We are in the Experience Economy in which the demand for Assurance is increasing exponentially. Our quality systems are improving linearly, and we are falling behind in delivering the assurance needed by patients to realize therapeutic benefits of medicine we deliver. Industry's need to continually improve is urgent, but their ability to do so remains constrained despite the FDA initiatives. To realize FDA's vision of an agile pharmaceutical manufacturing systems ... Without the need extensive regulatory oversight, industry should be encouraged to "self-author" "performance standards" and regulators should harmonize on the global accessibility of the self-authored performance standards. #AAPS2017 Need and Urgency for Harmonization and One Quality Voice. A. S. Hussain. Insight, Advice & Solutions LLC.

1. Urgency for Harmonization
& One Quality Voice
Ajaz S. Hussain, Ph.D.
Insight, Advice & Solutions, LLC
The National Institute for Pharmaceutical Technology & Education, Inc.
11/3/2017 AAPS Annual Meeting 2017 1

2. FDA CDER Long-
standing Vision
• A maximally efficient, agile, flexible
pharmaceutical manufacturing sector
that reliably produces high quality
drugs without extensive regulatory
oversight.
• Continual Improvement – Urgently Needed
• Without Extensive Regulatory Oversight –
Performance Standards – Self-authored
• Harmonize (in ICH) on the global
acceptability of – Self-authored
Performance Standards
11/3/2017 2

3. “Continuous Improvement” (CI) Urgently Needed
1
FDAOPQ
proposal on
“performance
standards”
makes very
good sense
2
Decreasing
variance &
improving
efficiency.
No penalty
for large N!
3
CAPA
effectiveness
is necessary;
but, in and of
itself, it is not
CI
4
Improvement
is change;
Supplements-
antithesis to
CI
5
Effective
PQS needs a
critical
mass of
“Self-
authored”
leaders
6
“Self-
authorship”
is necessary
for systems
orientation
7
Industry
“Self-
authoring”
performance
standards –
the Tipping
Point
Insights I wish to share today

4. 21 CFR 211.25
11/3/2017
AAPS Annual Meeting 2017
4
• Education, Training &
Experience
• Systems Orientation?
• PQS Effectiveness?

5. Need for Assurance
increasing
“exponentially”
• Our ability to provide the
needed Assurance is only
increasing “linearly”
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AAPS Annual Meeting 2017
5
Welcome to the Experience Economy

6. We all are
experiencing
pain today,
differently.
11/3/2017 AAPS Annual Meeting 2017 6

7. …painful medical
debt, bankruptcies
– CNBC 29 May 2014
• "I was paying the pharmacy what I owe,
but I had a hard time paying my credit
card bills," said Dolores, who suffers
from chronic obstructive pulmonary
disease, partial heart blockage and
extreme anxiety. Her 79-year-old
husband has congestive heart failure,
kidney failure and COPD as well.
• "Without the insurance, it was real
tough," said Dolores, who stopped going
to her pulmonologist and heart
specialist during the time she lacked
health coverage.
11/3/2017
AAPS Annual Meeting 2017 7 Photo credit: Todd Keith | Vetta | Getty Images

8. Experiencing
Drug Shortages
11/3/2017 AAPS Annual Meeting 2017 8
Screen-shot September 2017

9. Experiencing Automatic Substitution
Annals of internal medicine.
161(2), pp.96-103 2014
Burden of Changes in Pill Appearance
for Patients Receiving Generic
Cardiovascular Medications After
Myocardial Infarction.
The Washington Post. 14 July 2014.
If Color or Shape of Generic Pills
Changes, Patients May Stop Taking
Them.
Final Guidance. June 2015
Guidance for Industry. Size, Shape, and
Other Physical Attributes of Generic
Tablets and Capsules. Pharmaceutical
Quality/CMC.
Generics for
Me, but a
Brand for
You! #@*
Research in
Social and
Administrative
Pharmacy, 8(6),
pp.574-578
(2012)

