Little Secret: Unverified assumptions; adequate education, training & experience. Professional development; Elephant in the Dark. The Nation needs a “Critical Mass” of pharmaceutical professionals. We have 18 glinting candles, it is flooding all over; floodlights are needed. One Voice of suitable timber and consistency; improve awareness of opportunities NIPTE can offer.

1. “Third Leg for Suitability & Capability”
Pharmaceutical Quality System, Professional
Development and Continual Improvement
Ajaz S. Hussain, Ph.D. , President
The National Institute for Pharmaceutical Technology and Education, Inc.
8/17/2018 Email: ajaz@nipte.org 1

2. For:
• In support of or in favor of
• On behalf of or to the benefit of
• Tablets? Egyptian? Apple? Ahh,
you mean “pills”!
• Pharmaceutical
Technology & Education
8/17/2018 Email: ajaz@nipte.org 2

3. For Pharmaceutical
Technology & Education
• One Voice exorcising Pill Ghost’s dogmas
and blind spots
• Why: We need New Prior Knowledge SM &
Professional Development
• How: Focus Groups to Centers of Excellence
for careful feedback
• What: Careful feedback on research &
professional development to “know ledges” in
policies and to inform 21st-century practices
• Suitability and capability to pull the real
world of pharma away from the precipice
3

4. Suitability and Capability
for a Pull System
• 21st Century Pharmaceutical Quality
(BCS, PAT, QbD, PQS, …….)
• 21st Century Cures Act
• Real-world validation
• Internal validation
• Self-assurance
• Assurance
• Availability
• Affordability
Email: ajaz@nipte.org 8/17/2018 4
Professional Development
All Professionals
Global supply chain
Anyone who registers for medical intervention is labeled “patient”; we all are patients!

5. Performance of a
system depends on
how the parts
interact, never on
how the parts act
separately.
Prof. Russell Ackoff
SUITABLE 2
CAPABLE IN
COMPLEXITY
CAPABLE 2
SUITABLE IN
UNCERTAINTY
CAREFUL
PROPENSITY &
DISPOSITION
INTERNAL &
EXTERNAL
VALIDATION
SELF-
ASSURANCE 2
ASSURANCE
STABLE &
CAPABLE
PROCESSES
QUALITY BY
DESIGN
QUALITY
SYSTEM
Essential Parts of Pharmaceutical Professional Pull System

6. Answers to why
questions are
called explanations
which are outside
the system, never
inside it.
Prof. Russell Ackoff
SUITABLE 2
CAPABLE IN
COMPLEXITY
CAPABLE 2
SUITABLE IN
UNCERTAINTY
CAREFUL
PROPENSITY &
DISPOSITION
INTERNAL &
EXTERNAL
VALIDATION
SELF-
ASSURANCE 2
ASSURANCE
STABLE &
CAPABLE
PROCESSES
QUALITY BY
DESIGN
QUALITY
SYSTEM
QbD
Kabaddi
A system is the product of the interactions of its parts.

7. Pharmaceutical
Professional’s
Explanation:
Anyone who
registers for
medical
intervention is
labeled “patient”;
we all are patients!
SUITABLE 2
CAPABLE IN
COMPLEXITY
CAPABLE 2
SUITABLE IN
UNCERTAINTY
CAREFUL
PROPENSITY &
DISPOSITION
INTERNAL &
EXTERNAL
VALIDATION
$
SELF-
ASSURANCE 2
ASSURANCE
STABLE &
CAPABLE
PROCESSES
QUALITY BY
DESIGN
QUALITY
SYSTEM
QbD
Kabaddi
System assumes “competence”.

8. Technology for “stable” and “capable” pharmaceutical processing available for decades.
8/17/2018 Email: ajaz@nipte.org 8
Dogmas and unverified assumption socialized “Don’t Use and Don’t Tell”

9. Emerging Science Issues in Pharmaceutical Manufacturing 16 November 2001
8/17/2018 Email: ajaz@nipte.org 9
“Pharmaceutical Industry Has a Little Secret” WSJ 3 September 2003

10. Unverified assumption of competence is the “little secret”
Inability to recognize “suitable and capable” is the practice of “one size fits all”; it is Procrustean.
8/17/2018 Email: ajaz@nipte.org 10

11. Knowing that gaps exist in knowledge needed, ability to adapt to complexity (capability), to
be self-assured in uncertainty to take actions to confront dogmas (suitability).
8/17/2018 Email: ajaz@nipte.org 11
Symptoms of Atherosclerosis: Root cause?
Bio-batch
OOS, Warnings
Root-cause?
People
Suitability & capability?
Materials, Measurement, Process..
Suitability & capability?
One Voice, of timber and consistency, for One Quality Voice to resonate with Voices of Patients.

