Culture of Quality Bagladesh AAPS 8 August 2015 Final

Culture of Pharmaceutical Quality:
What, Why, How?
AABPS Convention 2015
Philadelphia Marriott Downtown, Philadelphia, Pennsylvania
Saturday, August 8, 2015
ajaz@ajazhussain.com
8/9/2015 © Ajaz S. Hussain Insight Advice & Solutions LLC 1

Thanks for this kind invitation to share some thoughts
about Culture of Quality
Environment
Organizations
Cultures
Systems
FDA
AABPS
NovartisGSK
Merck
Others
Today @ Philadelphia Marriott Downtown

Outline
What is
Culture of
Quality?
Why we are
discussing
Culture of
Quality?
How can it
help?

What is Pharmaceutical Quality?
‘I know is when I see it’
• FDA approval & acceptable
compliance status

Legal enforcement
Why do we regulate?
Pharmaceuticals exhibit market failures that can have devastating
consequences
What do we regulate? Human behavior
How do we regulate? Laws, regulations, policies, review, inspections, criminal prosecutions,…
Who are the
regulators?
All of us, not just the FDA
What is the
foundation for
modern regulations?
Scientific evidence and compliance with regulations and ‘Good
Practices’

Medicine _ Evidence
Better than Placebo Double-blind Randomized Placebo-controlled
Clinical Trials - long history of being the standard
• Placebo effects are genuine psychobiological events; can be robust in
both laboratory and clinical settings. The Lancet, February 2010.
• In clinical trials minimize the placebo effect; following approval, in
clinical use, it should be maximized by harnessing patients'
expectations and learning mechanisms to improve treatment
outcomes. Nature Reviews Drug Discovery March 2013
Note – blinding for clinicians and other professionals
involved is to minimize errors/scientific misconduct
• Reminder of one thing that is sometimes forgotten.
Scientists are human, too. (Misconduct in science. An
array of errors. September 2011)
Without integrity of evidence
there is no medicine (quality,
safety and efficacy)
Blinding is one tool to safeguard
against observer bias. We must
guard against many such biases.
Scientific methodology, Good
Practices & [Management] Systems
approach are a part of Culture of
Pharmaceutical Quality.

Why we are now discussing Culture of Quality?
Journey to
improve current
practices ..
To reduce
errors
To fulfill this responsibility, both industry and the
FDA need a culture of quality.
Industry and the FDA have the shared obligation to
reduce quality errors …
The American public is facing unprecedented drug
shortages and recalls (erosion of confidence)
Lawrence X. Yu, Ph.D

To reduce errors
Irrational
Behaviors
Increasing
• Uncertainty
• Complexity
• Placebo effect
Decreasing
• Affordability
• Availability
• Confidence
?
?
Purchased at http://www.jantoo.com/download/255350/web/03130525.jpg

For example….
Current Challenge
Increasing number of manufacturers in India, China and
elsewhere observed to be non-compliant. ‘Breaches in
data integrity’ (BDI) is among the most serious observation.
This is a global issue – not about India or China; but local norms need to be considered
for effective correction and prevention..
Data Integrity Key to GMP Compliance September 2014
FDA Bans Drugs Made by Indian Manufacturer Over GMP Problems January 2015
Data Integrity: The Whole Story

Trends: Lab & Manufacturing
“Deletion of Data”
“Testing Into Compliance”
“BMR manipulation is a
slippery slope”
“Suggestive of faulty
manufacturing process or
practices, even if this is not the
case”
“It is top management’s
responsibility to ensure the
training program is robust and
effective!”
Recent inspectional trends (Bangalore, Nov 13 2014 - Nov 14 2014)
Growing concern @ some
companies “data looks too good
to be true”
Ajaz S. Hussain. [‘Excipient’] Knowledge Management: 2015 & Beyond

Patterns suggestive of ‘intentional holes’
“….records not
completed
contemporaneously”
“…observed analyst
back-date logbooks”
“…trial injections…..”
“…results failing
specifications are
retested until
acceptable results are
obtained….”
“…over-writing
electronic raw data…..”
“…OOS not
investigates per XYZ
SOP”
“…appropriate controls
not established….”
Each additional
observation adds
reasons to confirm
that this is very
likely a system
with intentional
‘holes’ in its
defenses.