10. Goods – Services - Experiences
Manufacturer
– Provider -
Stager
Standardized
– Customized-
– Personal
User – Client –
Guest
Attributes –
Benefits –
Sensations
Welcome to the Experience Economy
B. Joseph Pine II and James H. Gilmore, Harvard Business Review July–August 1998

11. Experience and The Gold Standard
Clinical Trial System is
“Broken” and there
need to be new ways to
collect and utilize
patient data
Dr. Janet Woodcock
(September 2017)
1
Interactions between
the brain and spinal
cord mediate value
effects in nocebo
hyperalgesia.
Science, 358(6359), 105-
108 (2017).
2
Pharmacodynamics of
Placebo: Expectation
effects of price as a
proxy for efficacy.
Neurology. 10: 766-767
(2015)
3
The double-blind,
randomized, placebo-
controlled trial: Gold
Standard or Golden
Calf?
Journal of Clinical
Epidemiology, 54(6): 541-
549 (2001)
4
Why Is the Placebo Effect Exploding in The U.S. But Nowhere Else? Forbes. 7 October 2015

12. Experience of
the most
vulnerable in
the pharma
community
11/3/2017 AAPS Annual Meeting 2017 12
• Those on the front-lines
• Fear of losing their job
• Finding an OOS
• In a supporting QC environment?
• In a less than ideal QC environment?

13. Adult human
development
• Some of us develop but at different
rates. Many do not.
• Between stimulus and response, there
is a space. In this space is our power to
choose our response. In our response
lies our growth and our freedom.
Victor E. Frankl
11/3/2017

14. 11/3/2017 AAPS Annual Meeting 2017 14

15. To QbD or not QbD Experience
11/3/2017 AAPS Annual Meeting 2017 15
Current FDA OPQ Efforts

16. Levothyroxine: A Canary in Our Coal Mine
11/3/2017 AAPS Annual Meeting 2017 16
• Need for Assurance increasing
“exponentially” Vs. Our ability to
provide the needed Assurance is only
increasing “linearly”
• Tortuous regulatory legacy
• Assurance in “new specifications and
BE” vs. Assurance in outcomes
• New Formulation vs Continual
Improvement
• Ignoring Nocebo-effects Vs. Mechanism
of Nocebo-effect (see: Science,
358(6359), 105-108 (2017))

17. Experience New & Improved Formulation!
Assuring the
Quality of the
Most Prescribed
Drug
New
formulation
launched in
France, March
2017
Within a few
weeks, the social
media started
buzzing.
The backlash
intensified; the
media storm
posed political
problem for the
French
government!
Just wondering if anyone else is taking the new Levo formula from XYZ. I've been on it about 2 or 3
weeks and so far gained three kilos. 😩😩!
“France brings back a phased-out drug after patients rebel against its
replacement” - Science Magazine. 27 September 2017
Germany, New Zealand,….
Continuous Improvement is Assurance!

18. To Experience
Continuous
Improvement
11/3/2017 AAPS Annual Meeting 2017 18
• What is “experience”?
• What is “continuous improvement”?
• [The few] companies that have
demonstrated this “experience”

19. The Continuous Improvement Experience
Experience is
Consciousness
• Integrated information theory:
From consciousness to its
physical substrate. Giulio
Tononi, et. al. Nature Reviews
Neuroscience 17: 450–461
(2016)
Orders of
Consciousness
• Constructive development
theory of adult human
development.
• Kegan, R., 1995. In over our
heads: The mental demands of
modern life. Harvard University
Press
• Kegan, R. and Lahey, L.L., 2009.
Immunity to change: How to
overcome it and unlock
potential in yourself and your
organization. Harvard Business
Press.
Amgen’s six
sigma journey
• From several presentations by
Martin Van Trieste
• “CAPA within the
Pharmaceutical Quality System.”
ICH Q10 Conference. October
2011.
• “Improving the Quality of
Investigations.” PIA Meeting.
June 2012.
• “The Journey from Good to
Great: Process Monitoring Leads
to Improving Product Quality.”
2nd Annual FDA/PQRI
Conference. October 2015.

