From my experience, how can I describe an intuitive and self-organizing social force around "attractors" patients' value to be assured of therapeutic equivalence?

1. TOWARDS GLOBAL
REGULATORY
RESILIENCE
Out of the Crisis to Ensure
Therapeutic Equivalence
12/2/2023
© AJAZ | INSIGHTS 2023 1

2. Global Regulatory Resilience
 In May 2023, the US FDA issued an "Immediately in Effect Guidance for Industry"
requiring testing for diethylene glycol in high-risk drug components, highlighting
the vulnerability of the global pharmaceutical supply chain. It also reminds us
that there is a significant difference between knowing what to do and doing it.
 The need for proactive, forward-looking, and strategic approaches to resilience is
becoming palpable worldwide. Was such a condition discernible in 1937 when
the Elixir of Sulfanilamide tragedy was a tipping point for enacting the US Food,
Drug, and Cosmetic Act of 1938? Or was it a “never let a crisis go to waste”
mindset leveraging another crisis for a political agenda? What does it mean? I
anticipate an exponential increase in uncertainty and a decline of trust in our
practice environment, and to exercise our duty to care, we will need to find a way
to make common sense via careful meaning and sensemaking.
 Al-Ghazali (c.1056–1111) and René Descartes (1596–1650) argued against the
infallibility of sense perception, and we, too, must acknowledge that "common
sense is not so common," as Voltaire once said. Yet, we must work to make safety
and quality a matter of common sense.
© AJAZ | INSIGHTS 2023 12/2/2023 2

3. Commonsense
steps to Resilience
essential for
continued
development
Intuitionally ↔
institutionally
 Don’t fear; learn to channel fear and anger to a purpose you care for
 Beware and keep expanding the scope and depth of your awareness
 In a moment and minutes, reflect on past experiences to reframe in new
knowledge
 Do so repeatedly. It presents us with insightful intuitions to be wiser today than
yesterday and a step closer to resilience needed in the chaos that surrounds us
 A commonsense approach to moving towards global regulatory resilience is
your responsibility, as it once was my duty
 A duty to make common sense of the efforts in the “Office of Pharmaceutical
Science,” the predecessor of the “Office of Pharmaceutical Quality,” of the US
FDA, to come out of the generic drug crisis and to ensure therapeutic
equivalence
© AJAZ | INSIGHTS 2023 12/2/2023 3

4. © AJAZ | INSIGHTS 2023 12/2/2023 4
From my experience, how can I describe an intuitive and self-organizing social force around "attractors" patients'
value to be assured of therapeutic equivalence?

5. © AJAZ | INSIGHTS 2023 12/2/2023 5
Following Ranbaxy,* in 2014, there was a
significant surge in BAD-I (breaches in the
assurance of data integrity) observations by
the US FDA. A trade magazine sought four
perspectives: Confronting Illusions of Quality
in Indian Generics Manufacturing (24 March
2014).
FDA: Takahashi: Look Out for These Data Integrity
Issues
A GMP consultant: Cahilly: Focus on India Masks the
Real Data Integrity Problems,
A corporate whistleblower: Thakur: Data Integrity
Requires Stronger Local Enforcement
Myself: Hussain: Empowering Workers is the Key to
Data Integrity
*Bottle of Lies: The Inside Story of the Generic Drug
Boom by Katherine Eban | May 2019
FDA ACPS Meeting November 28, 2001
2014/15: Why FDA reverted to the 21st Century Initiative [2.0.] after it “lost” its original “team” approach

6. The heart of the
matter
 Experience, the third qualifying leg of “good
practices” alongside education and training,
 How, in [professional] routines, I learn (and
fail to understand) from experience, mine
and others, presents a way to help you
consider how you learn from your
experiences.
 Why epistemology matters in science,
particularly how it influenced my efforts at
the Office of Pharmaceutical Science, CDER,
US FDA advancing BCS, PAT, Process
Validation, and ICH Q8, 9, and 10 guidance.
© AJAZ | INSIGHTS 2023 12/2/2023 6

7. OUTLINE
Background
• From my portfolio of contemporaneously noted experience, which experience would be most relevant to share in this conversation?
Sequence and Process: How?
• To start and continue this conversation, how should I arrange the chosen experiences?
Experiments and a Plan
• Journey to 2020: To see more clearly now
Synthesis
• Some consideration for assuring TE in Saudi Arabia
Closing
• What if I say we need more common sense?
12/2/2023
© AJAZ | INSIGHTS 2023 7

8. BACKGROUND
From my portfolio of contemporaneously noted experience,
which experience would be most relevant to share in this conversation?
12/2/2023 © AJAZ | INSIGHTS 2023 8

