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?

1. CONTINUAL IMPROVEMENT (CI) AND
CONTINUOUS DEVELOPMENT (CD)
Ajaz S. Hussain, Ph.D.
5/31/2023 © AJAZ | INSIGHTS 2023 1

2. INVITATION TO CSF
BOSTON 2023
Reminded me that Life is a journey that changes
your life. I believe it is an original sentiment –
from the heart, dil se. Thank you!
A “Triaxial Compaction” project in the early ’80s
is perhaps a thought akin to a Butterfly Effect,
subtly transforming my life in Pharmaceutical
Science. Realizing how profoundly; it is now, on
Memorial Day 2023, a memory for the record.
I am eager my share my insights with CSF. The
anticipatory likelihood of making common sense
with those passionate about CS seems high.
I will actively seek feedback during the day and
regroup my SMARTs as needed to be a better
Shepherd to my Practices and share
5/31/2023 © AJAZ | INSIGHTS 2023 2

3. Why did the company not design a formulation for a better tablet
that did not “cap”? Why did CMC review at FDA [discount]
Pharmaceutical Development Reports, while in the EU and Japan, is it
an essential part of the regulatory review? Why wouldn’t NIH fund
my proposal for CAFD? I am thankful they didn’t support my
research; it was liberating. I secured academic tenure and bid
goodbye to embark on a journey to see the world from so many
viewpoints!
Triaxial Compaction
5/31/2023 © AJAZ | INSIGHTS 2023 3
Akin to a Butterfly Effect., in not-so-
strange attractors - Fairness &
Responsibility! It subtly changed my life
in Pharmaceutical Science via the
“disorienting dilemma” I encountered at
FDA.

4. “DISORIENTING DILEMMA” I ENCOUNTERED AT
FDA WERE SEVERAL, SUCH AS
Expert witness for the FDA prosecution of CGMP violations; why is the system so
dependent on whistleblowers? Why were issues not detected in the CMC review or
CGMP inspections?
Fully automated continuous air-separation unit for medical gas manufacturing –shut
down for not 3-batch process qualification and not doing USP organoleptic testing.
Are analytical methods for physical attributes such as dissolution, particle size, blend
uniformity, etc., appropriately validated?
The one that left me stunned - adhesive failures on “Adhesive Transdermal Patches.”
It is a deeply personal experience.
5/31/2023 © AJAZ | INSIGHTS 2023 4

5. Few “experts” appreciate measurement uncertainties adequately, particularly of solid-state.
Past, Present, and Future of Pharmaceutical Dissolution Testing: A Disciplined Reflection and Synthesis 2019 (researchgate.net)
A disorienting dilemma! Before the FDA, I taught a graduate course on dissolution IVIC – why didn’t I know then?
5/31/2023 © AJAZ | INSIGHTS 2023 5

6. IT TAKES A PROFESSIONAL LIFE CYCLE TO
TRANSFER AWARENESS OF X TO GOOD PRACTICE
Premature
accidental
deaths
Slow to
investigate Awareness Guidance
Need Good
Regulators of
Pharmaceuticals
Current Good Regulators of Pharmaceuticals (cGRP) | LinkedIn April 5, 2016
We (all of us and not just the FDA staff) are the regulators.
5/31/2023 © AJAZ | INSIGHTS 2023 6

7. MATURITY IS SENSITIVE TO
INITIAL CONDITIONS
Growing up in Inda expected to be a chemical
engineer, but instead, B.Pharm – why do you want to
be a compounder? UC, Merrell Dow…
Daubert v. Merrell Dow Pharmaceuticals, Inc. 509 U.S. 579 (1993) ::
Justia US Supreme Court Center
On January 6, 1817, Lyman Spalding formally proposed the
framework for the (usp.org)
In 1906, the Pure Food and Drug Act defined drugs as “all
medicines and preparations recognized in the USP or NF
Formulary (NF)
Federal Food, Drug, and Cosmetic Act (FD&C Act) | FDA
kefauver-harris_amendments.
The generic drug scandal Judge Wolin's interpretations of CGMP
1995 to OPS to SUPAC, PQRI, BCS, to PAT QbD to
Pharmaceutical Quality for the 21st Century
My
Initial
conditions
to
OPS
OOS, “omission or commission,”
“common or special cause,”
CAPA, validation, CPV, CI
“imagined chart” Suitable and Capable, CD?
"Common sense is the collection of prejudices acquired by eighteen,” Einstein.
“Give me the child for the first seven years, & I will give you the [adult.]” Loyola
Maturity of the FDA and CDER Quality Management Maturity | FDA
The Compliance and Science of Blend Uniformity Analysis
PM 483
PM
My
understanding
Need help to make common sense?
5/31/2023 © AJAZ | INSIGHTS 2023 7

