Pharmaceutical culture of quality

PharmaceuticalCultureofQuality,
AssuranceofDataIntegrity&Qualityby
Design:ConnectingtheDots
Ajaz@ajazhussain.com
8/1/2014 © Ajaz S. Hussain | INSIGHT, ADVICE & SOLUTIONS LLC 1
A modified version of a
presentation @ Patheon –
Bridgewater, NJ Seminar
Thursday, July 31, 2014
Quality by Design -
Experience, Trends and
Outlook

Prologue
These slides were used for a invited presentation @ Patheon Seminar –
Bridgewater, NJ, 31 July 2014.
• Some modification have been made to connect the dots for the audience who will review this
slide-deck on the internet.
• This presentation provides a very brief snap-shot of a day long training program conducted
recently at a company in India.
In preparing the day long training session I had asked the following
questions
• How to effectively communicate to an audience of a group of young and bright Indian
professionals in any company in India and their supervisors/management about the
importance of cGMPs and QbD?
• How do I understand their challenges, perspectives and biases?
• How do I connect with them to share the joy of Quality by Design?
The response received has been overwhelming from the audiences in India
and yesterday at the Patheon Seminar in Bridgewater, NJ
• I hope you will also the see some of the important dots and the connections
• How this content connects to regulatory requirements is not covered in this slide deck – it
connects via ‘A, B, C, D’ to 21 CFR, Quality SystemsApproach to cGMP, ICH 7, 8, 9, 10, and 11.

“TheGoldSheet”
March 2014
Cox:Confronting
Illusions ofQuality
in IndianGenerics
Manufacturing
Thakur:
• Data
Integrity
requires
stronger
local
enforcement
Cahilly:
• Focus on
India masks
the real data
integrity
problems
Hussain:
• Empowering
workers is
the key to
data integrity
Takahashi:
• Look out for
these data
integrity
Issues
Understanding the behaviors –
it is a human issue & this is not about India.
http://www.pharmamedtechbi.com/publications/the-gold-sheet/48/3/confronting-illusions-of-quality-in-indian-generics-manufacturing

Empowering
workers is the
key to data
integrity -thisismy
personaljourneytoseeifIcan
help.
 How to effectively communicate to an audience of a
group of young and bright Indian professionals in any
company in India about cGMPs and QbD?
 How do I understand their challenges, perspectives and
biases?
 How do I connect with them to share the joy of Quality
by Design?

Quality by
Design
Deming -The journey
requires leadership with
Profound Knowledge as
a guide.
The challenge at hand is that
of human reliability – it is a
global issue
We must do certain things
consciously; and cultivate
some good habits -
subconsciously.
Irrationality, Biases,Thinking
Fast, and Slow – connections
to econometrics suggested.
Where do corporate
managers, schooled in
rational assumptions ….go
from here?
When organizations
acknowledge and anticipate
irrational behavior, they can
learn to offset it and avoid
damaging results.
Is there a culture of error
management where there’s a
genuine effort to learn from
mistakes, or is it one of error
aversion, where errors are
avoided at all cost?

Quality by
Design –What is it?
Doing things consciously – stuck in my mind
FDA’s ACPS Meeting October 2005
Topic - Achieving and demonstrating “Quality by Design” with respect to
drug release/dissolution performance for conventional or immediate
release solid oral dosage forms
A PhRMA Perspective – presented by C. Sinko and R. Reed.
“Features of Quality by Design: Doing things consciously”

Doing
something
Consciously or
Subconsciously
The End of Rational Economics -
“[Allen Greenspan] made a
mistake in presuming that the
self-interest of organizations,
specifically banks and others, was
such that they were best capable
of protecting their own
shareholders.” Dan Ariely
Harvard Business Review July
2009
• Scientific methodology
• Engineering Design
• Plan-Do-Check-Act
Consciously
• Habits (work to get rid of bad ones)
• Habits (work to cultivate good one)
• Keystone habits (Safety @ Alcoa;
A.L.C.O.A. of data integrity)
Subconsciously
The Power of Habit: Why We Do What We Do in Life and Business. Charles Duhigg