9.  In a 2018 report of a conference sponsored by
King Saud University, what was on the minds of
participants?
 “Quality is not an act; it is a habit.”
 Saudi 21st century pharmacovigilance practices
 Regulatory transparency in Saudi Arabia
 Should there be “reference regulatory systems”?
 SFAD should conduct its bioequivalence studies?
 Bioequivalence information should be provided …in
leaflets.
 Lack of national standards regarding therapeutic
switching
 Intuitions and habits are subconscious and
highly efficient, so they better be good (=valid)
and, in uncertainty, intuition is our only guide. ,
and, in uncertainty, intuition
© AJAZ | INSIGHTS 2023 12/2/2023 9
Local concerns

10. Saudi 21st century
pharmacovigilance
practices?
 ICH Topic E 2 E
Pharmacovigilance Planning
(Step 5, June 2005)
 Adoption in Saudi Arabia,
and associated training,
 Option for SFDA to propose
for revision, considering
Generics are now part of ICH
 Some lessons in the USA,
the case of a generic
transdermal patch?
© AJAZ | INSIGHTS 2023 12/2/2023 10

11. Regulatory
transparency in Saudi
Arabia
 “Therapeutic- In-equivalence,
detection and correction, and
improvement report”?
 In the context of generic drugs,
why does the US FDA continue
to struggle? What lessons may
help inform efforts in Saudi
Arabia?
© AJAZ | INSIGHTS 2023 12/2/2023 11

12. Should there be
“reference regulatory
systems”?
 The systems in the West are in
the modes of “Build Back
Better,” and, perhaps in
anticipation, letting the existing
systems decay.
 With the progress at SFDA,
committing to. Self-authorship
is the way to go forward with a
commitment to Self-
transforming
© AJAZ | INSIGHTS 2023 12/2/2023 12

13. Should SFAD conduct its
bioequivalence studies?
 The immediate answer is No!
Why SFDA should not take this
on needs to be explained.
 SFDA should utilize a team
approach to ensure Therapeutic
Equivalence via its established
functions.
 Perhaps, as an additional layer
of security, independent, not-
for-profit CRO-type institutions
associated with an academic
unit should be considered.
© AJAZ | INSIGHTS 2023 12/2/2023 13

14. Yes, bioequivalence
information should be
provided …in leaflets
[package inserts]
12/2/2023 14
© AJAZ | INSIGHTS 2023

15. Lack of national standards regarding therapeutic
switching: A version of the US FDA “Orange Book”?
 Faculty at the King Saud University, Riyadh, Saudi
Arabia, and other collaborators have pondered
Prospects of Establishing a Saudi Version of the
United States Food and Drug Administration Orange
Book – ScienceDirect
 Perhaps some aspects should be emphasized with a
focus on real-world considerations, including a user
interface that patients can also use with their
devices,
 Please do not print a book with an orange cover.
Donald Hare, my former colleague who led the
Orange Book effort at the FDA, once told me that he
chose orange because it reminded him of the
Halloween season.
© AJAZ | INSIGHTS 2023 12/2/2023 15
Pharma Times - Vol. 52 - No. 09 - September 2020

16. Sequence and
Process: How?
To start and continue this
conversation, how should I
arrange the chosen experiences?
© AJAZ | INSIGHTS 2023 12/2/2023 16

17. Parts and System
 Systems thinking is essentially holistic.
 We can not build the ‘best’ car by combining
the best parts of all the vehicles on the
market. (they won’t fit) ~ Russell Ackoff
 Moreover, since we are discussing a social
system, it is essential to infuse it with an
intuitive and self-organizing force with
foundational "attractors" such as care and
competence, which are highly valued by the
community and institutions.
© AJAZ | INSIGHTS 2023 12/2/2023 17

18. Intentionality that intuitively generates responsibility to self-organize
around value "attractors" of the community and institutions: SMART
© AJAZ | INSIGHTS 2023 12/2/2023 18
SMART

19. Resources
12/2/2023 19
 Out of the Crisis, W. Edwards
Deming, The MIT Press
 In Over Our Heads: The Mental
Demands of Modern Life, Robert
Kegan, Harvard University Press
 Thinking, Fast and Slow, Daniel
Kahneman, Farrar, Straus and Girou
 The Master and His Emissary: The
Divided Brain and the Making of the
Western World, Iain McGilchris, Yale
University Press
© AJAZ | INSIGHTS 2023

20. My Memories,
Materials, and
Methods.
 Our memories are a product of
our experiences, but their
accuracy is far from reliable.
 I kept contemporaneous notes
(since 2014), material for my
memories
 For topics and context before
2014, I refer to FDA meeting
transcripts, presentations, and
writing in the public domain
 This is my “method” to assure
the “integrity of experience”
illustrated in the discussion
12/2/2023
© AJAZ | INSIGHTS 2023 20

21. © AJAZ | INSIGHTS 2023 12/2/2023 21

22. Insights I derive from
intuitions in my experiences I
note contemporaneously.
 To promote the integrity of my
subjective experiences,
complementing memories and
correcting biases when needed
 On LinkedIn there are 111
insightful articles, some stand-
alone and others editions of my
”SMART” Newsletter.
 Self-monitoring assumptions,
researching and testing to
generate “new prior
knowledge”,
© AJAZ | INSIGHTS 2023 12/2/2023 22