8. I wonder, a PAT team-building event over two decades ago, was it to reorient disorienting dilemmas
or to make common sense?
Disorienting dilemmas?
What forces us to evaluate what we
believe in may need to be revised.
Disorientation causes discomfort
and dissociation
Chuck didn’t believe there could be a
basis for formulation science.
Dancing for
“Team Science”
5/31/2023 © AJAZ | INSIGHTS 2023 8

9. A 9/11 MEMORY REMINDS ME MORE AND
LESS EMOTIONALLY THAT SENSEMAKING
AND UNDERSTANDING DIFFER
Shared sensemaking aligns and integrates
across the shared understanding
Understanding differs between different
[technical disciplines] cohorts with similar
awareness worldviews and prior knowledge
(in the real world, we experience differently
from a classroom or conference room)
Expanding and sharing awareness to make
sense and integrate differences in
understanding is the first step to common
sense.
Sense-making is experiential (it is to feel); a
good sensemaking process requires
experience and integrity! A key to CD!
5/31/2023 © AJAZ | INSIGHTS 2023 9
Adapted from Dennis K. Leedom. Final Report, Sensemaking
Symposium, October 2001. Command and Control Research
Program, Office of the Assistant Secretary of Defense, for
Command, Control, Communications, and Intelligence.

10. A “VISION 2020” AT FDA SET MY JOURNEY TO 2020: WHAT DID I
LEARN TO SHARE HOW TO PREVENT “CAPPING IN MIND.”
5/31/2023 © AJAZ | INSIGHTS 2023
• “Chaos before 2020” in our microcosm? What do I mean? Why
is it now (2023) palpable [more] broadly in macroeconomics?
The need to make good sense and then make it commonsense is
more urgent; why? Make good sense and then make it
commonsense – how am I practicing to do so in the context of
the FD&C Act? Why is it essential to continuous development?
• Considering the capping tendency in tablets as a case study,
why is the need to understand, predict and prevent this
tendency more urgent than ever? Metaphorically, how it relates
to “capping in mind”? What lessons can we draw out in the
context of CI and CD?

11. @ CSF, A NEURAL NETWORK EPOCH 2023
5/31/2023 © AJAZ | INSIGHTS 2023 11

12. A LUBRICANT WITH
REJECTION FORCE?
Blending with Mg.
Stearate a mechanism
of slow release by
design [?].
But was it Quality by
Design?
5/31/2023 © AJAZ | INSIGHTS 2023 12
CPY Document (fda.gov)

13. DILANTIN: A TRICKY
EPILEPSY DRUG?
Or is it the formulation? No, it might
be the process.
Lower phenytoin serum levels in
persons switched from brand to
generic phenytoin | Neurology
(October 26, 2004)
Impact Story: Addressing Concerns
About the Quality of Generic Drugs
for Treating Epilepsy | FDA
Generic Epilepsy Drugs Not Same
as Brand Name | Fox News
(January 14, 2015)
Epilepsy Generics: Yes, No or
Maybe So? | Epilepsy Talk (June 24
2021)
5/31/2023 © AJAZ | INSIGHTS 2023 13
084349Orig1s045BIOEQ_REV.pdf (fda.gov)