20. Amgen’s Journey
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Hussain, A. S.: How To Break The Pharmaceutical 2-3 Sigma Barrier (Like Amgen).
Pharmaceutical Online September 18, 2017 https://www.pharmaceuticalonline.com/doc/how-to-break-the-pharmaceutical-sigma-barrier-like-amgen-0001

21. Experience for CI: 4th Order Consciousness +
11/3/2017 AAPS Annual Meeting 2017 21

22. Order of Consciousness and Systems Orientation
3rd Order of
Consciousness – the
Socialized Mind
• “If I don’t look there is no
problem”; “Don’t use or
don’t tell”; Guidance =
Regulation; check-the box
The 4th Order –Self-
Authored Mind
• Systems orientation begins
at the 4th Order. For
building and maintaining
an effective PQS, a critical
mass of 4th Order is needed
in the work environment
with all of its time, cost, and
other pressures and
stressors.
The 5th Order – Self-
Transforming Mind
• The prevention mindset
requires us to appreciate
multiple systems which are
often separated by time &
space (e.g., a system for
development as in R&D and
system for quality
assurance as in Operations)

23. Different
legacies,
different
experiences
Synthetic chemistry based
drug products
Drug Price Competition
and Patent Term
Restoration Act
Biotechnology based drug
products
Biologics Price Competition
and Innovation Act
Complexity:
Underappreciated Vs.
Anticipated
Good Practices such as use
of SOP’s are for
“complicated” processes
that are predictable; given
a set of starting conditions
Complicated is why we
have 21 CFR 211.25;
education, training &
experience
11/3/2017 AAPS Annual Meeting 2017 23

24. Solid Dosage Form
Manufacturing:
“Tipping Point” not
feasible without an
“Angle of Repose”
• Certificate of Analysis -Uncertainty in solid-state
material attributes
• Research laboratory measurement systems -
Life-cycle stability and reproducibility in QC?
• Fixed equipment and process parameters -
Committed in submissions, difficult to change
post approval; why bother finding the real cause?
• Uncertainty in the stability and capability of
measurements and manufacturing process -
Raises questions on adequacy of sampling and
obstructs risk-based decisions
• Globalization – variable empowerment &
oversight; “FDA Approved” and “Validated”;
frames the mindset and provides reasons to
rationalize.
11/3/2017 AAPS Annual Meeting 2017 24

25. “Continuous Improvement” (CI)
FDAOPQ proposal on
“performance
standards” makes very
good sense
Decreasing variance &
improving efficiency.
No penalty for large N!
CAPA effectiveness is
necessary; but, in and
of itself, it is not CI
Improvement is
change; Supplements-
antithesis to CI
Effective PQS needs a
critical mass of
“Self-authored”
leaders
“Self-authorship” is
necessary for
systems orientation
Industry “Self-
authoring”
performance
standards – the
Tipping Point
Urgently Needed

26. Performance
Standards
11/3/2017 AAPS Annual Meeting 2017 26
• The “pull vector”; self-
authored (e.g., ASTM and
others)
• PQS effectiveness (e.g.,
low error rates such as
six sigma), technology
platforms,….
• Leaving the tortuous
legacy behind
• Performance standards
for effective CAPA, etc.
• Global regulatory
acceptance of industry
self-authored
performance standards
would be a useful
harmonization effort
7

27. NIPTE
beginning its
efforts to fill
the many
legacy gaps
that remain
11/3/2017 AAPS Annual Meeting 2017 27
• Experiencing a new trans-
functional and transdisciplinary
Education with Epistemic
Certification: QbD to CPV in a PQS
• New Prior Knowledge to get the
QTPP focused on needs of the
patients and capability to get to
six sigma
6

28. Thank you for your
attention.
• Continual Improvement
• Urgently Needed
• Without Extensive Regulatory
Oversight
• Performance Standards; Self-authored
• Harmonize (in ICH)
• On the global acceptability of Self-
authored Performance Standards for
Continuous Improvement
11/3/2017 AAPS Annual Meeting 2017 28