23. The Intuitive Mind is a Sacred Gift, and the Rational Mind
is a Faithful Servant. INTUITION IS THE HIGHEST FORM OF INTELLIGENCE (FORBES.COM)
 But the gift is wrapped, and we need to learn how to unwrap it properly to peel
away confirmation biases that favor external validation over internal validation
 What [thought] comes to mind quickly, often instantaneously as it seems, is the
"available" information in the unconscious. It comes via an availability heuristic (a
shortcut (our lazy) mind takes around the effort needed to reason). What comes
instantaneously to mind varies with the “state of mind” - fearful, angry, anxious,
depressed, or rational. Expanding the available and exploring without fear.
 Take a moment, listen to the silence in sounds, and pay attention to breathing
(slow your exhalation to tip the balance from sympathetic to parasympathetic);
practice repeatedly shifting your on-demand mind to a higher “Order of
Consciousness,” an empathetic, self-transforming mind.
 Having channeled my anger, not that I was angry at that moment, I achieved a
purposeful, empathetic state to ask, am I anchoring onto a familiar and
comfortable situation? How should I “pull up” my anchoring bias and sail out of
my comfort zone? In mere asking, I have taken a developmental stance, ready to
begin good (valid) sensemaking.
 This is my sensemaking process to learn from experience (feelings); I suggest you
probe how you know from your subjective experience and find a way to improve
the process – to make this seamless.
© AJAZ | INSIGHTS 2023 12/2/2023 23
SMART Sensemaking Civility, Collapse
& "Cartesian Anxiety" | LinkedIn
A SMART present of deeds wrapped in
recollections of past and future
visualizations. | LinkedIn

24. Challenges to Pharmaceutical Quality 2014/15:
Lacking “One Quality Voice”
 White-Paper--FDA-Pharmaceutical-Quality-Oversight.pdf (2015)
 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 knowledge gained from
product review. Inspections often cannot cover all products and
processes
 [“21st Century Initiative 2.0.” What happened to 1.0?]
© AJAZ | INSIGHTS 2023 12/2/2023 24

25. © AJAZ | INSIGHTS 2023 12/2/2023 25
Did you know that since its inception in 1984, the US Generic Market has remained chaotic?

26. © AJAZ | INSIGHTS 2023 12/2/2023 26
Is observing (1) to (8) in the same picture rational?

27. © AJAZ | INSIGHTS 2023 12/2/2023 27
After leaving the US FDA, I was in the biotech, not the generic, divisions of the company on the left and then the same in the company on the right.

28. 12/6/2020
AJAZ | INSIGHTS 28
Who insisted on the particular dissolution test and acceptance criteria?

29. 12/6/2020
AJAZ | INSIGHTS 29

30. Oxymoronic
intentionally
 Current challenges in approval of ANDA’s. [A] For 10% of all FDA-approved NDAs (100%), no
ANDA has been submitted despite expired patents and exclusivities
 [B] Quoting an FDA-issued Federal Register notice—“The drugs described in more than half
of all FDA-approved ANDAs are never marketed, marketed only after a substantial delay after
approval, or marketed only intermittently. Such failures to market contribute to drug
shortages and hinder consumer access to approved products.”
 [C] Percentage of approved and commercialized ANDAs
© AJAZ | INSIGHTS 2023 12/2/2023 30

31. [D] ANDA’s that can
take eight or more
years to approve
 A case example that highlights
a struggle to ask the right
question at the right time and
information silos within the
organization that hinders an
integrative design and system
approach to assessing the
“totality of evidence.”
 A “scientific dispute resolution”
process is often needed in such
cases to force all parts of the
system to be in the same room
and then on the “same page,”
© AJAZ | INSIGHTS 2023 12/2/2023 31
Totality of Evidence & Theraputic Equivalence 15 October
2016 | PPT (slideshare.net)Therapeutic

32. © AJAZ | INSIGHTS 2023 12/2/2023 32
FDA Guidance: Size--Shape--and-Other-Physical-Attributes-of-Generic-
Tablets-and-Capsules (2015).pdf (FDA.GOV) [Why in 2015?]
A Survey of Patients’ Perceptions of Pill Appearance and Responses to
Changes in Appearance for Four Chronic Disease Medications | 2019
SpringerLink [a change in the appearance of a generic medication matters]
2015
2019

33. Intuitively, I (we) have known quality is an expectation; can we now
[institutionally] acknowledge it?
Speaking metaphorically, it seemed an FDA Commissioner, who in a previous role had worked with me in the
context of the 3 September 2003 Wall Street Journal report about the PAT initiative, had taken “the Blue Pill.”
© AJAZ | INSIGHTS 2023 12/2/2023 33
Color a proxy for lack of assurance!