Intention to care
– duty of care

KahnemanandTversky,the
firstresearcherstoidentify
andrigorouslystudy
cognitivebiases,provedthat
asimpleversionofexpected
utilitytheorydidnot
accuratelydescribehuman
behavior.Theirresponsewas
todevelopprospecttheory,a
modelofhowpeoplereally
makedecisions.
Daniel Kahneman, Nobel Prize 2002
KAHNEMAN, Daniel,
and AmosTVERSKY,
1979. Prospect
Theory: An Analysis of
Decision under
Risk. Econometrica, 47
(2), 263–292

Chemometric,
Pharmacometrics
& Econometrics
AjazS.Hussain.SWISS
PHARMA34(2012)Nr.6.
Chemometrics
Econometrics
Review & Approval
Commercial operations,
profitability & availability

Two products –
Medicineand
Evidence.
Better than
Placebo
Evidence of benefit and risk is collected carefully in well controlled
clinical trials to eliminate many sources of variability and biases
To be on the market the evidence must convincingly conclude that
the benefit outweighs the risks, often compared to a placebo
There is no evidence without adequate assurance of data integrity
Our assurance of data integrity distinguishes our products from
adulterated and counterfeit products

FDACDER
Challenges &
Changes
FDA’sSternWarningOnDataIntegrity
(ThePinkSheets,21July2014)
If the agency’s trust is
lost it will be difficult to
earn it back; posing
challenges far beyond an
initial manufacturing
setback.
Complete honesty after a
slip up will go a long way
Although India and
China have been the
current focus, FDA is
seeing data integrity
breaches everywhere to
some degree.
Thenew(proposed)Officeof
PharmaceuticalQuality,CDER,FDA
One QualityVoice;Value
Statements
Put patients first by
balancing risk and
availability
Have one quality voice
by integrating review
and inspection across
product lifecycle
Other points; see:
FDA/CDER’sOffice of
PharmaceuticalQualityhttp://www.fda.gov/downloads/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/UCM404568.pdf

Life cycle of
regulatory
communications
 Review (CMC,…)
 Design of specifications and controls; prior knowledge and statistical
confidence
 Clinical relevance, failure-mode and risk-based
 New, Biosimilar, and Generic; differences in review approaches
 Question base Review – improvements on going
 Tightening specifications after development – not aligned with QbD
 cGMPCompliance & Inspection
 Life-cycle approach to process validation
 Continued process verification and statistical confidence
 cGMP remediation in response to 483 orWL
 Life-cycle approach to error management
 Quality Metrics & Culture of Quality

What does it
take to come
out of the
cGMP crisis?
Persuasive
demonstration of:
(1) Ability to face
facts
(2) Legal & regulatory
requirements,
3) Systems approach
to quality,
4) Changing behavior
& culture
What is often missed
or is unconvincing is
how you will
strengthen culture of
quality.
“Let one who wants to
move and convince
others, first be
convinced and moved
themselves.” Thomas
Carlyle
Signals that question the
competence, motivation,
and/or integrity of
company personnel
Do not defend the plainly
indefensible; it adds
further serious credibility
costs

Effective format for
communication
Evidence/
Data
Claim(s)
Warrants
Evidence/Data
Claims

“Let one who
wants to move
and convince
others, first be
convinced and
moved
themselves.”
ThomasCarlyle
How do we
communicate
Culture of Quality
Within the organization?
In response to 483’s andWL?
In drug applications?
Today the phrase
Culture of
Quality is a hot
topic of
discussion
Why is it so?
What is it?
How do we strength it?

