly metabolized at/in the intestinal wall to glucose and fructose, both exhibit complete
absorption
39. Lowpermeabilityexcipientcanreducebioavailabilityofa low
permeabilitydrug!
7/11/2013 Ajaz | Insight 39
Ranitidine: 150 mg
Sucrose: 5 g
Sorbitol: 5 g
A Modern View of Excipient Effects on Bioequivalence: Case Study of Sorbitol
M.-L. Chen, A. B. Straughn, N. Sadrieh, M. Meyer, P. J. Faustino,A. B. Ciavarella, B. Meibohm, C. R. Yates and A. S. Hussain
Pharmaceutical Research,Volume 24, Number 1 (2007),73-80, DOI: 10.1007/s11095-006-9120-4
40. Question:Howdo we selectandevaluatethe impactofexcipients
onBA/BE?
• Has it been used previously?
• Many other issues
• http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProc
ess/HowDrugsareDevelopedandApproved/ApprovalApplications/A
bbreviatedNewDrugApplicationANDAGenerics/UCM291010.pdf
FDA’s Inactive
Ingredient Guide
• A case example of micro-emulsion
A logical extension –
What gaps exist in the
current definition of
‘Pharmaceutical
Equivalence”?
7/11/2013 Ajaz | Insight 40
41. Prescriptionfor trouble*
How flaw in FDA safety net may pose
risk to public with generic drugs
• Tom Abate, Todd Wallack, Chronicle Staff Writers
• San Francisco Chronicle. Sunday, December 22,
2002
The issues
• “[Company X] had tested its generic with chocolate
milk. [Ref.product] was chased with apple juice.”
• “Did that matter?”
7/11/2013 Ajaz | Insight 41
http://www.sfgate.com/cgi-bin/article.cgi?f=/c/a/2002/12/22/MN35888.DTL&ao=all
42. Howpreciseshouldouranswerbe?
In parallelto development of BCS
guidance the FDA had proposed
replacing the “average bioequivalence”
criterionwith population and
individual bioequivalencecriteria
• To consider variances in additionto
the difference of averages.
• One of these variancesin the
individual bioequivalencecriterion
measuressubject-by-formulation
interaction, the extent to which the
test-reference differencevaries from
person to person.
7/11/2013 Ajaz | Insight 42
http://www.fda.gov/ohrms/dockets/ac/00/slides/3657s2_07.pdf
Ranitidine AUC in individuals as a function of
sucrose or sorbitol
43. PolicyRecommendation:Waiverofin vivoBE studiesbasedonBCS
(8/30/2000)
7/11/2013 Ajaz | Insight 43
Recommended for a solid oral Test product that exhibit
rapid (85% in 30 min) and similar in vitro dissolution
under specified conditions to an approved Reference
product when the following conditions are satisfied:
Products are
pharmaceutical
equivalent
Drug substanceis
highly soluble and
highly permeable
and is not considered
have a narrow
therapeuticrange
Excipientsused are
not likely to effect
drug absorption
44. BCSa toolforriskmanagement(2000)
7/11/2013 Ajaz | Insight 44
• What is the risk of bio-in-equivalence between two
pharmaceutical equivalent products when in vitro dissolution
test comparisons are used for regulatory decisions?
• Likelihood of occurrence and the severity of the
consequences?
Assessment of
risk
• whetheror not the risks are such that the
project can be persued with or without
additional arrangementsto mitigatethe risk
Regulatory
Decision
• is the decision acceptableto society?
Acceptability
of the Decision
45. Relianceoncurrentdissolutionpracticecanposesan
unacceptablelevelofrisk(2000)
Compared to high
solubility drugs Risk is higher for low solubility drugs
Products with slow or
extended dissolution
profiles pose a higher
risk (dissolution rate
limiting)
Need for a rapid dissolution criteria
Potential for
differences between
in vivo and in vitro
“sink” conditions and
impact of excipients
Higher for low permeability drugs
7/11/2013 Ajaz | Insight 45
46. Re-cap(2000)&Update(Currentstate)
At the time the BCS guidance
was being developed
Focus on the “right question”
during FDA review needed
improvement
Understanding of excipient*drug
interactions was evolving
Improved criteria for
pharmaceutical equivalence
assessment was needed
Debate on “average
bioequivalence”, population and
individual bioequivalence criteria
Following issuance of the
BCS guidance
FDA maintained “avg. BE” &
launched the PAT/QbD program
FDA-OGD adopted a “Question
based Review” process to focus on
the “right questions”
OGD is now actively seeking to link
QbD to Pharmaceutical Equivalence
Assessment
“Pharmaceutical equivalence by
design for generic drugs: modified-
release product” Pharm Res. 2011
Jul;28(7):1445-53
7/11/2013 Ajaz | Insight 46
47. Re-capandNextSteps
Application
of BCS
beyond the
2000
Guidance?
54321
7/11/2013 Ajaz | Insight 47
A successful application of BCS principles to a
specific “locally acting” drugs (low to no
permeability). FDA willing to make ‘case-by-case’
decision. Broad policy recommendation yet to be
formulated.
(5) How should
you ‘connect the
dots’: CMC –
BA/BE? (QbD)
(2) What
questions should
you ask?
(4) How precise
should your
answers be?