34. The Pharmaceutical Industry has a “little secret.”
NEW PRESCRIPTION FOR DRUG MAKERS: UPDATE THE PLANTS - WSJ
 As recognized in the FDA’s Orange Book, “Therapeutic Equivalence” is an
expectation. Expectation effects are in play in the real world where patients use
the medicine. [Relevance to Saudi ecosystem: Prospects of Establishing a Saudi
Version of the United States Food and Drug Administration Orange Book –
ScienceDirect]
 Might we have been assuming that “placebo-controlled” trials do not merely
“account for” but also remove such an effect in the real world? Perhaps now,
this may be the “little secret”?
 Since its release in 1999, The Matrix has endured as a potent representation of
the technologically motivated identity crisis of the early 21st century. The red and
blue pill represents a choice between the willingness to learn a potentially
unsettling or life-changing truth [taking the red pill] or remaining in the contented
experience [the blue pill]. It is a helpful metaphor, which in this context is eerily
poignant.
 Perhaps we are unwilling to learn to learn any potentially
unsettling or life-changing truth?
© AJAZ | INSIGHTS 2023 12/2/2023 34

35. Initiative 1.0, erased from memory?
 How the initiatives got launched and progressed is outlined in
the FDA 2004 White Paper, Innovation, and Continuous
Improvement in Pharmaceutical Manufacturing:
Pharmaceutical CGMPs for the 21st Century. The PAT Team
and Manufacturing Science Working Group Report: A
Summary of Learning, Contributions and Proposed Next
Steps for Moving Towards the “Desired State of
Pharmaceutical Manufacturing in the 21st Century. September
2004 (it is hard to find as it no longer exists on the FDA
Internet, and one has to use the “Wayback Machine” to find
it).
 Also available is a short video recording (~2004) of me
explaining How the PAT/QbD Journey Began.
© AJAZ | INSIGHTS 2023 12/2/2023 35
Pharmaceutical
Quality for the
21st Century 1.0?

36.  "We're a very small part of FDA," says
Hussain. "The rest of the FDA still needs to
come on board.”
 ” The challenge in the industry is even
greater, says Afnan. However, the FDA's PAT
squad has already begun transforming the
Agency's, and the industry's, mindset about
quality and compliance.”
 “FDA'S PAT TEAM, PAT (Process Analytical
Technologies) is the rarest of revolutions. It
needed brilliant thinkers and some prodding
to get off the ground, but it is now a team-
driven movement. If it succeeds, it will mean
unprecedented changes for industry and
regulators.”
© AJAZ | INSIGHTS 2023 12/2/2023 36
FDA's PAT Team: Shall We Dance? | Process Analytical Technology | Pharmaceutical Manufacturing | 6 April 2005
PAT Team and Guidance

37. EMA PAT TEAM
Mandate-process-analytical-
technology-team_en.pdf (Europa.eu)
Should I have insisted on a mandate
for the FDA PAT Team?
I estimated the sector would take a
decade or so (2020) to transform. A
mandate in the US FDA context
would not be appropriate. Also,
mandating would make me an
imperialist!
The challenge is the deep division
between the Review and Inspection
functions (as reflected in the
following:
CDER’s Janet Woodcock “Nobody
Can Really Tell Me If FDA
Inspections Are Effective” (April 23,
2013 pharmaceuticalonline.com)
© AJAZ | INSIGHTS 2023 12/2/2023 37

38. © AJAZ | INSIGHTS 2023 12/2/2023 38
State of QbD Implementation: Adoption, Success, and Challenges:
Ted Fur, McKinsey & Co (June 2010), FDA ACPS Meeting 27 July 2011
?
?
Underestimated complexity QTPP = Compendial monograph, “subjective” risk-matrix,……….
Video: 360 Degree View of Quality by Design, USP International Conference 2017

39. It takes work to
make common
sense.
 Our compartmentalized
functions focus on local
objectives, cascaded down
from a system output aiming
at profit and productivity.
 R&D and Regulatory Affairs
incentivized for “file first”:
Generics are about “file first;
figure it out later.”
 “Huge amount of reviewer
inconsistency”
© AJAZ | INSIGHTS 2023 12/2/2023 39
State of QbD Implementation: Adoption, Success, and Challenges:
Ted Fur, McKinsey & Co (June 2010), FDA ACPS Meeting 27 July 2011
FDA PAT Guidance 2004
ICH Q8 (2006)

40. © AJAZ | INSIGHTS 2023 12/2/2023 40
SMART Triaxial Compaction, Social Form 483, and VAI
or OAI to an Avenger (2023) (slideshare.net)
Reflecting on a 2010 FDA conference notes in Pharmaceutical Manufacturing Magazine.
“Divide and Rule,” not appreciating
the systemic foundation