Data integrity –
deviant
behaviors
AliciaM.Mozzachio,RPh,MPH ,July15,
2014,FDLI,Washington,DC
 Not recording activities contemporaneously
 Backdating
 Fabricating data
 Copying existing data as new data
 Re-running samples
 Discarding data

“It may take
more than a
letter to resolve
this issue”
CarmeloRosa,Psy.D.; Director-DIDQ,
CDER/OC/OMPQ,July15,2014(FDLI)
WL in 2013 + 31%
WL in 2014
(7/14/14) + 92%
Assurance of Data
Integrity ?
A keystone

Blaming failure
on a Nation’s
culture is a cop-
0ut!
“What must be admitted, very painfully, is that this was a disaster ‘Made
in Japan,’ ” Dr. Kurokawa said in his introduction to the English version
of the report. “Its fundamental causes are to be found in the ingrained
conventions of Japanese culture: our reflexive obedience; our reluctance
to question authority; our devotion to ‘sticking with the program’; our
groupism; and our insularity.”The Japanese version contained a similar
criticism.
Reaction was swift. “To pin the blame on [a Nation’s] culture is the
ultimate cop-out,” Columbia University professor Gerald Curtis wrote in
the FinancialTimes. “If that is Japanese culture, then we are all
Japanese”.
“Is there a culture of error management - where there’s a genuine effort
to learn from mistakes, or is it one of error aversion, where errors are
avoided at all cost, people can expect to be metaphorically dragged out
in to the alley as a prelude to the evidence being covered up?”
The chairman of the
Fukushima Nuclear
Accident Commission
blamed the disaster on “the
ingrained conventions of
Japanese culture”.
http://mbs.edu/mbshub/Pages/Article/How_Fatal_is_your_firms_Error_culture.aspx

Quality is
everyone's
responsibility.
Learning isnot
compulsory...neither is
survival.
Ittakesyears,plusa
degree oferosion of
confidence in oursystem,
toresolve cGMP issues.
Lack of
knowledge...
that is the
problem.
If you do not
know how to
ask the right
question, you
discover
nothing.
If you can't
describe
what you are
doing as a
process, you
don't know
what you're
doing.
Rational
behavior
requires
theory.
Reactive
behavior
requires only
reflex action.
Whenever
there is fear,
you will get
wrong
figures.
Selected quotes, W. Edwards Deming

“Out of the
Crisis”
W.EdwardDeming,MIT
Press(2000)
The journey
requires
leadership with
Profound
Knowledge as
a guide.
• As leaders responsible for system change, top
management is most in need of profound
knowledge
• Quality is often determined in the boardroom.
• Problems arise when management reacts to
common cause or chance variation as if it were
special cause variation
• Prediction based in theory provides a
foundation for planning a course of action.
Plan – Do – Check – Act
• The leader serves the people with clear vision
and guidance to empower them.To be
empowered is to share ownership in the
identity
• Giving people a certain degree of control over
their work fulfills the need for freedom and
provides opportunity for taking joy in work

“Wecannotchange
thehumancondition.
But…wecan change
theconditionsunder
whichhumanswork”
JamesReason
J. Reason. Human error:
models and management.
BMJ. Mar 18, 2000; 320: 768–
770
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

High reliability
organizations
J. Reason. Human error:
models and management.
BMJ. Mar 18, 2000; 320: 768–
770
Perhaps the most important distinguishing
feature of high reliability organizations is
• They expect to make errors and train their
workforce to recognize and recover them.
• They continually rehearse familiar
scenarios of failure and strive hard to
imagine novel ones.
• Instead of isolating failures, they
generalize them. Instead of making
local repairs, they look for system
reforms.

An increasingly
common pattern
in recent FDA
483’s
“….records are 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….”
From individual to
system failure –
with each
additional
observation,
confirmation of a
system with
intentional ‘holes’
in its defenses.