Risk of unintended or intended normative support for
‘testing into compliance’?
attitude
toward
performin
g the
behavior
Process
validation is
done so
quality is
good;
test prone to
error
“Batch failure
means I
made a
mistake”
subjective
norm
Documents
not critical;
Compendial
testing
sufficient
Local
regulators
collect & test
samples – no
issue there!
“Testing into compliance”

Why a need to emphasize Culture of Quality?
In an organization errors are detected reported/escalated without fear; i.e., error detection, correction and
prevention is normal, easy and rewarding.
We have to constantly work to ensure there is a comprehensive and consistent understanding of what
pharmaceutical quality is across all functions and levels – ‘blind-spots’ and/or incomplete understanding
contributes to errors, non-compliance and protracted/uncertain remediation?
Although we have made progress on Quality by Design, Life Cycle Approach to Method and Process
Validation, and in adopting a Systems approach to Quality Assurance – we still have more work to do to
achieve an effective and integrated implementation

Questions?
• What are few examples of ‘blind-spots’?
• Please see: http://www.slideshare.net/a2zpharmsci/product-
quality-patient-safety-usp-workshop-mumbai-12-june-2015
• How does ‘blind-spots’ and incomplete understanding
contributes to errors, non-compliance and protracted/uncertain
remediation?
• This insight and advice is not free 

How to describe/define
a Culture of Pharmaceutical Quality?
It should help us understand and inform on how people behave – specifically
misbehave - in an pharmaceutical organization – specifically when making
and executing decisions on quality
• Culture is dynamic, emergent properties based on interactions (within and
outside the organization) -it, ideally is an open system with feedback-loops
• Is it a sub-system of an Organizational Culture?

Being human means…..
“we can be blind to the obvious, and we are
also blind to our blindness.”
We like to think of ourselves as rational in our
decision making, the truth is we are subject to many
biases.
We are predictably irrational.
Daniel Kahneman, Thinking, Fast and Slow http://web.mit.edu/persci/people/adelson/checkershadow_proof.html

Cognitive biases
• The way you feel filters the way you interpret the worldAffect heuristic
• People are over-reliant on the first piece of information they
hearAnchoring bias
• We tend to listen only to the information that confirms our
preconceptionsConfirmation bias
• Failing to recognize your cognitive biases is a bias in itselfBias blind spots
• When you choose something, you tend to feel positive about
it, even if the choice has flaws.Choice-supportive bias
• Tendency to see patterns in random eventsClustering illusion
• Overestimate the importance of information that is available
to themAvailability heuristic
• Where a word, name or thing you just learned
about suddenly appears everywhereFrequency illusion
• The tendency for people to want an immediate payoff rather
than a larger gain later on.Hyperbolic discounting:

1
Fast
Practice
Practice
Practice
Develop Good Habits
Overshadow Bad Habits
Awareness
of Biases
2
Slow
Daniel Kahneman, Thinking, Fast and Slow
The largely subconscious System 1 makes intuitive snap judgments based on emotion, memory, and hard-
wired rules of thumb. The conscious System 2 laboriously checks the facts and does the math, but is so
"lazy" and distractible that it usually defers to System 1.
Facts, Knowledge, Logic
Training, Assessment,
Scientific methodology
Plan-do-check-act

Pre-conditions for malice or disregard
Rationalization &
Attitude
Pressure &
Incentive
Opportunity –
‘holes in the QMS”
Most individuals, operating on their own and
given the opportunity, will cheat—but just a little
bit, all the while indulging in rationalization that
allows them to live with themselves.
The Honest Truth about Dishonesty: How We Lie to Everyone--
Especially Ourselves. Dan Ariely, (2012). HarperCollins Publishers.

What is Organizational Culture?
• Organizational culture is a system of shared
assumptions, values, and beliefs, which governs how people
behave in organizations*.
• These shared values (unwritten rule) have a strong influence on the
people in the organization and dictate how they dress, act, and perform
their jobs.
* Please note source/reference is hyperlinked. Also see a useful video available here.

Causal chain:
From Antecedents to Culture through to Outcomes
Antecedents
Structure
System
Technology
Skills
Constructive
norms
Passive/
Defensive
norms
Aggressive/
Defensive
norms
Individual Outcomes
Role clarity
Communication Quality
“Fit” in organization
Behavior conformity
Job satisfaction
Organizational Outcomes
Quality of products/services
Commitment- customer satisfaction
Adaptability
Turnover
Quality of workplace
Know-how management
*Pierre A. Balthazard, Robert A. Cooke, Richard E. Potter, (2006) "Dysfunctional culture,
dysfunctional organization: Capturing the behavioral norms that form organizational culture
and drive performance", Journal of Managerial Psychology, Vol. 21 Iss: 8, pp.709 - 732
Constructive norms – ‘emphasize quality over quantity’,
‘good human relations skills’, ‘help others to grow and develop’
Defensive/Passive norms – ‘do what is expected’, ‘switch to please others’
Defensive/Aggressive: ‘look for mistakes’, ‘turn job into contest’, ‘authority of position’

