Why criticality of CGMPs not widely appreciated as expected by the customer (US FDA)? What “norms” provide reasons to rationalize cGMP deviations? How a company can re-build lost credibility? Better option improve credibility?

1. Insights on Culture of Quality
What have I learned from Teaching a course on
Culture of Pharmaceutical Quality?
Ajaz S. Hussain, Ph.D. Insight Advice & Solutions LLC
9/20/2015© Ajaz S. Hussain Insight Advice and Solutions LLC 1

2. Outline
Background
• Breaches in data
integrity
• My viewpoints
• About the training
program
Challenges
•Breaches – being
detected currently are not
necessarily new;
•GMP remediation's slow
and/or ineffective (repeat
violations)
•Assumptions and blind-
spots; irrational decisions
and behaviors of
Management and Staff
Questions
•Why criticality of CGMPs
not widely appreciated as
expected by the customer
(US FDA)?
•What “norms” provide
reasons to rationalize
cGMP deviations?
•How a company can re-
build lost credibility? Better
option improve credibility?
Insights
On the three
questions posed
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3. Critical Importance of Data Integrity
My Viewpoints on ‘Culture of Quality’
Training Program on ‘Culture of Quality’
Background
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4. Data Integrity: One of the most important and
relevant topics currently discussed
 “Testing into compliance, data manipulation, data deletion/ record
destruction, misreporting, disregarding failing and/or questionable
results, all leading to possible breaches in the integrity of critical
data, has become one of the most important and relevant topics
currently discussed by industry and regulators from around the
world.”
 Carmelo Rosa. Data Integrity, Essential Part of a Quality System. DIA Multicenter International Data
Integrity Workshop. 13-14, Nov. 2014. Bangalore, India.
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5. My Viewpoints
Education, Training & Experience
 B. Pharm. (Mumbai)., Ph.D. (Cincinnati)
 Teaching Pharmacy @ Ohio Northern University &
University of Cincinnati
 US FDA
 Sandoz (Biosimilars)
 Philip Morris International (Plant based vaccines &
Harm reduction)
 Wockhardt (Biosimilars & Complex Generics)
 Since 2013 - Insight Advice & Solutions LLC (50%)
 Since 2014 - National Institute of Pharmaceutical
Technology & Education (50%)
Culture of Quality Training
 Effective training [and resolution of issues] requires us
to make effort “Dil Se”; “without ‘finger-pointing”
 A framework based on ‘Behavioral Economics’, as
opposed to ‘Ethics/Morality’, developed
 Highlight consequences of biases, blind-spots and
irrational behaviors & showcase importance of
System!
 Linked to current and emerging regulatory
expectations; but not focusing on specific regulatory
requirements
 See authors LinkedIn and Slideshare sites for
additional information
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Decision under risk and uncertainty are
subject to a “framing effect” – and it is
powerful. How we ask a question –
“framing” -can influence how people
react to it. This can also affect our
memories of the event. We are subjected
to many other biases. We are
predictably irrational!
Professor Kahneman’s System 1 and System 2 of human cognition conceptualized

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Behavioral Economics:
Predictability Irrational Behaviors
 The psychological principles that govern the
perception of decision problems and the
evaluation of probabilities and outcomes produce
predictable shifts of preference when the same
problem is framed in different ways.
 Reversals of preference are demonstrated in
choices regarding monetary outcomes, both
hypothetical and real, and in questions pertaining
to the loss of human lives.
 … A man [or woman] could be judged irrational
either because his [her] preferences are
contradictory or because his desires and aversions
do not reflect his/her pleasures and pains.
 Amos Tversky and Daniel Kahneman. The framing
of decisions and the psychology of choice.
Science. 1981 Jan 30;211(4481):453-8
 Daniel Kahneman and Amos Tversky. Prospect
Theory: An Analysis of Decision under Risk.
Econometrica, 47(2), pp. 263-291, March 1979
 Losses have a bigger emotional impact than an
equivalent amount of gain.
 People often make decisions to avoid a loss
(short-term) at the expense of gains (often long-
term)
 Company finances are allocated differently –
R&D is a “Gain” or “Investment” where as
Operations are “Costs” or “Losses” (in the
extreme)
 This imbalance creates many challenges in the
day-to-day operations - which, among others, is
what a Culture of Quality must address