Why are
remediation
efforts not
uniformly
effective?
Past: “…results
failing
specifications are
retested until
acceptable results
are obtained….”
Serious
enforcement
actions
cGMP
remediation
3rd party
oversight
3rd party data
integrity
training
Repeat: “…results
failing
specifications are
retested until
acceptable results
are obtained….”
What will it take to
change behavior?
3-4 years Same company different people/site

Understanding
the behaviors -
“testing into
compliance”.
Ajen, I.The theory of planned
behavior. ORGANIZATIONAL
BEHAVIOR AND HUMAN
DECISION PROCESSES 50, 179-
211 (1991)
Attitude
towards the
behavior
Subjective
norm
Perceived
behavioral
control
Intention
Future
Behavior
usually found to predict
behavioral intentions with a high
degree of accuracy
intentions, in combination with
perceived behavioral control, can
account for a considerable
proportion of variance in
behavior.
Past
Behavior

At the individual
level, inQC
function– how
often does this
occur?
Ingeneral–lowempowerment
isasignificantchallenge (low
perceivedbehavioral control);
plustherearereasonsto
rationalize….
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
Indian regulators
collect & test
samples – no
issue there
“Testing into compliance”
Reasons that are often used to rationalize deviant behavior
Extension to organizational dynamics: If the root cause is product design,
would QC/QA be able to question/challenge R&D?

Understanding -
Why cGMPs are
critical?
USCongressHearingApril2008
THE HEPARIN DISASTER
 November 2007,Children's
Hospital in St. Louis,
Missouri, began noticing
adverse reactions
 On January 17th, almost 3
months later, Baxter, started
recalling products
 On February 11th, FDA
announced that Baxter had
halted manufacture of multi-
dose vials
US Congress called this the
American Failures
 We may never know whether
an FDA pre-approval
inspection would have
prevented this ….
 However, it is regrettable that
FDA did not inspect this plant
sooner, …
 Make no mistake about it:
…have failed the American
public.
https://house.resource.org/110/org.c-span.205093-1.raw.txt

Understanding -
Why cGMPs are
critical?
Detection&QClimitations
Testing/Pharmacovigilence
FDA reports 149 deaths with allergic or
hypersensitivity symptoms during that period
•Contaminated heparin from China
QCTesting
•Initial testing failed to detect the contaminant
Pharmacovigilence
•Signals in the pharmacovigilence systems responded slowly
and
Eventually, the severity of reactions associated
made it likely that the contamination would be
detected,
•albeit too late.
Questions
•(a) Don’t know,
•(b) higher than what it was for
Heparin in 2007, or
•(c) lower than what it was for
Heparin in 2007
What is the
likelihood, in
the US, of
detecting a
less toxic
contaminant
or an or
sub‐potent
formulation?
•(a) USP test for Heparin were not
designed to test this particular
contaminant
•(b) The QC labs involved did not
know how to test the samples
•(c) QC lab was manipulating the
data
Why do you
think testing
did not
detect the
contaminant?

Why – the
reminder -
Heparin tragedy
(2007-2008)
Whenthe drugsafety
system fails,people get
sick.Some die…
CongressmanShimkus
(Illinois)
• Some of these people are already very vulnerable,
and proving the cause of harm from impurities,
adulteration, and counterfeits can be elusive.
It is hard to detect harm
• Certainly the companies are obligated to ensure a
culture of quality and maintain vigilance as well.
This reflects a systems approach to safety.
FDA inspectors look for
a culture of quality at
manufacturing facilities.
• FDA policies led to the failure to inspect the
Chinese plant.
This system approach
wasn't at play here.
• While it doesn't deny the counterfeit source, tries
to say that counterfeits didn't cause the reaction,
as if the adulteration itself was no big deal.
This brings me to China
and its quality culture or
lack thereof.
https://house.resource.org/110/org.c-span.205093-1.raw.txt

21CFR PART
211:SUBPARTS
Whyacombinationof
deviationscansignala
seriousneedtostrengthen
CultureofQuality–for
example…..
• GENERAL PROVISIONSA
• ORGANIZATIONAND PERSONNELB
• BUILDINGSAND FACILITIESC
• EQUIPMENTD
• CONTROLOF COMPONENTSAND DRUG PRODUCT CONTAINERS
ANDCLOSURESE
• PRODUCTION AND PROCESS CONTROLSF
• PACKAGINGAND LABELING CONTROLG
• HOLDINGAND DISTRIBUTIONH
• LABORATORYCONTROLSI

Culture of
Quality:
Environment that
facilitates individuals
to guide their behavior
to workinthe interest
ofpatients andto
continually improve
this ability.
 An organization is a complex
system which makes many
thousands of decisions each
day – writing a SOP for each
decision is not always
practical.
 A systems approach to
quality is essential!
 It should recognize that the
weakest link in the system is
often human fallibility –
variable capacity to act
consciously – when no one is
looking.