41. EXPERIMENTS
AND A PLAN
Journey to 2020: To see more
clearly now
12/2/2023 41
© AJAZ | INSIGHTS 2023

42. A journey to reflect,
Reframe and
Respond,
 A: For 10% of all FDA-approved NDAs (100%), no ANDA has been submitted despite expired
patents and exclusivities
 B: Quoting an FDA-issued Federal Register notice—“The drugs described in more than half
of all FDA-approved ANDAs are never marketed, marketed only after a substantial delay after
approval, or marketed only intermittently. Such failures to market contribute to drug
shortages and hinder consumer access to approved products.”
 C: Percentage of approved and commercialized ANDA’s
© AJAZ | INSIGHTS 2023 12/2/2023 42
Pharmaceutical “New Prior Knowledge”: Twenty-First Century Assurance of Therapeutic Equivalence | AAPS PharmSciTech (2019)
Roadblocks-to-Roadmap-2017-with-A-2020-Vision-
12182016-Final-Version.pdf (NIPTE.ORG)

43. © AJAZ | INSIGHTS 2023 12/2/2023 43
Physicochemical failure modes for Narrow Therapeutic Index (NTI) drugs (2 July 2021 europeanpharmaceuticalreview.com)

44. © AJAZ | INSIGHTS 2023 12/2/2023 44
Corporate training with capstone experience and certification

45. © AJAZ | INSIGHTS 2023 12/2/2023 45
Industrial Policy and NIPTE: Goodbye NIPTE |
PPT (7 December 2020)
Do we need a new curriculum and ways of educating?
“Backward Design” to prioritize the intended learning outcomes
instead of topics to be covered* (a pilot program @ US FDA)
*Kari L. Clase, Loran C. Parker, Kenneth R. Morris, Stephen R. Byrn, Vadim J. Gurvich: Design of a NIPTE
certificate curriculum in industrial pharmacy, drug formulations, and drug quality (to be published)
Do we need a new curriculum and ways of training CMC Review staff at the US FDA?

46. CHAOS TO
CONTINUAL
IMPROVEMENT:
PATH TO
HARMONIZATION
 After taking a break in 2018, partly to make sense of
why chaos with continual improvement juxtaposes
in the highly regulated environment, I am pleased
to contribute to the 2019 CPhI Worldwide report.
 This report builds on my previous two contributions
to CPhI Worldwide reports, 2016-2017. [
 The following musing seeks the emergence of a
“Butterfly Effect” around two, not so “strange
attractors,” real-world satisfaction in
pharmaceuticals and professional development in
the sector.
 These attractors are intuitive; “common sense.” But
it can be in a “blind spot”- and in a globalized
supply chain, often needing a reminder.
© AJAZ | INSIGHTS 2023 12/2/2023 46
CPhI Annual Industry Report 2019

47. NIPTE goes to Capitol Hill: New Prior Knowledge & Centers for Excellence:
US CONGRESS PASSES BILL SUPPORTING NEW ERA OF BIOPHARMA ADVANCED CONTINUOUS MANUFACTURING (JANUARY
2022)
In and Beyond COVID-19: US Academic Pharmaceutical Science and Engineering Community Must Engage to
Meet Critical National Needs - PubMed (May 2020)
© AJAZ | INSIGHTS 2023 12/2/2023 47

48. © AJAZ | INSIGHTS 2023 12/2/2023 48

49. SYNTHESIS
© AJAZ | INSIGHTS 2023 12/2/2023 49

50. Saudi 21st-century
pharmacovigilance practices?
 Pharmacovigilance system in Saudi Arabia –
(2017) PubMed (nih.gov) was helpful
background. You can read it as I did. My
comments are based on my experience.
 ICH Topic E 2 E Pharmacovigilance Planning
(Step 5, June 2005)
 Adoption in Saudi Arabia and associated training:
Consider including case examples of what worked
and didn’t work well following the implementation
of ICH guidelines SFDA is adopting. It will provide
an opportunity to reflect and reframe the issue in
the local context and how responding to similar
situations locally can be of value.
 The merit of an option for SFDA to propose for
revision, considering Generics are now part of
ICH?
© AJAZ | INSIGHTS 2023 12/2/2023 50
Regulatory Training on ICH Quality Guidelines | Saudi Food and Drug
Authority (sfda.gov.sa)

51. What did I learn from
experiences over these years:
1995, 2005, 2006, 2014, 2016,
and 2023?
 Transdermal drug delivery system (TDDS) adhesion as a critical safety, efficacy,
and quality attribute – (2006) ScienceDirect
 Current Good Regulators of Pharmaceuticals (cGRP) | LinkedIn (5 April 2016)
 Assessing Adhesion With Transdermal and Topical Delivery Systems for ANDAs
Draft Guidance for Industry | FDA (April 2023)
© AJAZ | INSIGHTS 2023 12/2/2023 51
Good Regulators of Pharmaceuticals (GRP) 22 October 2014 |
PPT (slideshare.net) at University of Iowa.
Intuition, Investigation, insight, Institutionalization, Industrialization of an Improvement that saves lives. But..