14. 5/31/2023 © AJAZ | INSIGHTS 2023 14

15. “If I do not
look, there is
no problem.”
Stuff Happens! “We are here to
serve patients.”
© Ajaz | Insights 2023 5/31/2023 15
Guest Column | September 18, 2017: How To
Break The Pharmaceutical 2-3 Sigma Barrier
(Like Amgen) (pharmaceuticalonline.com)

16. CHANGE CONTROL,
MANAGEMENT, AND
CONTINUAL IMPROVEMENT
Market standards in the community, small sample
size, penalty built in for larger sample size (no
unit outside “90-110” and std. dev x%), and risk
“testing into compliance.”
The “market standard” for QC lab – lot release
akin to Pandora's box, with no hop at its bottom.
Root cause unknown a better option.
“[When did Pharma culture] shift from what
influential cultural historian Warren Susman called
a culture of character to a culture of personality
[1906], and opened up Pandora's box of
personal anxieties of which we would never
recover." ~ Susan Cain
Pharmaceutical 6 Sigma and QbD, May 2005 Ball State University (slideshare.net)
ASTM E2281-03 Standard Practice for Process and Measurement Capability Indices.
ASTM E2709-10 Standard Practice for Demonstrating Capability to Comply with a Lot
Acceptance Procedure [PV Guidance 2011]
What prevents change, as in continual improvement?
5/31/2023 © AJAZ | INSIGHTS 2023 16

17. PHYSICOCHEMICAL FAILURE
MODES FOR NARROW
THERAPEUTIC INDEX (NTI) DRUGS
(EUROPEANPHARMACEUTICALREVIEW.COM) (2 JULY 2021)
A a first insight into the complications and
complexities involved in resolving the structure of
anhydrous phenytoin sodium
Threefold Superstructure of the Anti-epileptic
Drug Phenytoin Sodium as a Mixed Methanol
Solvate Hydrate (2019)
The current system for physicochemical
corrections in the context of pre-formulation,
formulation development, and knowledge
curation continues to be neglected even for NTI
drugs.
New Prior Knowledge – a border solution. Or
perhaps, we let Digital Twins do our job and, in
the transition phase, control and supervise us?
5/31/2023 © AJAZ | INSIGHTS 2023 17

18. “NEW PRIOR
KNOWLEDGE”
Hussain, A.S., Gurvich, V.J. & Morris, K.
Pharmaceutical “New Prior Knowledge”:
Twenty-First Century Assurance of
Therapeutic Equivalence.
AAPS PharmSciTech 20, 140 (2019).
https://doi.org/10.1208/s12249-019-1347-6
5/31/2023 © AJAZ | INSIGHTS 2023 18

19. Question: Is “Use and Tell” in the 2020s easier than
"Don't Use or Don't Tell" in 2001?
• Compaction Simulation
and Digital Twins
facilitate “looking to
detect, correct and
prevent problems,”
improve regulatory
applications as in an
NDA, Comparability
Protocol, CAPA,
Warning Letter
Response, ….
Supporting Quality
Management Maturity.
5/31/2023 © Ajaz | Insights 2023 19

20. 5/31/2023 © AJAZ | INSIGHTS 2023 20

21. 5/31/2023 © AJAZ | INSIGHTS 2023 21

22. Critical Path Initiative Challenges: FDA ACPS Meeting 19 October 2004 (slideshare.net)
ICH Q8 envisioned facilitating SMART Review in 2004, but slow progress was frustrating in 2010; placed in context later (PM 483)
5/31/2023 © AJAZ | INSIGHTS 2023 22

23. CHALLENGES, BROADLY
Not achieving One Quality Voice ( FDA Paper
2015)
 The oversight system cannot adequately
address specific risks to consumers or
individual product failure modes.
 Furthermore, the process of post-approval
supplements "locks in" the manufacturing
process before it can be fully optimized.
 There are concerning trends in the frequency
of product recalls and unacceptable defect
reports.
 Additionally, there are alarming shortages of
crucial medications.
5/31/2023 © AJAZ | INSIGHTS 2023 23