Going beyond
rules pays..

How to
Connect?
 Behaviors beyond GXP
 Predictors of a Culture of Quality
 Culture
 Culture of Quality creates an environment needed to facilitate every
individual to guide his/her own behavior to work in the interest of
patients and to continually improve this ability.
 System
 A systems approach to quality is essential! It recognizes that the
weakest link in the system is often human fallibility – variable
capacity to act consciously – when no one is looking.
 GXP, Behavior
 An organization is a complex system which makes many thousands
of decisions each day – writing a SOP for each decision by each
individual (controlling behavior) is not always practical.

Humanbehavior:
Connectingthe
Dots;With the
RightConnectors
GXPs – rational behaviors
How proactive compliance is achieved? X,Y, Z
Quality Management System
What makes a QMS reliable?A, B, C, D
Culture of Quality
Why people change their behavior: 1, 2, 3
Human Behaviors Beyond GXPs
Predictors of Culture of Quality
Why,What, and How of
Culture of Quality?

‘Connecting the
Dots’ helps to
communicate
Behaviors
beyond
GXPs
I
II
III
IV
Culture of
Quality
1
2
3
QMS
A
B
C
D
Behavior -
GXPs
X
Y
Z

Creating aCultureof
Quality: Financial
incentives don’treduce
errors.Employees
mustbe passionate
abouteliminating
mistakes.
AshwinSrinivasanand
BryanKurey. Harvard
Business Review,April
2014.
Only four
attributes
actually predict
a culture of
quality:
Leadership
Emphasis
Message
Credibility
Peer
Involvement
Employee
Empowerment
People will
change their
behavior if they
see the new
behavior as
Normal (1)
Rewarding (2)
Easy (3)
Act consciously in the interest of patients – when no one is looking.

Culture of
Quality
Consciously–bydesign:
ScientificMethodology,
EngineeringDesign,or
Plan-Do-Check-Act
InterestofPatients:
Regulatorycommitments+
Act consciously in
the interest of
patients –
specially when no
one is looking.
(1) It is Normal to Do
(2) It is Rewarding
(satisfaction)
(3) It is Easy to Do
Leadership
Emphasis
Message
Credibility
Peer
Involvement
Employee
EmpowermentEnvironment

Quality
Management
System
AnyBodyCanDance
Culture of
Quality
1. Normal
2. Rewarding
3. Easy
QMS
A
B
C
D
Leadership
Emphasis
Message
Credibility
Peer
Involvement
Employee
Deming's System of Profound Knowledge + James Reason’s Swiss Cheese Model

A, B,C, D
Deming'sSystemof
ProfoundKnowledge+
JamesReason’sSwiss
CheeseModel
TrainingtoensureAnyBody
CanDance
• Appreciation for System
• Organization viewed as a system; an
orchestra
A.
• Theory of Knowledge
• Without theory – there is no learning; Asking
the right questions; Plan-Do-Check-Act
B.
• Knowledge ofVariation
• Common cause and special cause variability;
control charts
C.
• Human behavior (pride/satisfaction +
conscious/subconscious biases)
• System support and safe guards; system for
error management
D.

CoQ to
QMS toGXP
Behaviors
Facilitatingerrordetection
andcorrection.
C.vanDyck.Puttingerrors
togooduse:error
managementculturein
organizations(2000).
http://dare.uva.nl/document/83803
CoQ
1
2
3
QMS
A
B
C
D
GXP
Behaviors
X
Y
X
Message
Credibility
Peer
Involvement
Employee
Leadership
Emphasis
A poor quality product is an error consequence and is not
necessarily related to error management per se. In fact, a poor
quality product may be the result of lack of error management.