52. Regulatory
transparency in Saudi
Arabia
 “Therapeutic- In-equivalence,
detection and correction, and
improvement report”?
 In the context of generic drugs,
why does the US FDA continue
to struggle? Case of “cherry
picking” BE studies!
 What lessons may help inform
efforts in Saudi Arabia? The
beginning of the US generic
sector (1984) was scandalous.
The root cause then persists.
Which SFDA can avoid.
© AJAZ | INSIGHTS 2023 12/2/2023 52
A case of ignoring Pharmaceutical Equivalence (micro-emulsion vs
solution in propylene glycol) and Label (RLD with apple juice, whereas
generic BE was with chocolate milk). FDA’s conflicting roles,
assessment, and promotion, in general, hinder transparency and
“generic hesitancy” and continue to erode confidence. The case led to
a rule change – failed BE students must be reported.

53. © AJAZ | INSIGHTS 2023 12/2/2023 53
Prescription for trouble / How flaw in FDA safety net may pose [a] risk to [the] public with generic
drugs (22 December 2002, sfgate.com)
2004 2013
The US FDA struggles with conflicting roles, assessment, and promotion and is concerned
with “generic hesitancy.” It struggles to self-correct and continues to erode confidence.
Hussain041122.pdf (nihs.go.jp)

54. © AJAZ | INSIGHTS 2023 12/2/2023 54
Structural or a functional flaw? Common cause or special cause? Or perhaps Structural functionalism?
The FDA
emphasizes that
this is a special
case -- a complex
drug for highly
sensitive patients --
that should not
undermine the
presumption that
generics can be
safely exchanged
for brand names in
most instances.
Compromising in the name of “generic hesitancy”……?

55. Should there be
“reference regulatory
systems”?
 The systems in the West are in
the modes of “Build Back
Better,” and, perhaps in
anticipation, letting the existing
systems decay.
 With the progress at SFDA,
committing to. Self-authorship
is the way to go forward with a
commitment to Self-
transforming
© AJAZ | INSIGHTS 2023 12/2/2023 55
The Kingdom has unique and advantageous cultural,
economic, political, and social aspects that affect leadership
and leadership development compared to the US and EU.

56. ICH in the “Fourth
Turning”?
 Sen. Johnson Introduces Legislation to
Protect American Sovereignty Against World
Health Organization, May 27, 2022
 Path of Political Disintegration? Common
ground, common cause, and common sense
 “Sometime before the year 2025, America will pass
through a great gate in history, commensurate with
the American Revolution, Civil War, and twin
emergencies of the Great Depression and World
War II.” ― William Strauss and Neil Howe, The
Fourth Turning: What the Cycles of History Tell Us
About America's Next Rendezvous with Destiny
(1996)
© AJAZ | INSIGHTS 2023 12/2/2023 56

57. The topic of public health response
to COVID-19 is now getting mired in
controversy, and how it evolves in
the chaos it precipitates is still
being determined. What is certain
is that it will profoundly impact our
lives and practices.
 In the USA, grave questions
have arisen along with
allegations.
 Amidst the “bipolar politics”
and censorship, there are
ongoing investigations
 I have informed opinions, a clip
from a report in the New York
Times that quoted me.
© AJAZ | INSIGHTS 2023 12/2/2023 57

58. Should SFAD conduct its
bioequivalence studies?
 The immediate answer is No!
Why SFDA should not take this
on needs to be explained.
 SFDA should utilize a team
approach to ensure Therapeutic
Equivalence via its established
functions.
 Perhaps, as an additional layer
of security, independent, not-
for-profit CRO-type institutions
associated with an academic
unit should be considered.
© AJAZ | INSIGHTS 2023 12/2/2023 58

59. Yes, bioequivalence
information should be
provided …in leaflets
[package inserts]
12/2/2023 59
© AJAZ | INSIGHTS 2023

60. The FDA ensures
“bioequivalence,” so
what's the argument
about?
 Within the FDA, we asked the
following questions in the
Bioprmaceutics Coordinating
Committee Committee, where
my focus was on BCS-based
waiver of in vivo BA/BE studies
(see: 2000).
 What is the primary question of
the study?
 What are the tests that can be
used to address the question?
 What degree of confidence is
needed for the test outcome?
© AJAZ | INSIGHTS 2023 12/2/2023 60
Bioavailability and Bioequivalence: An FDA Regulatory Overview (2001)| SpringerLink
Bioequivalence – Still a Quality Achilles’ Heel? 16 October 2014 | University of Heidelberg

61. Reactions to the 13-November 2014
FDA Action on Generic
Methylphenidate ER tablets
 Social Media Megaphone,
the new Voice of the
Patients, see my posts:
 Voice of the Patient | PPT
(slideshare.net)
 Voices of/for Patients | PPT
(slideshare.net)
© AJAZ | INSIGHTS 2023 12/2/2023 61