(3) What
assumptions
should you
accept?
(1). Class
boundaries, rapid
dissolution
48. DrugRelease&QualitybyDesign
• Christopher Sinko, Ph.D., at the Advisory Committee for Pharmaceutical Science meeting,
on October 25, 2005
• www.fda.gov/ohrms/dockets/ac/05/.../2005-4187S1_05_Sinko.ppt
• Clinical relevanceof releaseand stability specifications
• Correlationbetweenprocess parametersand ability to achieve specifications(and thereforeremain
clinically relevant
• Once a formulation scientist understands the patient’s requirements, they can
design a formulation using either or both approaches:
• Prior knowledge: choose API form, excipients and processes that will achieve the expected
release profile
• QBD: select API form, excipients and processes that have greatest impact on quality attributes
that affect release of drug
• Selectionsbased on theoretical/fundamentalunderstanding,alternativemeasurementsand heuristic
development
7/11/2013 Ajaz | Insight 48
49. Drug
Release
Rate
Disintegration,
Erosion and
Granule
Dissolution
API Solubilization
(rate/extent)Porosity
API Form Selection
(Salt, Polymorph, Particle Size)
Hardness Wetting
Swelling/
Water
Penetration
DP Excipient Selection, DP Process Selection
API Form Selection, API Process Selection
Quality Attributes
Of Drug Product
Features of “Quality by Design”: doing thingsconsciously*
*A Quality by Design Approachto Dissolution Based on the
Biopharmaceutical Classification System, R. Reed
www.fda.gov/ohrms/dockets/a
c/05/.../2005-
4187S1_05_Sinko.ppt
7/11/2013 Ajaz | Insight 49
50. DesignSpace:API Particle Size
7/11/2013 Ajaz | Insight 50
Granulation Time
Temperature
Agitation Rate
Seeding
Cool down rate
Solvent quality
Filter heel
Blow down time
Cake thickness
Slurry thickness
Filter cloth/mesh
Cake smoothing procedure
Wash temperature
Wash solvent quality
Hold time
Transfer procedures
Agitation rate
Inlet temperature
Nitrogen blanketing
Drying time
Agitation blade
Particle shape
Drying vacuum
Heel
Transfer procedures
Set up procedures
Feed rate
Screen size
Mill speed
Particle size
Agglomeration
Operator training
Size measurement
Particle shape
Shape measurement
Mill temperature
Crystallization/
Filtration Wash/Drying Milling
Represents a known interaction
www.fda.gov/ohrms/do
ckets/ac/05/.../2005-
4187S1_05_Sinko.ppt
52. Opportunities;onlywhenthedisciplinarydividesarebridged
• Estimate of variance in PK/PD &
outcomes (e.g., intra- and inter-
individual variability)
Pharmacometrics
• Estimate of variance in critical to quality
attributes (in the context of PK/PD
variability)
Chemometrics
• Estimate of variance in cGMP compliance
(in the context of acceptable variance in
critical to quality attributes)
Econometrics
7/11/2013 Ajaz | Insight 52
53. A visionbecoming reality….
“I can see clearly now”
Vision 2020
• Perspectives on Regulation:
Law, Discretion, and
Bureaucratic Behavior
(Kagan and Scholz, May
1980)
• ‘Good citizens’Vs. {‘political
citizens,‘incompetent’,
and/or ‘amoral’}
• For FDA to be science and
risk-based it needs scientific
data & information,
capability, ..
“Scientific explanation yields
understanding”
7/11/2013
Ajaz | Insight 53
http://www.fda.gov/ohrms/dockets/ac/04/briefing/2004-4052B1_09_Hussain-Arden-UK-Presentation.ppt
54. Learningobjectives
(1). Considerations
for developing the
FDA guidance
“Waiver of In Vivo
Bioavailability and
Bioequivalence
Studies for
Immediate-Release
Solid Oral Dosage
Forms Based on a
Biopharmaceutics
ClassificationSystem”
(August 2000)
Broadly, gain an
understandingof
considerationsin
translating
scientific
knowledgeinto
regulatorypolicy
(2) What questions
should you ask?
(3) What
assumptions
should you accept?
(4) How precise
should your
answers be?
Develop a basis to
critically evaluate
considerations
utilized for
developmentof
the FDA guidance
document
(5) How should you
‘connect the dots’:
CMC – BA/BE?
Can you justify new
applications of BCS
(i.e., beyond the
2000 guidance)?
Identify and
explain how
future regulatory
applicationsof
BCS may be
realized in the
context of ‘Quality
by Design’
7/11/2013 Ajaz | Insight 54
55. PresentationSummary
Application
of BCS
beyond the
2000
Guidance?
54321
7/11/2013 Ajaz | Insight 55
VIROPHARMA INCORPORATED, Plaintiff,
Vs.
MARGARET A. HAMBURG, M.D., et al., Defendants.
IN THE UNITED STATES DISTRICT COURT
FOR THE DISTRICT OF COLUMBIA
Civil Action No. 12-cv-00584-ESH
Filed 04/17/12
(5) How should
you ‘connect the
dots’: CMC –
BA/BE? (QbD)
(2) What
questions should
you ask?
(4) How precise
should your
answers be?
(3) What
assumptions
should you
accept?
(1). Considerations
for developing the
FDA guidance