24. 5/31/2023 © AJAZ | INSIGHTS 2023 24

25. ROADMAP TO QBD IS (SHOULD
BE) A ROADMAP TO ADULT
HUMAN DEVELOPMENT
(SLIDESHARE.NET).
@ QUALITY BY DESIGN MOVING TO
NEXT GENERATIONS, SEPTEMBER 7TH -
8TH, 2016, PATHEON-GREENVILLE
Some adults continue to develop
at different rates; many do not!
5/31/2023 © AJAZ | INSIGHTS 2023 25

26. AM I DEVELOPING
CONTINUOUSLY WITH EACH
EXPERIENCE?
Understanding (also process
understanding in PAT) requires
disciplined study. Sensemaking is
experiential. Why do I often fail to
make common sense?
What if a “PM 483” analogous to
FDA’s Form 483 is issued on my
“professional maturity” based on
observations on my participation @
CSF 2023?
How might it help me in
transdisciplinary communication and
cross-functional negotiations to set
SMART objectives for Continual
Improvement following APR (annual
product review)? Will it help me
make common sense?
5/31/2023 © AJAZ | INSIGHTS 2023 26

27. IN OVER OUR HEADS: THE MENTAL DEMANDS OF
MODERN LIFE, ROBERT KEGAN (1994)
PM 483 for the Avenger: VAI
OX (2010) = (0.3)*O1 +
(0.2)*O2 + (0.00)*O3 +
(0.5)*O4 + (0.00)*O5
[Ox (2023) = ?]
5/31/2023 © AJAZ | INSIGHTS 2023 27

28. ONGOING RESEARCH INFORMS CONTINUAL IMPROVEMENT
PLANS & COMPARABILITY PROTOCOLS.
Policy
Opportunity
Intent
Continuous
Improvement
Capping of biconvex tablets: towards a better
understanding and prediction
Predicting capping for a given formulation
Compaction simulator use at Genentech – 5
Years Later.
Assessing the tableting risks of NMEs
Understanding air-entrapment-induced fissures
during tablet compression through tooling
design
Defect reduction
In silico modeling of roller compaction processes
for scale-up and tech transfer: One step closer to
digital twins
QbD during process scale-up and tech
transfer
5/31/2023 © AJAZ | INSIGHTS 2023 28

29. 5/31/2023 © AJAZ | INSIGHTS 2023 29
Mindset
Reply
Ask
Define
Continual
Improvement
What is it in
pharma?
It is not CAPA! Remain ignorant
How can it be
achieved?
Effective CAPA to
achieve stability to
begin CI
“Root cause
unknown”
Why is it so
difficult in
pharma?
The system is
trapped in a
“correction” cycle.
Develop
continuously
Ongoing research

30. 5/31/2023 © AJAZ | INSIGHTS 2023 30
As the next generation of leaders, you must go beyond your technical understanding. Strive to make commonsense!
Continuous development goal? Aim high. OX (2025) = (0.0)*O1 + (0.0)*O2 + (0.2)*O3 + (0.4)*O4 + (0.3)*O5

31. REFRAIN FROM REORIENTING. MAKE
COMMON SENSE OF DISCOUNTING
DISORIENTING LEGACY DILEMMAS TO
“LEAPFROG” TO 4.0.
Doing more is recognizing that our systems
are socio-technical systems. Their maturity is
our maturity, to be suitable and capable of
moving from “don’t use and don’t tell” and
“if I don’t look, there is no problem” and
“fail and fix” to be able to “predict and
prevent” harm.
Hussain, A.S., Morris, K. & Gurvich, V.J. Pharmaceutical
Quality, Team Science, and Education Themes: Observations
and Commentary on a Remarkable AAPS PharmSciTech
Theme Issue. AAPS PharmSciTech 22, 88 (2021).
https://doi.org/10.1208/s12249-021-01970-7
5/31/2023 © AJAZ | INSIGHTS 2023 31

32. PREVENTING CAPPING WITH SMART
TRIAXIAL COMPACTION
Finding a Purpose that changes your life in Science
5/31/2023 © AJAZ | INSIGHTS 2023 32

33. 5/31/2023 © AJAZ | INSIGHTS 2023 33
For those interested in a quick overview of my journey to 2020 and currently.
[Additional Slides]

34. 5/31/2023 © AJAZ | INSIGHTS 2023 34
Get to the rut in
the system.
BAD-I is a
global issue!
Empower!
Look out!