62. © AJAZ | INSIGHTS 2023 12/2/2023 62
Bioequivalence – Still a Quality Achilles’ Heel? 16 October 2014 | University of Heidelberg
Janssen Quietly Ends Concerta Authorized-Generic (27 April 2023, adhdrollercoaster.org)

63. © AJAZ | INSIGHTS 2023 12/2/2023 63
FDA asked that within six
months, Mallinckrodt and
Kudco (now UCB/Kremers
Urban) confirm the
bioequivalence of their
products using the revised
bioequivalence standards
(see 2009 on slide #28) or
voluntarily withdraw their
products from the market.
What was the right question to
have asked in the first place?
Patients still in 2021 are
saying: “Concerta Generic Is
Not Created Equal: ADHD
Medication
(additudemag.com).”
Readers are reporting getting Concerta, sometimes covered by their pharmacy insurance
benefit. However, some have had to go through Prior Authorization (sometimes called an
Exception Process). They had to try two other methylphenidate generics first, to poor effect.
Only then could they access the brand Concerta.
Bioequivalence – Still a Quality Achilles’ Heel? 16 October 2014 | University of Heidelberg

64. What went wrong?
Questions and Answers Regarding
Methylphenidate Hydrochloride
Extended-Release Tablets (generic
Concerta) made by Mallinckrodt and
UCB/Kremers Urban (formerly Kudco) |
FDA
© AJAZ | INSIGHTS 2023 12/2/2023 64
One-size-fits-all
approach to BE,
recall in 2009, partial
AUC approach was
in place.

65. © AJAZ | INSIGHTS 2023 12/2/2023 65
Leadership, Butterfly Effect, Levothyroxine Therapeutic
Equivalence LIU, Brooklyn, NY 13 February 2019 | PPT
Leadership for 21st Century Pharmaceuticals @ IMT Mines,
Albi, France, 14 November 2018 I PPT
Previous lectures on this case study:
Did you know that Therapeutic Equivalence is an
expectation?
Do you think expectancy effects are now more prominent
than 5, 10, or 20 years ago?

66. TE is an expectation.
 Therapeutic Equivalents. Approved drug
products are considered to be therapeutic
equivalents if they are pharmaceutical
equivalents for which bioequivalence has
been demonstrated, and they can be
expected to have the same clinical effect and
safety profile when administered to patients
under the conditions specified in the labeling
 What about Label and CGMP considerations?
Why not consider it here but separately?
© AJAZ | INSIGHTS 2023 12/2/2023 66

67. In the Orange Book: FDA classifies as therapeutically
equivalent those drug products that…
 (1) they are approved as safe and effective [1];
 (2) they are pharmaceutical equivalents in that they (a)
contain identical amounts of the identical active drug
ingredient in the identical dosage form and route of
administration, and (b) meet compendial or other applicable
standards of strength, quality, purity, and identity;
 (3) they are bioequivalent in that (a) they do not present a
known or potential bioequivalence problem, and they meet
an acceptable in vitro standard, or (b)if they do present such
a known or potential problem, they are shown to meet an
appropriate bioequivalence standard;
 (4) they are adequately labeled; and
 (5) they are manufactured in compliance with Current Good
Manufacturing Practice regulations.
© AJAZ | INSIGHTS 2023 12/2/2023 67
[1] Approval (based on safety and efficacy): Effectiveness is an expectation
(2)
(3)
(4)
(5)
(1) Effectiveness

68. Why, in 2022, is there a new draft
guidance on Therapeutic Equivalence?
 GUIDANCE_Draft:_Evaluation of Therapeutic Equivalence_Published_July
2022.pdf (fda.gov)
 Beyond reminding that Therapeutic Equivalence [TE] evaluations are a
“scientific judgment,” the draft begins to acknowledge that generic substitution
may involve social and economic policy administered by the states, e.g.,
reducing the cost of drugs to consumers. These evaluations [by the States, I
wonder if instance, as inequivalent] do not indicate that any product violates the
FD&C Act or is preferable to any other.
 The FDA may revise a therapeutic equivalence evaluation when new information
arises. The FDA has a provision to change a product’s TE code from an A-rating
to a B-rating if it obtains any information that raises questions about the data or
information on which the Agency relied while approving the drug product. This
includes issues related to the facility where the drug product was tested.
 It is a helpful summary with important Q&A. Between the lines, the nuances
hint at disagreement with some States, and reminders interspersed in the
familiar text suggest a concern or suspicion of fraud, perhaps accumulated
amidst the COVID-19 lockdown that hindered BIOMO inspections.
© AJAZ | INSIGHTS 2023 12/2/2023 68
Is it the month of May?
Or is it a distress signal,
a mayday call?