12. Dogmas & assumptions: Variable
awareness (Individual, Corp., Reg.)
• We approve a drug not a drug product; NDA, ANDA. We have been making “pills” for
thousands of years; why need Development Report (ICH Q8)? No new knowledge and
technology needed. SOP training sufficient. Why support academic programs?
• Excipients are Inactive Ingredients; Compendial purity and impurity profiles sufficient
for ‘Certificate of Analysis”
• Bioequivalence is “pivotal” (and trumps pharmaceutical equivalence)
• USP monograph sufficient prior knowledge to develop generics; context, the societal
incentive - file first for 180-day exclusivity
• Compendial monographs required and sufficient for batch release QC testing
• Verification criteria for Compendial test methods, particularly for physical attributes,
ensures their stability and capability in a QC laboratory
• Process validation (EQ, IQ, OQ, PQ) ensured processes are stable and capable (struggling
to implement FDA’s 2011 Guidance in part because of dogmas in CMC Review)
• SUPAC Defaults are justified knowledge
• Recalls, Warning Letters and Import Alerts cause no adverse effects to patients
• Placebo and nocebo effects accounted during clinical trials; irrelevant in real-world
Pull, NIPTE Pull!

13. What is the gap between
what we know and what
we can implement?
• The answer to this question is found in
Einstein’s warning that we will never
solve the problems tomorrow with the
same Order of Consciousness we are
using to create the problems of today
(Prof. Robert Kegan)
8/17/2018 Email: ajaz@nipte.org 13

14. Why some develop, but at different rates; many do not?
• Some routinely verify assumptions (S2~S1*),
are able to recognize gaps in knowledge and
are aware of variable feedback and likelihood
of it being absent. This is a path to continual
education & development.
• For many, awareness of dogmas and
unverified assumptions (e.g., blind-spots)
occurs infrequently, often a crisis (e.g., OOS).
Such recurring experience, in a unsupportive
environment, force adaptation of uncaring
propensities and disposition
• Adult development occurs in stages, by
overcoming “immunity to change”
(Constructive Development Theory, Prof.
Kegan). Recognizing this knowledge provides
an opportunity to consider design of
solutions.
8/17/2018 Email: ajaz@nipte.org 14
*S2~S1: Thinking Fast and Slow, Prof. Daniel Kahneman

15. Adult development occurs in stages, by
overcoming “immunity to change”
(Constructive Development Theory, Prof. Kegan).
• Professional Development is
to:
• Go beyond traditional
education & training
• Be self-authored in what we
know and how we know it
• Be self-transforming in filling
gaps between what we know
and what we can implement
• Feel the need, and know the
ways, to leverage our
collective experiential learning
• Understand the context for our
abstract nouns; increasing
Order of Consciousness

16. The consequence of errors can be dire but
often difficult to detect, or only apparent in
hindsight, hence often not experienced (i.e., in
practical contact and to feel)
• Recurring errors remind us of
persistent dogmas & assumptions
• Awareness that errors have
consequence should be a source of
cognitive dissonance; discomforting
feeling. It should invoke a yearning
to change attitudes, beliefs, and
behaviors
• Persistent dissonance in an
unresponsive system normalizes
uncaring propensities and
disposition
• Responsibility for system
responsiveness is a stage in adult
(professional) development
Pfizer
(16 November
2001; FDA
Science Board)
Amgen (2004)
Socialized Mind
Self-authored Mind
Hussain, A. S. How To Break the Pharmaceutical 2-3 Sigma Barrier (Like Amgen).
PHARMACEUTICAL ONLINE. Guest Column I September 18, 2017