35. 5/31/2023 © AJAZ | INSIGHTS 2023 35

36. 5/31/2023 © AJAZ | INSIGHTS 2023 36

37. EXPERIENCE EVOLVES WHEN
MEANING CHANGES WITH EVIDENCE
The varying definitions of "valid"
can serve as examples to depict
different stages of the evidence
system and professional maturity.
Appeal to authority fallacy; a logical
fallacy claiming that because an expert said
something is true, it must be true. Fallacies
(Stanford Encyclopedia of Philosophy)
The 2011 US FDA Guidance on
pharmaceutical process
validation follows more
comprehensive principles.
Previous mandates relied too
heavily on consensus [opinion] on
the adequacy of three qualified
batches without due diligence to
variance and uncertainty.
How do you know what you know is “valid”?
Click the picture to view the slides of my Lecture at IMT Mines, Albi, France, on November 14, 2018.
5/31/2023 © AJAZ | INSIGHTS 2023 37

38. 5/31/2023 © AJAZ | INSIGHTS 2023 38
The Kefauver Harris Amendment of 1962
And 21 CFR 211.25

39. AN INDICATOR OF IMMATURITY IN THOSE WHO CLAIM TO BE
SCIENCE-BASED – IS “ONE–SIZE–FITS [ALL],” THE PROCRUSTEAN
ATTITUDE. A R E Y O U N G C H I L D R E N C R U E L ? | P S Y C H O LO G Y TO DAY. A R E T H E Y, N O T M I N I - P R O C R U S T E S ? W H AT
M AY A P P E A R C R U E L I S A PA S S I N G P H A S E , L E A R N I N G I M P U L S E C O N T R O L A N D TA K I N G P E R S P E C T I V E . A D U LT C R U E LT Y,
L A C K O F E M PAT H Y, A N D I M P U L S E C O N T R O L A R E .
THE PROCRUSTEAN
DYSTOPIA OF 1984
C H E A P I L L U S I O N S : Medical Bankruptcy: Still
Common Despite the Affordable Care Act | AJPH |
Vol. 109 Issue 3 (aphapublications.org)
Prof. Les Benet frequently criticizes the fixed “80-125” stance (ACPS Transcripts ’95 and 2000). Adding on the 10X scale-up factor, 3-batches, and other issues that
followed the Hatch-Waxman Act (1984), the Generic Drug Scandal, crystallized and polymorphed “one-size-fits-all” system of regulatory practices.
5/31/2023 © AJAZ | INSIGHTS 2023 39

40. Procrustean
5/31/2023 © AJAZ | INSIGHTS 2023 40

41. Adult development
Sustain and Build a Quality Culture in Today's Realities (slideshare.net)
5/31/2023 © AJAZ | INSIGHTS 2023 41

42. Chemometrics, Pharmacometrics, and Econometrics: Dimensions of Quality by Design (slideshare.net) 25 May 2012
Hussain, A. S. Chemometrics, pharmacometrics, and econometrics: Dimension of Quality by Design. Swiss. Pharma. 34(6) 2012
5/31/2023 © AJAZ | INSIGHTS 2023 42

43. 5/31/2023 © AJAZ | INSIGHTS 2023 43
The answer to “Where is the science in pharmaceutical science” is in SMART Triaxial Compaction.
And that it prevents capping should be commonsense but isn't

44. MIND MATTERS
Safely and Modestly Acknowledge, Research,
and Test backpropagated errors to challenge
beliefs, assumptions, and prior knowledge; correct
and establish “new prior knowledge.”
Leverage scientific training and experience to
effectively self-author development reports,
proposals, plans, and SOPS
Negotiate fairly and responsibly SMART
management objectives to implement plans for
reducing development timelines, improving
continually, and remaining relevant in a
revolutionary SMART factory
Sentiment Monitoring Analysis Research and
Testing done right can help support project
management
5/31/2023 © AJAZ | INSIGHTS 2023 44