8. Case example: Testing into Compliance
 An analyst in a Quality Control (QC)
laboratory, after the requisite training is
doing dissolution test for a modified
release dosage form. The results he
obtains are ‘out of specification’
(OOS).
 Per SOP, analyst has to file a deviation
report so that an investigation can be
initiated. He does so.
 Later in the day the Head of operations
calls the analyst and his supervisor.
 Here are some messages to consider
on Leadership Emphasis and Message
Credibility
 Emphasis/Message Credibility L1: Head of Operations is
upset that the analyst did not do his job carefully. The
product is FDA approved and process validated. On
previous occasion after a lengthy investigation it turned
out to be an assay error. Complete the investigation
quickly and release the batch on time.
 Emphasis/Message Credibility L2: The Head of Analytical
department learns about what happened. He calls the
supervisor (in the discussion above). He is concerned
that when the owner of the company will learn about
this it will not look-good (for him, and his Analytical
department). He tells the supervisor – add as many
resources as needed for the investigations and get it
done quickly.
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9. Humans tend to select [irrational] risky option more often in
response to negatively framed problems; this effect is more
pronounced when there are [easy] “reasons to rationalize”
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Attitude
toward
performing
the behavior
Process
validation is
done so quality
is good;
Test prone to
error
“Batch failure
means I made
a mistake”
Subjective
norm
Documentation
not critical;
Compendial
testing sufficient
Regulators
collect & test
samples – no
issue there
“Testing into compliance”
In general – low empowerment is
a significant challenge (low
perceived behavioral control);
plus reasons to rationalize….

10. Additional Information
 CoQ Framework and Blind-spots - for more detail click on the following
 Explaining the Behavioral Economics context of Culture of Quality
 Product Quality & Patient Safety USP Workshop Mumbai 12 June 2015
 Good Regulators of Pharmaceuticals (GRP) 22 October 2014
 Dr Venkateswarlu Memorial Lecture 2015
 Chemometrics Pharmacometrics Econometrics of QbD. Swiss Pharma-6 2012
 Excipient Knowledge Management Mumbai 12 March 2015 Part 1 & 2
 If the links above fail to connect to the information please use:
http://www.slideshare.net/a2zpharmsci
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11. About the Culture of Quality Training
Conducted for?
 3 companies; WL, Import Alert (US FDA)
 1 Company; significant FDA 483
 2 Companies; Proactive (before US FDA
Inspection)
 > 3000 management & staff at facilities in the
states of Goa, Gujrat, Karnataka, Madhya
Pradesh, Maharashtra, and Telangana and in
the Union Territory of Dadra and Nagar Haveli.
 Key issue: Preventing “Breaches” in data
integrity
Learning Objectives
 Provide an opportunity to improve
understanding of Culture of Quality (CoQ) and
how it relates to Quality Management System
(QMS) and compliance with Good Practices
(GXPs)
 Focus on Why and not 21 CFR;
 Specifically to appreciate the value of
systems approach to quality, identify
behaviors that strengthen it and behaviors
that need to change
 Specifically to appreciate the value of
systems approach to quality, identify
behaviors that strengthen it and behaviors
that need to change
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12. Changing incorrect attitudes & mindset – “Quality is Good”
&”US FDA targeting India”
Regulator heterogeneity
Overcoming blind spots & irrational decisions
Challenges
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13. Overcoming the challenges
Starting point – agreement & commitment of Top management build a Culture of Quality
Deliberate breaches in data integrity is
cheating and fundamentally against the basic
principles of professional conduct and of
India’s founding principle – “Satyamev
Jayate”
Nothing is perfect (so avoid “zero tolerance”
slogans) –improve awareness and mastery
and remove fear to identify, report and
correct errors.
Walk the talk – not “Quality Policy on the Wall”
Emphasizing Why by sharing examples from
authors experience on topics such as:
“We make two products – medicine and
evidence”; both must be better than “placebo”;
data integrity distinguishes between legitimate
and criminal intent
Testing is not sufficient to assure quality; case
examples of harm caused by violating cGMPs
and why it is hard to detect harm; “lack of reports
of harm is not evidence of no harm”
Quality must be by design; i.e., by intent and
working consciously; ‘plan-do-check-act’
Systems approach to quality is a must; what is a
System, what is systems thinking, how to make a
Quality Management System effective
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14. Good Culture of Quality
When employees can say without hesitation:
 We do our best to develop products that meet the needs of patients – we
develop our products consciously – this Quality by Design.
 We recognize that nothing is perfect and there will be some errors in our design,
systems and procedures, or we may make mistakes in following set procedures.
 It is normal, easy and rewarding to work within our quality management system,
without fear, to detect, correct and to learn from errors.
 In doing so we act consciously in the interest of patients – especially when no
one is looking, and continually improve our quality by design and aim for right first
time.
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15. A simple framework for CoQ
Quality by Design
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One example of impact assessment: One month after completion of
training (anonymous survey via Survey Monkey).