17. An intrapersonal model to self-gauge
our “current” & “good” in our mind
(Hussain A. S. How to build and maintain an effective pQMS? (2018))
• Feeling system
• From the illusionary power of Procrustes, fear of “looking bad,”
seeking external validation, to ‘tribal passions” to arrogance of
“knowledge is power” with “internal validation,” to understanding
systems (remember “process understanding”)
• Change prevention system
• Procrustean or “one-size-fits-all” approach to specification setting,
insisting on the market or compendial standards (with “zero
tolerance” and built-in α & ß errors) as QTPP and QC tests and
“Default based Prior Approval Supplement” requirements
• Corporate management rewarding “file first – figure it out later”
stance and taking “FDA approved” and “Validated” as gospel and a
reason to “just do it” expecting “right first time every time”
• Regulators in asking more questions for “QbD applicants” in their
attempt to encourage “enabling regulatory considerations” (e.g.,
PAT Guidance and ICH Q8) and making it easier to continue using
the minimum “check-the-box” approach.
8/17/2018 Email: ajaz@nipte.org 17

18. “Immunity to change”
Email: ajaz@nipte.org
• Knowing system
• Management of Knowledge,
Information, and Data are
related, yet are distinct orders
• What we know is essential and,
how we know what we know is
equally important
• Self-authored in every job, at
every level in a corporation and
a regulatory agency
• Both “analysis” and “synthesis”
are essential; e.g., how good is
your Quality Overall Summary?
• Doing system
• Knowing is necessary but not
sufficient, wisdom is action
• Care, Knowledge and Action –
how we feel, think and act must
be aligned with no residual
dissonance
8/17/2018 18

19. System separates order from disorder
• Is pharmaceutical quality
system
• Simple
• Complicated
• Complex, or
• Chaotic?
• Knowing system
characteristics informs us
to be aware of how we feel
and think “in it and about
it.” It is a guardrail to the
precipice of disorder!
8/17/2018 Email: ajaz@nipte.org 19

20. Every system is contained in a
larger system
Email: ajaz@nipte.org
• In the context of Causes and
their Effects (C→&?E), a system
separates order from disorder
• Simple: C→E Self-evident, “Check
the Box”, Best Practices
• Complicated: Expertise needed
for C&E, “Plan Do Check Act”,
Good Practices
• Complex: C?E or known in
hindsight; Adapt careful
propensities and disposition
• Chaotic: (C→&?E) Extreme
sensitivity to initial conditions;
Attractors , “line in the sand”,
innovation, Jugaad, Hack,
Innovation.
• Disorder is not knowing which
system and how the parts of the
system we manage interact
8/17/2018 20

21. When σ > µ? To avoid cognitive dissonance don’t measure σ?
Adapt uncaring propensities and disposition?
G. K. Raju: Emerging Science Issues in Pharmaceutical Manufacturing 16 November 2001
8/17/2018Email: ajaz@nipte.org 21

22. The “Generic Drug Scandal” and
some parts of Judge Wolin’s 79-page
opinion, I think contributed a widely
held but ill-informed interpretation
of legal precedence justifying
maintaining legacy dogmas. I think it
also contributed to an illusion of
“Check the Box” as the path to
“Current” & “Good” in CGMP
“compliance” & “remediation.”
An informed patient looking in to our
struggles can ask: Does the Pharma
Industry know how to “blend powders”?
22

23. A legal opinion perhaps added
another reason to ignore the many
inherent sensitivities to “Initial
Conditions”
• Purchase of ingredients predominantly based on price as long
as “Certificate of Analysis” per a compendial monograph
• Powder blend and dose content uniformity measured on
chemical analysis of only “active pharmaceutical ingredients.”
• Analytical methods for “critical” physical attributes “validated”
based on an assumption of “a stock solution” as in chemical
solution analysis. Gauge R&R? Is the reference material
“stable” & “capable”?
• For decades manufacturing process “validation” hinged on 3
“qualifying batches”; representative of “commercial
manufacturing”? Many struggling to adopt FDA’s 2011
Guidance.
• After “FDA approved” and “validated” too scared to take
additional test samples or to use new analytical methods (see
US FDA’s PAT Guidance). Investigation of OOS? Root cause –
unknown? Normal, easy and rewarding to cycle: blame it on
“operator error”, GMP consultant tweak SOP, & re-train?

24. BAD-I a recurring
hurricane in our mind
• Widespread breaches in the assurance of data
integrity
• Pharmaceuticals
• Automobiles
• Healthcare
• All over
• Companies Everywhere Copied Japanese
Manufacturing. Now the Model Is Cracking (Wall
Street Journal Feb. 4, 2018)
• A string of scandals has tarnished concepts celebrated
in business publications worldwide.
• Corporate wrongdoing occurs the world over, but
Japan’s scandals cut to the core of what has kept
Japanese brands popular, as well as the country’s
perception of itself.