69. Lack of national standards regarding therapeutic
switching: A version of the US FDA “Orange Book”?
 Faculty at the King Saud University, Riyadh, Saudi
Arabia, and other collaborators have pondered
Prospects of Establishing a Saudi Version of the
United States Food and Drug Administration Orange
Book – ScienceDirect
 Perhaps some aspects should be emphasized with a
focus on real-world considerations, including a user
interface that patients can also use with their
devices,
 Please do not print a book with an orange cover.
Donald Hare, my former colleague who led the
Orange Book effort at the FDA, once told me that he
chose orange because it reminded him of the
Halloween season.
© AJAZ | INSIGHTS 2023 12/2/2023 69
Pharma Times - Vol. 52 - No. 09 - September 2020

70. Do not ignore the expectation vs. reality trap
 The US FD&C Act of 1938’s history highlights several
challenges that often go unnoticed
 It took several years to come up with a draft before 1938,
but there was no agreement reached
 The tragedy of the Elixir of Sulfanilamide in 1937 was a
significant factor that pushed the agreement forward.
 How do we remember the tragedy today – Sulfanilamide
Disaster | FDA. Why?
 The law formalized the requirements for "New Drug
Application" and "Inactive Ingredients," while the tipping
incident was a formulation issue unrelated to drug
safety.
 The FDA authorizes pharmaceutical products; it keeps a
“drug master file.” The term “pharmaceutical” is only
used in a small portion of the FDA’s legal vocabulary.
© AJAZ | INSIGHTS 2023 12/2/2023 70
Each amendment is born from a tragedy, some well-
known like Thalidomide and Heparin, others
unknown to the public.

71. Does anybody remember the
poor formulator?
© AJAZ | INSIGHTS 2023 12/2/2023 71
Testing of Glycerin, Propylene Glycol, Maltitol Solution,
Hydrogenated Starch Hydrolysate, Sorbitol Solution,
and Other High-Risk Drug Components for Diethylene
Glycol and Ethylene Glycol | FDA (MAY 2023)

72. CLOSING
© AJAZ | INSIGHTS 2023 12/2/2023 72

73. What if I say
we need more
common
sense?
Would you accept my answer? © AJAZ | INSIGHTS 2023 12/2/2023 73

74. Would you agree that
this is a case of common
sense not being so
common?
 An FDA Compliance Officer
noted quarantined albuterol
(API) batches and inquired
why.
 That’s for our animal product.
We are investigating
complaints. We found an
impurity.
 But isn’t albuterol made for
human use in the same
process?
 Yes, but it qualifies per USP!
Was the response of a master’s
degree holder.
© AJAZ | INSIGHTS 2023 12/2/2023 74
Product Quality & Patient Safety USP Workshop
Mumbai 12 June 2015 | PPT (slideshare.net)

75. © AJAZ | INSIGHTS 2023 12/2/2023 75
Ignoring problems by
avoiding them is
tempting, yet difficult
to overcome for
individuals and
corporations like "Big
Pharma.“ What
About the “Small
Pharma”?
How To Break The Pharmaceutical 2-3 Sigma Barrier (Like Amgen) 2017 (pharmaceuticalonline.com)

76. A practical, intrapersonal SMART, self-monitoring anger to reflect and transform guided by Constructive Theory of
Adult Development: In Over Our Heads: The Mental Demands of Modern Life, Robert Kegan (1994), Harvard University Press.
12/2/2023
© AJAZ | INSIGHTS 2023 76
With foundational education and training, the journey toward professional development begins with taking a deep breath and exhaling slowly.

77. “Pharmaceutical” Regulatory
Ecosystem in Saudi Arabia
 The education and training related to regulating
pharmaceutical products is comparatively more
established than what is often associated with
CMC review in the US. Strengthening statistics
and quantitative aspects, such as pharmaceutical
engineering, is essential.
 In the past, the FDA considered "development
pharmaceutics" more of an art than a science in
the US, which hindered the advancement of ICH
Q8 (Pharmaceutical Development Report).
 In the context of ICH, it is essential to consider
the significant implications and nuances that
arise from such ‘disciplinary” divide and
perceptions.
© AJAZ | INSIGHTS 2023 12/2/2023 77
Visiting My Alma mater, University of Cincinnati 20 April 2017 | PPT
(slideshare.net),
The Nation Needs a Comprehensive Pharmaceutical Engineering
Education and Research System (2005)
Statistical Thinking and Pharmaceutical Professional Development, a
keynote by Ajaz NCB 2023 20 June 2023 | PPT (slideshare.net)

78. A solid foundation in pharmacy, combined with knowledge of pharmaceutical engineering and a sense of
responsibility to self-author, is the first step towards achieving regulatory resilience on both local and
global scales. Understanding therapeutic equivalence (TE) is an essential requirement, and the ability to
manage expectations and satisfy others shows our professional maturity. Continuing to develop our skills
and knowledge is the path to achieving this level of maturity.
© AJAZ | INSIGHTS 2023 12/2/2023 78

79. Ajaz Hussain, Ph.D. | LinkedIn
Ajaz S. Hussain, PhD - YouTube
12/2/2023
© AJAZ | INSIGHTS 2023 79
Ajaz Hussain,Slideshare.net)