Culture of Error
गलती
Management
प्रबंधन
What words would you use
to describe how you feel
and react to mistakes?
Your own, of a co-worker, of
a subordinate.
How does your supervisor
react?
Picture purchased from www.pixtastock.com

X,Y,Z
C.vanDyck.Puttingerrorsto
gooduse:errormanagement
cultureinorganizations(2000).
http://dare.uva.nl/document/83803
X. Fear of Errors (reduce)
Error strain -
Covering up
Y. Mastery Orientation
Communicating
Analyzing errors
Error correction
Learning from errors to
QbD/RFT
Z. Awareness
Anticipation
Risk-taking

Reduce Fear of
Errors
(C.vanDyck.2000)
Error strain
 In general, people feel
embarrassed after making a
mistake.
 If an error occurs, people get
upset and irritated.
 If an error is reported it
becomes a topic of ridicule
 In this organization,
supervisors feel very
aggravated when mistakes
are made.
Covering up
 Our motto is; “Why admit an
error when no one will find
out?”
 It can be harmful to make
your errors known to others.
 Employees that own up to
their errors are asking for
trouble.
 People in this organization
prefer to keep their errors to
themselves.

Mastery
orientation
(C.vanDyck.2000)
Communication
 When someone makes an
error, (s)he shares it with
others so that they won’t
make the same mistake.
 When people are unable to
correct an error, they turn to
their colleagues.
 If people are unable to
continue their work after an
error, they can rely on others.
 When people do something
wrong they can ask others for
advice on how to continue.
Analyzing error
 After making a mistake,
people try to analyze what
caused it.
 In this organization, people
think a lot about how errors
could have been avoided.
 After an error people think
through how to correct it.
 Our errors point us to what
we can improve.
 In mastering a task, people
can learn a lot from their
mistakes

Mastery
orientation
(C.vanDyck.2000)
Learning from errors
 Our errors point us to what
we can improve.
 In mastering a task, people
can learn a lot from their
mistakes.
 An error provides important
information for the
continuation of the work
 When a error occurs we use
the learning to improve the
work process.
Error correction
 When an error has occurred
we usually know how to
rectify it.
 When an error is made, it is
corrected right away.
 If an error is restorable, we
usually know how to do it.
 Although we make mistakes,
we don’t let go of the final
goal.

Awareness
(C.vanDyck.2000)
Anticipation
 It is very likely that people
will make errors in the
process of mastering their
task.
 When people start to work on
something, they are aware
that mistakes can occur.
 In this organization, we take
into account that things will
go wrong from time to time.
Risk taking
 For an organization to
achieve something, it has to
risk the occurrence of errors.
 To get better in what we do,
we don’t mind that
something can go wrong in
the process.
 It’s fine to risk an error every
once in a while.

Expect it to fail
and build
safeguards
Team member
support
Technological safeguardsGood Design
Normal
Easy
Rewarding

Reduce
Fear of
Errors
Error strain
Covering up
Awareness
Anticipation
Risk taking
Mastery
orientation
QbD/RFT
Error detection
Communication
Analyzing errors
Correction

Maturity &
Responsibility
Richard L. Friedman, M.S. Management Oversight and Lifecycle Quality Assurance. FDLI Workshop, Washington DC, 14-15 July, 2014

Connecting the
Dots and
Communicating
Effectively
Culture
of
Quality
Normal
Rewarding
Easy
QMS
System
Knowledge
Variation
Behavior
Behavior
- GXPs
Fear
Removed
Mastery
Awareness

WhyQuality by
Design is the
foundation of
Culture of
Quality
Summary
We do our best to develop products that meet the needs of patients – we
develop our products consciously – this is our QbD.
We recognize 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 – specially when no
one is looking, and continually improve our quality by design and aim for
right first time.

Pharmaceutical culture of quality

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