45. “CHAOS BEFORE 2020” IN OUR
MICROCOSM? WHAT DO I MEAN?
Key highlights
5/31/2023 © AJAZ | INSIGHTS 2023 45
A Systems Perspective on Common and Special Excipients IFPAC 2019 (slideshare.net)

46. 5/31/2023 © AJAZ | INSIGHTS 2023 46

47. 5/31/2023 © AJAZ | INSIGHTS 2023 47
Do I want to be in this
system? My thoughts when
upset and angry and I
consider Advance Care
Planning. How do I
channel my anger to
passion and compassion
and be a part of the
solution?
Nobody Should Die Alone: A
Father’s Message to a Physician
Daughter (sagepub.com)
Hospital checklists are meant to save lives
— so why do they often fail? | Nature

48. PM 483
OBSERVATIONS:
“AJAZ THE AVENGER”
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?
No Action Indicated (NAI)
Voluntary Action Indicated (VAI)
Official Action Indicated (OAI) means
regulatory and administrative actions
will be recommended [banned from
future participation in CSF]
5/31/2023 © AJAZ | INSIGHTS 2023 48

49. IN OVER OUR HEADS: THE MENTAL DEMANDS OF
MODERN LIFE, ROBERT KEGAN (1994)
PM 483 for the Avenger: NAI, VAI, or
OAI; you decide. Also, assign (a) +
(b) + (c) + (d) + (e) = 1.
OX (2010) = (a)*O1 + (b)*O2 + (c)*O3
+ (d)*O4 + (e)*O5
[Ox (2023) = ?]
5/31/2023 © AJAZ | INSIGHTS 2023 49

50. 5/31/2023 © AJAZ | INSIGHTS 2023 50

51. 5/31/2023 © AJAZ | INSIGHTS 2023 51

52. IN OVER OUR HEADS: THE MENTAL DEMANDS OF
MODERN LIFE, ROBERT KEGAN (1994)
PM 483 for the Avenger: VAI
OX (2010) = (0.3)*O1 +
(0.2)*O2 + (0.00)*O3 +
(0.5)*O4 + (0.00)*O5
[Ox (2023) = ?]
5/31/2023 © AJAZ | INSIGHTS 2023 52

53. MATURITY IS SENSITIVE TO
INITIAL CONDITIONS
Growing up in Inda expected to be a chemical
engineer, but instead, B.Pharm – why do you want to
be a compounder? UC, Merrell Dow…
Daubert v. Merrell Dow Pharmaceuticals, Inc. 509 U.S. 579 (1993) ::
Justia US Supreme Court Center
On January 6, 1817, Lyman Spalding formally proposed the
framework for the (usp.org)
In 1906, the Pure Food and Drug Act defined drugs as “all
medicines and preparations recognized in the USP or NF
Formulary (NF)
Federal Food, Drug, and Cosmetic Act (FD&C Act) | FDA
kefauver-harris_amendments.
The generic drug scandal Judge Wolin's interpretations of CGMP
1995 to OPS to SUPAC, PQRI, BCS, to PAT QbD to
Pharmaceutical Quality for the 21st Century
My
Initial
conditions
to
OPS
OOS, “omission or commission,”
“common or special cause,”
CAPA, validation, CPV, CI
“imagined chart” Suitable and Capable, CD?
"Common sense is the collection of prejudices acquired by eighteen,” Einstein.
“Give me the child for the first seven years, & I will give you the [adult.]” Loyola
Maturity of the FDA and CDER Quality Management Maturity | FDA
The Compliance and Science of Blend Uniformity Analysis
PM 483
PM
My
understanding
Need help to make common sense?
5/31/2023 © AJAZ | INSIGHTS 2023 53

54. PREVENTING CAPPING WITH SMART
TRIAXIAL COMPACTION
Finding a Purpose that changes your life in Science
5/31/2023 © AJAZ | INSIGHTS 2023 54

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