25. Challenges to Pharmaceutical
Quality 2015: One Quality Voice
• 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
8/17/2018 Email: ajaz@nipte.org 25
What made the difference? Ranbaxy and BAD-I?

26. How “big” is the PD gap? It is
an elephant that we don’t see
Email: ajaz@nipte.org
• The current regulatory system is
founded on the assumption of adequate
education, training and experience (e.g.,
21 CFR 211.25), yet there are no
consensus standards to assess
education, training and PD
competencies of regulators and of
industry professionals (blind-spot)
• Globalization and international
harmonization was primarily driven by
economic growth (e.g., GDP),
discounting economic development
(e.g., HDI), assuming adequate
competencies.
• Today pharmaceutical supply chain is
distributed across developed and
developing economies; about 40% of
the US supply is imported from India
and about 90% of API’s from China.
• Today adequacy of professional
development in developed economies is
an open question; what do you expect in
developing economies?
8/17/2018 26

27. US Generic Drug Development and Regulatory Oversight System functions at about 40% efficiency!
Record-setting number of ANDA’s in 2017; sufficient reason to celebrate?
8/17/2018 Email: ajaz@nipte.org 27

28. For some the journey ahead: “666” –to- 2 σ –to- 6 σ
“Continuous manufacturing” is an opportunity and promoting it feels good. It is part of the overall
system. To progress with care, let us appreciate systems and account for Order of Consciousness.

29. Without the burden of BAD-I: It took Amgen About 10 years to 6 σ *
*Ajaz Hussain. How To Break The Pharmaceutical 2-3 Sigma Barrier (Like Amgen).
Pharmaceutical Online. September 2017. Note: The author has no affiliation with Amgen.
8/17/2018 Email: ajaz@nipte.org 29

30. Roadmap to suitability & capability
We lack the critical mass of the Order of Consciousness needed.
8/17/2018 Email: ajaz@nipte.org 30

31. NIPTE is for a
“Critical Mass” of
Current & Good
Professional
Development
SUITABLE 2
CAPABLE IN
COMPLEXITY
CAPABLE 2
SUITABLE IN
UNCERTAINTY
CAREFUL
PROPENSITY &
DISPOSITION
INTERNAL &
EXTERNAL
VALIDATION
SELF-
ASSURANCE 2
ASSURANCE
STABLE &
CAPABLE
PROCESSES
QUALITY BY
DESIGN
QUALITY
SYSTEM
Patient and process centric in the real-world context
Suitability & capability: Validated Mind & Matter

32. NIPTE increasing suitability and capability
• Demonstrable suitability and capability
for multi-disciplinary integrated research
• New Prior Knowledge SM to address legacy
challenges that can be categorized as
inadequate systems thinking in
development and assessment of
Therapeutic Equivalence
• Related projects and targeted discussions
initiated on patient centricity and utility of
real-world evidence mandated by the 21st
Century Cures Act.
• NIPTE Professional Development
Solutions
8/17/2018 Email: ajaz@nipte.org 32

33. NIPTE’s One Voice: How we can strengthen its timber and consistency
A question without a ? is a statement
8/17/2018 Email: ajaz@nipte.org 33

34. How will we
know NIPTE’s
Voice from
noise
Informs politicians, patients, and
professionals to achieve an accurate
valuation of contributions
pharmaceutical technology and
education makes, to source it
appropriately, and to support
accelerating implementation of
informed solutions therein.
8/17/2018 Email: ajaz@nipte.org 34

35. NIPTE for Pharmaceutical
Technology & Education
8/17/2018
• Little Secret: Unverified assumptions;
adequate education, training & experience
• Professional development; Elephant in the
Dark
• The Nation needs a “Critical Mass” of
pharmaceutical professionals
• We have 18 glinting candles, it is flooding all
over; floodlights are needed
• One Voice of suitable timber and
consistency; improve awareness of
opportunities NIPTE can offer
Email: ajaz@nipte.org 35

36. Why I know NIPTE can
change the “pharma” world.
Will it? It depends on us. Careful feedback is
the Third Leg for Suitability and Capability
8/17/2018 Email: ajaz@nipte.org 36