Chaos is not “disorder,” and in drawing this distinction, I posit chaos to continual improvement is a path forward, which the pharmaceutical sector should consider. How is this path different, and what steps would we need to take, for example, to leave behind unpredictability and move towards predictability.

1. KNOWLEDGE
RISK
SATISFACTION
MANAGEMENT
AJAZ S. HUSSAIN, PH.D.
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2. MAY 24, 1987: BRIDGE’S
GOLDEN ANNIVERSARY
 The Day Golden Gate Bridge Flattened
 The middle of the bridge sagged 7 feet.
 300,000 people on foot were stuck in
human gridlock for hours (satisfied?)
 Half-million other people waiting to cross
never got the chance to cross
(disappointed)
 Capacity 5,700 pounds per foot;
estimated weight 5,400 pounds per foot
 Bridge was not in danger of collapsing;
“safety margin”
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3. More billionaires per capita than anywhere else in the world and homeless problem that rivals some “third-world” nations!
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4. A BRIDGE TOO FAR?
 Numerous measles outbreaks
across the United States
 Legislation to remove or
restrict exemptions based on
religious or personal beliefs
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5. NEXT LEGISLATION TO RESTRICT
HOW CITIZENS THINK ABOUT
GENERICS AND BIOSIMILARS?
Figure from:
Nature Reviews
Rheumatology
14, 727–740
(2018).
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7. IS IT NOW THE TIME
TO TAKE A RED
PILL?
 In the real-world, the
assurance of quality, i.e.,
Therapeutic Equivalence is
causally related to
therapeutic outcome patients
experience in the real-world.
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8. IN A “FOG OF WAR” THE ONLY OPTION COULD BE:
“FDA APPROVED, IT MUST BE THE SAME, SHUT UP AND TAKE IT”
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9. “FOG OF WAR” IS A STATE
OF MIND: IT IS UP TO US
 21st Century Cures Act
 Patient-centric new drug development
 Personalized medicines
 Real-world evidence
 Continuous manufacturing
 Value-based pricing
 Outcome-based reimbursement
 Pay for performance
 Electronic Medical Records
 Analytics and AI
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10. SINCE 1990’S WE KNEW
WE HAVE A PROBLEM
“REGULATORY GUIDANCE
FACTORY” DIDN’T HELP
GOVERNMENT CAN'T
MANUFACTURE,
CERTAINLY.
THEN WHAT?
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11. RETURNING TO PHARMA
SECTOR (FROM TOBACCO)
 Illustrative Media Headlines
 US FDA to expand scrutiny into Sun
Pharma data. 23 May 2014, C.H.
Unnikrishnan, Leslie D'Monte
 India's Data Integrity Problems, 03
February 2015 | By Alexander Gaffney, RAC
 U.S. and EU regulators urge Indian
drug companies to step up standards.
FEBRUARY 23, 2016. Zeba Siddiqui
 Secrets and lies: Faked data and lack of
transparency plague global drug
manufacturing. Jun 10, 2016. Kelly Crowe
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12. CHAOS IS NOT DISORDER!
IN THIS DISTINCTION I FOUND A PATH FORWARD @ AN INDIAN UPSTART:
CHAOS TO CONTINUAL IMPROVEMENT
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13. AT AN INDIAN
UPSTART 1/2015
 MD of XYX: Email to me requesting advice
 “Proactive assurance of data integrity”;
 Previous US FDA inspection in 2012; no Warning Letter
 Approach: Self-author solution to Self-assurance
 The MD and leaders sign a Pledge & Code of
Conduct, agree to “no finger pointing”, draw a “line
in the sand” to move ahead with a commitment to
“Culture of Quality” (Training)
 Agree to an Audit of “Data” Systems by EY Fraud
Investigation & Dispute Services (whom I had nurtured
while on other assignments)
 Self-author protocols, evidence based CAPA and
solutions, i.e., no “CGMP Consultants”
US FDA Inspections:
Operations (Goa)
2015: No observations
(investigator informed of on-
going metamorphosis)
2018: No observations
2019: 6 Observations,
addressed rapidly + Continual
Improvement Plan