Organizational Culture, Good or Bad?
What can we learn from cases of
“Organizations Gone Wild”?*
Normative support for misconduct
can occur in three main ways:
Endorse it with varying degrees of
explicitness (e.g., ADM)
“Techniques of neutralization”; or a basis for
rationalization (e.g., SB)
Place a high value on achieving
extraordinary performance (e.g., Enron)
1
2
3
*HENRICH R. GREVE, DONALD PALMER, and JO-ELLEN POZNER. Organizations Gone Wild: The Causes, Processes, and
Consequences of Organizational Misconduct. The Academy of Management Annals Vol. 4, No. 1, (2010), 53–107
Also see: A Demon of Our Own Design
QMS

QC Staff (junior) behavioral norms are ‘passive –
defensive’ [e.g., approval seeking)*
QC Staff person - Passive
Intention –behavior
Doing Good,
Being Good, or
Looking Good
‘Good‘ as judged within an
organization
QC Supervisor – Constructive, Passive or Aggressive

How would you
respond to this
statement? 15.21
9.9
14.1
17.5
43.4
At many Pharma companies
[in India] the staff would
feel afraid to question a
supervisor’s order even
when they know for
sure that the supervisor’s
order is not in the
interest of patients.
I disagree with
this statement
I completely agree
with this statement
N=263
Skipped = 0

How would you respond
to this statement?
I think management
should urgently work
towards making
error/mistake
reporting Normal, Easy
and Rewarding.
5.8
6.6
17.4
32.8
31.54
It is already easy – so
this is not urgent.
It is very difficult currently so
this is very urgent topic
N=259
Skipped =4

Organization (Policies
& Sr. Mgmt.)
Technology
(Constraints & Controls)
Individual
(Training & Certification)
Team & Supervisor
(Soft Defenses)
Defenses
(Quality Management System)
Error
Latent अप्रकट conditions Goal conflicts & mixed messages
Design flaws
Production pressures
Fear of error
“WE CANNOT CHANGE THE HUMAN CONDITION. BUT…WE CAN CHANGE THE
CONDITIONS UNDER WHICH HUMANS WORK” JAMES REASON

Without fear, giving a full-hearted team performance
We are scientists, pharmacist, engineers, physicians and managers; trained to be good
practitioners of methodologies developed within our disciplines
We work in teams, to integrate our knowledge and aligning our methodologies, for
developing medicines and the evidence we must provide to satisfy the needs of patients
We recognize that nothing is perfect and there will be some errors in our design,
systems, and procedures, and 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 our mistakes
In doing so we work consciously in the interest of patients, even when no one is looking
– and this describes our Culture of Quality!
What is
Culture of
Quality?

Culture of
Quality
Normal
Easy
Rewarding
QMS
System
Knowledge
Variation
Behavior
Behavior -
GXPs
Fear
Removed
Mastery
Awareness
Environment
Leadership
Emphasis
Message
Credibility
Peer
Involvement
Employee
Empowerment
Connect
to CoQ
Connect
to GXPs
A Framework and a Tool (for gap analysis)

 Systems thinking: System is the product of interacting parts; improving the parts
taken separately will not improve the system
CEO &
Sr. Management
Culture
of Quality
Managers &
Leaders
Effective
QMS
GXP
Compliance
All
Employees
Quality is Easy

Going beyond rules pays..
How can
it help?

Many companies that have a strong culture of quality
and they should be recognized
• Lot Acceptance Rate
• Product Quality Complaint Rate
• Invalidated Out-of-Specification (OOS) Rate
• Annual Product Review (APR) or Product Quality Review (PQR) On Time Rate
Proposed Quality Metrics
• Senior Management Engagement; Was each APR or PQR reviewed and approved
by the following: (1) the head of the quality unit, (2) the head of the operations
unit; (3) both; or (4) neither?
• CAPA Effectiveness; What percentage of your corrective actions involved re-
training of personnel (i.e., a root cause of the deviation is lack of adequate
training)?
• Process Capability/Performance
• Establishment’s management calculated a process capability or performance
index for each critical quality attribute (CQA) as part of that product’s APR or
PQR?
• A policy of requiring a corrective action or preventive action (CAPA) at some
lower process capability or performance index. What is the process capability or
performance index that triggers a CAPA?
Importance of quality culture ….proposing…
How can
it help?

Our journey to improve current practices and system–
to more reliably deliver medicine & evidence
Process
validation
+ testing
First attempt
at ‘Quality
system’
Quality by
design +
Quality system
(revisited with
emphasis on
process
understanding)
Process
Validation -
emphasis on
process
understanding
& process
control)
Leveraging
integration
(CMC &
CGMP), OPQ..
Culture of
quality, quality
metrics,…
July 2015
error detection,
correction and
prevention is normal,
easy and rewarding.
This builds
confidence and
facilitates risk-based
oversight
Journey to
improve
current
practices ..

Culture of Quality Bagladesh AAPS 8 August 2015 Final

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