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•Leadership emphasis
•Message credibility
•Peer involvement
•Employee empowerment
Re-shaping the Environment
•Quality is normal
•Quality is easy
•Quality is rewarding
Re-setting the Norms
•Commitment to the System
•Knowledge based
•Understanding & controlling variations
•Safe-guards + pride of workmanship
Ensuring effective QMS
•Fear removed
•Mastery
•Awareness
Promoting proactive behaviors
Score-card; Key Areas of
Improvement and
Recommendations
 Illustrative Score Card: For a
company currently in cGMP
remediation.
 Stars & color codes
Good progress, continue efforts
already initiated
Blind-spots, current efforts need
additional considerations
Blind-spot + new targeted
projects/efforts needed

18. Why a growing cluster of cGMP issues [in India]?
What “norms” & behaviors need to change?
How a company can strengthen culture of quality?
Questions
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19. Why a growing cluster of cGMP issues?
 Are the cGMP issues now being noted “new”?
 Not likely – rigor and frequency of US FDA inspections changed; More “unannounced” inspections
& an increased fear component (for operators)
 Improved ability (of a few investigators) to conduct a through “IT” system review; Large “regulator
heterogeneity” blatantly visible
 Incorrect organizational assumptions – “FDA Approved”, “Process Validated”; push for
“speed” and uninformed “Lean” programs to improve efficiency
 Systemic weakness in QMS – inadequate systems thinking – and a general disregard for
the intrinsic (as opposed to just satisfy FDA) value of documentation and assurance of
data integrity; Quality by Design - much misunderstood & “file first and figure it out later”
 Local regulatory norms providing addional reasons to rationalize deviations from cGMPs
and attempt to justify interpretation of “adulteration” narrowly to analytics
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Why a growing cluster of cGMP issues? Holes in the system
Holes not filled or
filled after FDA InspectionBreaches
Reasons to rationalize irrational behaviors
‘Framing” effects & irrational decisions
Opportunity & “not harming anybody”
Namesake QMS
(A folder of papers – often written by consultants)
Ineffective training &
inadequate supervision
Inability to say NO or to
explain what is required
Push for results!
Assumption:
‘Quality is
Good”;
“FDA approved,
validated, past
inspections
okay”

21. What “norms” & behaviors need to
change?
 Differing “quality” to Quality Unit; quality is everyone's responsibility
 ‘Regulator heterogeneity’ is often used as an excuse; Adherence to commitment is a
Management responsibility
 Defense of domestic vs. export quality; this is the time to commit to ‘One Quality Standard” –
and a plan to achieve it in a reasonable time period
 Policies and SOP’s written by consultants to satisfy FDA; Systems thinking is essential to
strengthen QMS
 “First to file” without systematic preparation to mitigate risks; now a automatic “red flag” for
data integrity at FDA
 Reliance on “defaults” – 10X, 3-batches,etc., without questioning their relevance; Life-cycle
approach to process and analytical method validation a must
 Check-box training; need to improve training across the board and ensure it is effective in
providing ‘mastery’, improving ‘awareness’ and reducing “fear” and irrational behaviors
 Quality policy “on the wall”; management must walk-the-talk
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22. How a company can strengthen culture
of quality?
 It starts with the Top management! Walking the talk
 Leadership emphasis (and metrics), message credibility, peer involvement (top management)
and employee empowerment (reveres the need for all decisions to come to the top)
 Aiming high – not just to satisfy the next inspection; effective QMS
 Appreciation for the System, Theory of Knowledge (Plan-do-check-act), Knowledge of Variations
(common/special cause). Incentivize rational behavior (System 2- working consciously) and pride
of workmanship
 Preventative controls
 Effective training to improve awareness, ensure mastery, and reduce fear
 Nothing is perfect – avoid slogans such as “Zero tolerance”
 Make it normal, easy and rewarding to detect, report and correct errors
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23. Summary
Background
• Breaches in data
integrity
• My viewpoints
• About the training
program
Challenges
•Breaches – being
detected currently are not
necessarily new;
•GMP remediation's slow
and/or ineffective (repeat
violations)
•Assumptions and blind-
spots; irrational decisions
and behaviors of
Management and Staff
Questions
•Why criticality of CGMPs
not widely appreciated as
expected by the customer
(US FDA)?
•What “norms” provide
reasons to rationalize
cGMP deviations?
•How a company can re-
build lost credibility? Better
option improve credibility?
Insights
On the three
questions posed
9/20/2015© Ajaz S. Hussain Insight Advice and Solutions LLC 23