US FDA Inspections: R&D
(Mumbai)
2016: 5 Observations,
addressed rapidly + Continual
Improvement Plan
2019: No observation
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14. ADVISORY
BOARD IN 2019
RECENT REVIEW
New Targets & Recommendations
FDA Inspections are “reconfirmation” work to
make these “routine”, i.e. no additional
preparation needed
Most managers working ~16+ hours; Make “Go
Home” on time normal, easy and rewarding!
Each day go home 1-2 minutes before your left
the previous days!
Corporate and Individual
“Continual Development Plan”
Increased business complexity, continual staff turn-
over, palpable stress
Confidence building, but an FDA inspection still is a
“major event.”
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15. KEY LESSONS
LEARNED
 Widespread lack of self-assurance on matters related to
self-authorship and communication and systems
orientation & proficiency
 Weak investigative and statistical skills, e.g., Compendial
tests as QC release test without appreciating Type I and
Type II errors
 Culture: “FDA Approved” and “Validated” so all is Good
 Culture of Quality Training
 Systems orientation and proficiency a stage in adult and
professional development
 Internal Validation to External Validation
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16. Legacy blind-spots persist: Remedy “Culture of Quality” Training
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17. LEARNING TO
DISTINGUISH
ERRORS OF
COMMISSION VS.
ERRORS OF
OMISSION
EMERGING, GOOD AND
BEST PRACTICES
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18. APPRECIATING
SYSTEMS
CHAOS,
COMPLEX,
COMPLICATED,
& SIMPLE
SYSTEMS
UNKNOWN-UNKNOWN,
UNKNOWN-KNOWN,
KNOWN-UNKNOWN, & SELF-
EVIDENT CAUSES & EFFECTS
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19. SYSTEM CAUSE & EFFECT & STANCE? CHARACTERISTICS
Chaos
Unknown –unknown
Stance: Act, Sense & Respond
High turbulence, so pattern-based
leadership. Provide clear, direct
communication.
Complex
Unknown without research and
experimentation
Stance: Probe, Sense, Respond
Pattern-based leadership to guide
“Emerging Practices.” Research &
Development: A need for creative and
innovative approaches.
Complicated
Known unknowns, i.e., expertise needed to
understand cause-and-effect relationships
(transferred from R&D); more than one right
answer possible.
Stance: Sense, Analyze, Respond
Fact-based management. “Good
Practices” self-authored calibrated,
reproducible, and repeatable routines
or SOPs.
Simple
Self-evident, without specialized expertise.
Known knowns.
Stance: Sense, Categorize, Respond
Empowerment of staff, use of “Best-
Practices” with recognition of their value
and the limitations.
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Imagine ICH Q10 life-cycle model with three enablers as multiple cycles; stacked quarterly to become a spiral.

22. Disaster Impact Threat Vulnerabilities Table
Aligning risk
management in complex
and complicated
systems. (illustrative)
Natural All local systems Life & Infrastructure
Facility & headquarter
location
Geo-politics Global systems
Disorder, recession, institutional
ineffectiveness
Spread across the
global supply chain
Regulatory Disharmony: Local - ICH License to market Risk to Quality
RISK MANAGEMENT
(e.g., ICH Q9)
Detection Occurrence Severity
Patient-centric Lose trust, anxiety, fear
Increased in complaints and
adverse effects
Nocebo effects
Lower adherence rates
“NTI” drugs
Generics
Complex Generics
Supplier (if no
system failure)
Process suitability &
capability
Increased OOS Legacy products
Process
Time to market and
market presence
Warning Letters, Import Alerts
Legacy products
New products, not
“QbD.”
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ComplicatedComplex&Chaos

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ACommunityofKnowledge&Authors

24. SELF-AUTHORSHIP
TO SELF-
ASSURANCE
TO GIVE ASSURANCE, FRIST
BE SELF-ASSURED!
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